Hepatitis B e antigen–negative patients with persistently normal alanine aminotransferase levels and hepatitis B virus DNA &gt; 2000 IU/mL #
Authors: George V. Papatheodoridis, Emanuel K. Manesis, Spilios Manolakopoulos, Ioannis S. Elefsiniotis, John Goulis, Athanasios J. Archimandritis
Journal: Hepatology (2008)

We thank Dr. Dai et al. for their interest in our article and for supporting our findings that liver biopsy does not usually affect the decision for treatment in hepatitis B e antigen (HBeAg)-negative patients with abnormal alanine aminotransferase (ALT) and hepatitis B virus (HBV) DNA ≥ 20,000 IU/mL, although it offers valuable information for patients receiving long-term therapies. There is also no disagreement on the need for biopsy in HBeAg-negative patients with persistently or transiently abnormal ALT and HBV DNA < 20,000 IU/mL. The optimal management of HBeAg-negative patients with persistently normal ALT (PNALT) has always been debatable. We intentionally did not perform biopsies in such patients with HBV DNA ≤ 2000 IU/mL, because we believe that only cases with HBV DNA > 2000 IU/mL represent a controversial group with some likelihood of significant histological lesions. There was no selection bias in our study because there was no patient with PNALT and HBV DNA ≥ 20,000 IU/mL during the inclusion period. Such patients are extremely rare in Greece.1, 2 Among the last 300 HBeAg-negative PNALT patients seen at our clinics, <1% had HBV DNA > 20,000 IU/mL (<200,000 IU/mL, minimal necroinflammation and fibrosis in both cases). We have previously commented on the recent definition of "inactive carriers",3 which does not include PNALT patients with HBV DNA > 2000 IU/mL [however, such patients are not included under any term in recent guidelines4, 5]. Regarding the conflicting reports on histology and HBV DNA > 20,000 IU/mL in HBeAg-negative PNALT patients, we believe that there are two main reasons. First and most important, not all studies use the same criteria for defining PNALT (a less strict follow-up increases the likelihood of misclassifying patients with ALT fluctuations). We used a strict first-year follow-up with five ALT determinations (every 3 months), while three or fewer ALT determinations (every 6 months) were sufficient for PNALT cases in a study from India (only two ALT values required for inclusion)6 or the United States,7 and no relevant information is provided in a study from Taiwan.8 Second, differences in viral (e.g., genotypes) or host genetic characteristics might be also responsible for such discrepancies; data different from ours are reported in non-European studies.6-8 Inactive carriers represented <8.4% of chronic HBV cases in the study from India,6 whereas they represent a large proportion of chronic HBV European patients. Our data are in agreement with another European (French) study9 including 85 PNALT patients under strict ALT follow-up; HBV DNA > 20,000 IU/mL was exceptionally rare (2%), necroinflammation score was always ≤6, and Ishak fibrosis score was ≤2 in 91% (score 3-4 in 5 of 58 cases). We also agree with Feld et al. that HBV DNA > 20,000 IU/mL is highly predictive of future ALT elevation,10 as we have reported an increased risk of future reactivation in HBeAg-negative PNALT patients with HBV DNA levels of even >2000 IU/mL.2 In conclusion, we believe that our findings are valid and support the suggestion that HBeAg-negative patients with HBV DNA < 20,000 IU/mL and PNALT under strict follow-up, at least in Europe, will not benefit from liver biopsy, which is not expected to show significant lesions. All such cases should be followed for life, whereas patients with HBV DNA > 2000 IU/mL warrant closer follow-up. George V. Papatheodoridis*, Emanuel K. Manesis*, Spilios Manolakopoulos*, Ioannis S. Elefsiniotis , John Goulis , Athanasios J. Archimandritis*, * Second Department of Internal Medicine, Athens University Medical School, "Hippokration" General Hospital of Athens; Greece, University Department of Internal Medicine, "Helena Venizelou" Hospital, Athens; Greece, Fourth Department of Medicine, Aristotelian University of Thessaloniki, Hippokration General Hospital of Thessaloniki; Greece.