Potential conflict of interest: Nothing to report.
Serum hepatitis B virus-DNA cutoff levels in hepatitis B e antigen–negative chronic hepatitis B virus infection†
Article first published online: 27 JUL 2007
Copyright © 2007 American Association for the Study of Liver Diseases
Volume 46, Issue 2, pages 606–607, August 2007
How to Cite
Papatheodoridis, G. V., Manesis, E. K., Manolakopoulos, S. and Archimandritis, A. J. (2007), Serum hepatitis B virus-DNA cutoff levels in hepatitis B e antigen–negative chronic hepatitis B virus infection. Hepatology, 46: 606–607. doi: 10.1002/hep.21864
- Issue published online: 27 JUL 2007
- Article first published online: 27 JUL 2007
To the Editor:
We read with great interest the recent chronic hepatitis B (CHB) (AASLD) practice guideline written eminently by 2 of the most experienced hepatologists in CHB.1 Hepatitis B e antigen (HBeAg)-negative CHB is characterized by increased levels of alanine aminotransferase (ALT)/ aspartate aminotransferase (AST), serum hepatitis B virus (HBV)-DNA > 2,000 IU/mL, and moderate/severe necroinflammation, whereas the inactive hepatitis B surface antigen (HBsAg) carrier state is defined as persistently normal ALT/AST on ≥3-4 determinations made every 3 months (then every 6-12 months) and HBV-DNA < 2,000 IU/mL.1
According to our unpublished, recent, prospective cohort of 150 HBeAg-negative chronic HBV patients with a close biochemical and virological follow-up, a substantial proportion (22% of cases or 28% of 228 serum samples tested) of 85 patients with persistently normal ALT/AST levels have HBV-DNA > 2,000 IU/mL (15% at 2,000-5,000 IU/mL and 7% at 5,000-20,000 IU/mL). Such patients are excluded from the inactive carrier state according to the new definition due to high HBV-DNA and cannot be classified into HBeAg-negative CHB because of persistently normal ALT/AST. Given that minimal necroinflammation with no-minimal fibrosis (Ishak-grading ≤ 4, Ishak-staging ≤ 1) was always observed in 8 such cases, who had a liver biopsy, we think that they represent inactive carriers. Thus, HBV-DNA > 5,000 IU/mL significantly weakens and >20,000 IU/mL excludes the diagnosis of inactive carrier, but an upper HBV-DNA limit of 2,000 IU/mL may leave unclassified 20%-25% of cases.
Problems in clinical practice may also arise with the new and definitely improved definition of HBeAg-negative CHB due to the lower HBV-DNA limit of 2,000 IU/mL.1 In the same prospective study from our group, 5% of HBeAg-negative CHB patients and 16% of their serum samples had HBV-DNA < 2,000 IU/mL. Moreover, HBV-DNA was persistently ≥2,000 IU/mL in 82% or occasionally <2,000 IU/mL in 18% of our CHB patients. In another study from Lok's group, 42% of CHB patients had occasional levels of HBV-DNA < 10,000 copies/mL (approximately <2,000 IU/mL).2 HBeAg-negative patients with increased ALT/AST and HBV-DNA < 100,000 copies/mL (approximately 18,000 IU/mL) or recent levels of <2,000 IU/mL have been ignored from past and recent guidelines,3–5 although they represent a sizable proportion of CHB patients who are HBeAg-negative. In another retrospective, multicenter Greek study that included 335 patients with CHB who were HBeAg-negative with increased levels of ALT/AST, at least moderate necroinflammation and/or moderate fibrosis were detected in the majority (61%) of such cases with HBV-DNA < 2,000 IU/mL, who represented 12% of the total study population.6
In summary, all existing data suggest that there is no clear cut-off HBV-DNA level to differentiate inactive HBsAg carriers from individuals with CHB who are HBeAg-negative.2, 7, 8 Any attempt to define such a cut-off level may create more problems, because it would not correctly diagnose not only a substantial proportion of inactive carriers, perhaps leading to unnecessary liver biopsies, but also >10% of patients with CHB who are HBeAg-negative who may not receive appropriate treatment. Close follow-up still remains the cornerstone of diagnosis. All patients with any persistent or transient ALT/AST elevation may benefit from a liver biopsy regardless of viremia levels, whereas patients with persistently normal ALT/AST and HBV-DNA < 20,000 IU/mL should be followed for life. In the latter setting, an HBV-DNA level ≥ 2,000 IU/mL warrants closer follow-up. HBeAg-negative cases with persistently normal ALT/AST and HBV-DNA ≥ 20,000 IU/mL are extremely rare, if they really exist.
- 6Is there a meaningful serum HBV DNA cut-off level for therapeutic decisions in HBeAg-negative chronic hepatitis B (CHBe-)? [abstract] HEPATOLOGY 2006; 44(Suppl. 1): 541α., , , , , , et al.
George V. Papatheodoridis*, Emanuel K. Manesis*, Spilios Manolakopoulos*, Athanasios J. Archimandritis*, * Second Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital, Athens, Greece.