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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According to our unpublished, recent, prospective cohort of 150 HBeAg-negative chronic HBV patients with a close biochemical and virological follow-up, a substantial proportion (22% of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.

References

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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.