Published online Apr 28, 2023. doi: 10.3748/wjg.v29.i16.2479
Peer-review started: January 31, 2023
First decision: February 23, 2023
Revised: March 5, 2023
Accepted: April 7, 2023
Article in press: April 7, 2023
Published online: April 28, 2023
Processing time: 82 Days and 21.5 Hours
Chronic hepatitis B (CHB) patients can be divided into treatment indication and non-treatment indication individuals. Normal alanine transaminase (ALT) patients in ‘immune-tolerant’ phase with hepatitis B virus (HBV) DNA higher than 107 or 2 × 107 IU/mL and in ‘inactive-carrier’ phase with HBV DNA lower than 2 × 103 IU/mL do not require antiviral therapy. In fact, we should pay more attention to those who do not match the treatment indications (gray-zone patients both in the indeterminate phase and in the ‘inactive-carrier’ phase).
In order to analyze the correlation of HBV DNA level and liver histopathological severity, and to explore the significance of HBV DNA for CHB with normal ALT. Patients who are in the indeterminate phase or regarded as the ‘inactive carriers’ (low HBV DNA, low-level viremia) may have severe liver disease pathologically and hematologically.
The states of CHB disease (natural course) were not that suitable judged by the defined values of HBV DNA level. The classification of CHB may be revised based on whether HBV DNA exceeds the detection value. Patients who are in the indeterminate phase or regarded as the ‘inactive carriers’ (low HBV DNA, low-level viremia) should receive antiviral therapy.
From January 2017 to December 2021, a retrospective cross-sectional set of 1299 patients with chronic HBV infection (HBV DNA > 30 IU/mL) who underwent liver biopsy from four hospitals, including 634 with ALT less than 40 U/L. The degrees of liver necroinflammatory activity and liver fibrosis were evaluated according to the Metavir system. Patients were divided into two groups: Low/moderate replication group, HBV DNA ≤ 107 IU/mL [the European Association for the Study of the Liver (EASL) guidelines] or ≤ 2 × 107 IU/mL [the Chinese Medical Association (CMA) guidelines]; high replication group, HBV DNA > 107 IU/mL or > 2 × 107 IU/mL. Relevant factors for liver histopathological severity were analyzed by univariate analysis, logistics analysis and propensity score-matched analysis.
At entry, there were 21.45%, 24.29%, and 30.28% of the patients had liver histopathological severities with ≥ A2, ≥ F2, and ≥ A2 or/and ≥ F2, respectively. HBV DNA level (negative correlation) and noninvasive model liver fibrosis 5 value (positive correlation) were independent risk factors for liver histopathological severities (liver necroinflammation, liver fibrosis, and treatment indication). HBV DNA level (negative correlation) was still an independent risk factor when diagnostic models were excluded. For the propensity score-matched pairs, whether based on EASL guidelines or CMA guidelines, the group with significant liver histology damage (≥ A2 or/and ≥ F2) showed much lower HBV DNA level than the group with non- significant liver histology damage (< A2 and < F2). Patients in the moderate replication group (with indeterminate phase) had the most serious liver disease pathologically and hematologically, followed by patients in the low replication group (with ‘inactive-carrier’ phase) and then the high replication group (with ‘immune-tolerant’ phase).
HBV DNA level is a negative risk factor for liver damage. The phase definition of CHB may be revised by whether the level of HBV DNA exceeds the detection low limit value. Normal ALT patients who are in the indeterminate phase or ‘inactive carriers’ should receive antiviral therapy.
How to define the natural history of chronic HBV infection and how to identify the patients with normal ALT who need treatment?