Skip to main content
Download PDF

Lower HBV DNA level is associated with more severe liver fibrosis in HBeAg-positive chronic hepatitis B with normal alanine transaminase

Virology Journal volume 21, Article number: 127 (2024) Cite this article

Abstract

Background

The association of hepatitis B virus (HBV) DNA levels and liver fibrosis in chronic hepatitis B (CHB) patients with immune-tolerant phase remains unclear. We explored the association between liver fibrosis and HBV DNA levels in HBeAg-positive CHB patients with normal alanine transaminase (ALT) with relatively high HBV DNA.

Methods

Six hundred and twenty-two HBeAg-positive CHB patients with normal ALT were included. Patients were divided into three categories: low (6 log10 IU/mL ≤ HBV DNA < 7 log10 IU/mL), moderate (7 log10 IU/mL ≤ HBV DNA < 8 log10 IU/mL), and high (HBV DNA ≥ 8 log10 IU/mL). APRI, FIB-4, transient elastography, or liver biopsy were used to assess liver fibrosis.

Results

The median age of patients was 33.0 years and 57.9% patients were male. 18.8%, 52.1%, and 29.1% of patients had low, moderate, and high HBV DNA levels, respectively. The APRI (0.33 vs. 0.26 vs. 0.26, P < 0.001), FIB-4 (1.03 vs. 0.71 vs. 0.68, P < 0.001), and LSM values (7.6 kPa vs. 5.6 kPa vs. 5.5 kPa, P = 0.086) were higher in low HBV DNA group than other two groups. Low HBV DNA group had higher proportions of significant fibrosis (24.8% vs. 9.9% vs. 3.3%, P < 0.001) and cirrhosis (7.7% vs. 2.5% vs. 1.1%, P = 0.004) than moderate and high HBV DNA groups. Moderate (OR 3.095, P = 0.023) and low (OR 4.968, P = 0.003) HBV DNA were independent risk factors of significant fibrosis.

Conclusion

Lower HBV DNA level was associated with more severe liver fibrosis in HBeAg-positive CHB patients with ALT.

Introduction

Chronic hepatitis B virus (HBV) infection is closely related to the development of cirrhosis and hepatocellular carcinoma (HCC) [1]. It is estimated that 296 million individuals are suffering from chronic hepatitis B (CHB) and more than 800,000 people die from this illness each year worldwide [1]. The typical natural history of CHB is a dynamic process and determined by the interplay between host immune response and viral status [2]. The immune-tolerate (IT) or hepatitis B e antigen (HBeAg) positive chronic infection phase usually occurs in the early phase of HBV infection and characterized by hepatitis B e antigen positivity, high serum HBV DNA load, and normal alanine transaminase (ALT) level, suggesting absence of immune-mediated liver damage [2].

Antiviral therapy is generally not recommended for IT subjects according to current guidelines due to the minor liver injury [2, 3]. However, a growing body of evidence suggested that IT phase patients defined by serological parameters had relatively high risk of progressive liver injury, including liver fibrosis, cirrhosis, and HCC [4,5,6]. Kim et al. reported that untreated IT phase patients had higher risks of severe complications than treated immune active phase patients [4]. A meta-analysis also showed that nearly 20% of IT phase patients had significant liver histologic changes, and antiviral therapy should be initiated immediately for these patients [5]. Therefore, the management strategy for IT patients is in debate.

The associated factors with significant liver fibrosis remains unclear in IT patients. Previous studies reported that age, sex, transaminase, HBV DNA, and HBV variants were related to significant liver fibrosis in IT patients [7,8,9]. Among these indexes, HBV DNA level has always been a major affecting factor of liver disease progression in patients with CHB [10, 11]. However, few studies evaluated the association between HBV DNA levels and liver fibrosis in CHB patients with IT phase. Thus, the purpose of this study was to explore the association of HBV DNA levels with liver fibrosis in HBeAg-positive CHB patients with normal ALT with relatively high HBV DNA levels by a large multi-center treatment-naïve CHB cohort.

Methods

Study population

The multi-center, retrospective study screened 19,911 treatment-naïve patients with CHB between January 2015 and August 2022 at three medical institutions in Jiangsu, China. In the present study, HBeAg positive CHB patients with normal ALT with relatively high HBV DNA levels was included. In detail, patients who met the following inclusion criteria were eligible for this study: (1) positive for hepatitis B surface antigen (HBsAg) over six months; (2) HBeAg positivity; (3) serum HBV DNA levels ≥ 106 IU/mL, (4) normal ALT (< 1 × upper limits of normal [ULN]). The ULNs of ALT were 35 for male and 25 for female, respectively2. The excluded criteria were as follows: (1) concurrent with nonalcoholic fatty liver disease, hepatitis C virus infection, hepatitis D virus infection, immune-related liver diseases, hereditary and metabolic liver diseases; (2) HCC or other types of cancer; (3) excessive drinking (> 30 g for men and > 20 g for women per day); (4) insufficiency of clinical data. We did not define patients as IT phase since the phase definition required adequate assessment interval instead of only one timepoint measurement.

The study protocol was approved by the Internal Review Board of Nanjing Drum Tower Hospital (IRB number: 2,008,022) and adhered to the ethical guidelines of the Declaration of Helsinki. A waiver of informed consent was granted by the ethics committees due to a retrospective design. This study was registered under ClinicalTrials.gov (NCT03097952).

Data collection and definition

Demographic characteristics, medical history, laboratory, and imaging data were retrospectively collected from electronic medical records, including blood routine examination, biochemistry tests, serological markers of HBV, liver histological features, and transient elastography. The HBsAg and HBeAg levels were measured by the ARCHITECT assay (Abbott Gmbh, United States) with the positive threshold values for HBsAg and HBeAg levels of 0.05 IU/ml and 1.0 S/CO, respectively.

Aspartate aminotransferase (AST) to platelet (PLT) ratio index (APRI), fibrosis index based on 4 factors (FIB-4), transient elastography were used to identify significant liver fibrosis and cirrhosis in this study. In addition, some patients underwent liver biopsy and Scheuer scoring system was used to identify liver fibrosis stage (S) [12]. The calculated formulae were as follows: [AST (U/L)/ULN of AST]/PLT (109/L) × 100 for APRI and [age (years) × AST (U/L)]/[PLT (109/L) × (ALT [U/L])1/2] for FIB-4 [13, 14]. Individuals who met any of the following criteria were defined as significant liver fibrosis: (1) APRI ≥ 1.5; (2) FIB-4 ≥ 3.25; (3) liver stiffness measurement (LSM) values ≥ 8 kPa [15]; (4) liver histology ≥ S2. Correspondingly, the cirrhosis criteria were as follows: (1) APRI ≥ 2.0; (2) FIB-4 ≥ 6.5; (3) LSM values ≥ 11 kPa [15]; (4) liver histology of fibrosis stage 4.

Statistical analysis

Continuous and categorical parameters were showed as median (interquartile [IQR]) and number (percentage), respectively. The former were compared by independent-group t-tests (normal distribution) or Mann-Whitney U tests (abnormal distribution), while the latter were compared by chi-squared test. The correlation between HBV DNA levels and liver fibrosis stages was analyzed by Spearman’s method. The risk factors of significant liver fibrosis were identified by logistic regression analysis. A sensitivity analysis was conducted to validate the correlation of HBV DNA levels with liver fibrosis in patients underwent liver biopsy. P < 0.05 was considered statistically significant. All analysis was conducted using Statistical Package for the Social Sciences version 23.0 software program (IBM, Armonk, NY, USA) and R software (version 4.2.0; R Foundation, Vienna, Austria; www.R-project.Org).

Results

Clinical features of study population

A total of 19,911 treatment-naïve CHB patients were initially screened. According to exclusion criteria, 19,289 patients were excluded and 622 patients were included for the final analysis. Figure S1 shows the flow chart of patient selection.

Of 622 patients, the median age was 33.0 years and male patients accounted for 57.9%. The median levels of ALT, HBsAg, HBeAg, and HBV DNA were 24.0 U/L, 4.6 log10 IU/mL, 3.1 log10 S/CO, and 7.7 log10 IU/mL, respectively (Table 1). The median values of APRI and FIB-4 were 0.27 and 0.72, respectively (Table 2). The data of transient elastography and liver biopsy were available in 152 patients and 66 patients, respectively. The median value of LSM was 5.7 kPa, and the proportions of patients with biopsy-determined significant fibrosis (≥ S2) were 36.4% (Table 2).

Table 1 Comparison of clinical features among different HBV DNA subgroups
Full size table
Table 2 Comparison of liver fibrosis degree among different HBV DNA subgroups
Full size table

Comparison of clinical features and liver fibrosis among different HBV DNA subgroups

Patients were classified into three categories base on the serum HBV DNA levels: low (6 log10 IU/mL ≤ HBV DNA < 7 log10 IU/mL), moderate (7 log10 IU/mL ≤ HBV DNA < 8 log10 IU/mL), and high (HBV DNA ≥ 8 log10 IU/mL). The proportion of patients with lower, moderate, and high HBV DNA levels were 18.8%, 52.1%, and 29.1%, respectively.

In aspect of clinical features, patients with low HBV DNA were older (37.0 years vs. 33.0 years vs. 32.0 years, P < 0.001) and had higher proportion of male gender (70.1% vs. 59.3% vs. 47.5%, P < 0.001), levels of AST (24.0 U/L vs. 21.8 U/L vs. 21.0 U/L, P < 0.001), alkaline phosphatase (ALP) (71.7 U/L vs. 64.0 U/L vs. 62.0 U/L, P < 0.001), gamma-glutamyl transpeptidase (GGT) (21.6 U/L vs. 16.9 U/L vs. 15.7 U/L, P < 0.001), and total bilirubin (Tbil) (13.0 µmol/L vs. 12.2 µmol/L vs. 11.6 µmol/L, P = 0.011), while had lower levels of PLT (183.0 × 109/L vs. 200.0 × 109/L vs. 219.0 × 109/L, P < 0.001), albumin (ALB) (42.7 g/L vs. 44.6 g/L vs. 44.5 g/L, P < 0.011), and HBsAg (3.9 log10 IU/mL vs. 4.7 log10 IU/mL vs. 4.7 log10 IU/mL, P < 0.011) compared to patients with moderate, and high HBV DNA (Table 1).

With regards to liver fibrosis, the APRI (0.33 vs. 0.26 vs. 0.26, P < 0.001), FIB-4 (1.03 vs. 0.71 vs. 0.68, P < 0.001), and LSM values (7.1 kPa vs. 5.6 kPa vs. 5.5 kPa, P = 0.086) were higher in patients with low HBV DNA than those of patients with moderate, and high HBV DNA. A subgroup analysis was conducted in 66 patients who underwent liver biopsy, which revealed that patients with low HBV DNA had higher proportion of significant fibrosis (72.7% vs. 34.1% vs. 14.3%, P = 0.009) and cirrhosis (18.2% vs. 2.4% vs. 0%, P = 0.009) than other two groups (Table 2). Overall, patients with low HBV DNA had higher proportion of significant fibrosis (24.8% vs. 9.9% vs. 3.3%, P < 0.001) and cirrhosis (7.7% vs. 2.5% vs. 1.1%, P = 0.004) compared to patients with moderate and high HBV DNA (Fig. 1A and B). In addition, we also compared the clinical features between patients with and without significant fibrosis, which suggested that patients with significant fibrosis had a lower HBV DNA level (7.1 log10 IU/ml vs. 7.8 log10 IU/ml, P < 0.001) than those without significant fibrosis (Table S1).

Fig. 1
figure 1

The proportions of significant fibrosis and cirrhosis among different HBV DNA subgroups

Full size image

Associated factors of significant liver fibrosis in CHB patients with immune-tolerate phase

Logistic regression analysis was performed to identify associated factors of significant fibrosis in CHB patients with IT phase (Table 3). Of note, several parameters were not included into logistic regression analysis due to multicollinearity, including age, PLT, ALT, and AST. In the univariate analysis, male sex, higher levels of neutrophils, lymphocytes, ALP, GGT, Tbil, low levels of ALB and HBV DNA were associated with significant fibrosis. Low HBV DNA (odds ratio [OR] 4.968, 95% confidence interval [CI] 1.706–14.473, P = 0.003) and moderate HBV DNA (OR 3.095, 95% CI 1.165–8.222, P = 0.023) remained independent risk factors of significant liver fibrosis in the multivariate analysis.

Table 3 Analysis of clinical parameters associated with significant liver fibrosis
Full size table

Association of HBV DNA levels with liver fibrosis in different age subgroups

Further analysis was conducted in patients with age < 30 years and age ≥ 30 years (Table 4). The proportion of patients with low HBV DNA, moderate HBV DNA, and high HBV DNA were 11.0%, 58.1%, and 31.0% in patients age < 30 years, respectively. The values of APRI, FIB-4, LSM, and the proportion of significant liver fibrosis and cirrhosis were comparable among three groups (Fig. 1C and D). Eight patients underwent liver biopsy in age < 30 years group. Although more patients with low HBV DNA (75.0%) had significant liver fibrosis than patients with moderate HBV DNA (25.0%) and high HBV DNA (20.0%), the differences were not statistically significant (P = 0.129). However, for patients age ≥ 30 years, those with low HBV DNA had higher values of APRI (0.35 vs. 0.27 vs. 0.25, P < 0.001), FIB-4 (1.16 vs. 0.79 vs. 0.71, P < 0.001), and LSM (7.4 vs. 5.5 vs. 5.5, P = 0.033) compared to those with moderate and high HBV DNA levels. Patients with low HBV DNA also had the highest proportion of significant liver fibrosis (26.0% vs. 11.1% vs. 2.3%, P < 0.001) and cirrhosis (9.0% vs. 3.0% vs. 0.8%, P = 0.003) than those with moderate HBV DNA and high HBV DNA (Fig. 1E and F). Moreover, we also conduct similar subgroup analysis between patients with age < 35 years and age ≥ 35 years, age < 40 years and age ≥ 40 years. Similar results were observed (Table S2 and Figure S2).

Table 4 Comparison of liver fibrosis degree in different age subgroups
Full size table

Logistic regression analysis was performed to identify associated factors of significant fibrosis in patients with age < 30 years and age ≥ 30 years, respectively (Table 5). In age < 30 years group, HBV DNA levels were not associated with significant fibrosis. However, moderate HBV DNA (OR 6.487, 95% CI 1.489–28.255, P = 0.013) and low HBV DNA (OR 8.618, 95% CI 1.836–40.458, P = 0.006) were independent risk factors of significant fibrosis compared to high HBV DNA in group aged ≥ 30 years.

Table 5 Analysis of clinical parameters associated with significant liver fibrosis in different age subgroups
Full size table

Further correlation analysis was conducted between HBV DNA levels and APRI, FIB-4, LSM values, and fibrosis stages (Table S3). Overall, HBV DNA levels were negatively associated with APRI (r =-0.226, P < 0.001), FIB-4 (r =-0.244, P < 0.001), LSM (r =-0.158, P = 0.051), and fibrosis stages (r =-0.287, P = 0.020). Similar results were observed in patients with age ≥ 35 years and ≥ 40 years.

Subgroup analysis of clinical features and liver fibrosis in immune-tolerate patients diagnosed by at least two tests

A total of 134 patients met the IT phase criteria with at least two tests taken more than three months apart within a 1-year period, including 15 patients in low HBV DNA group, 73 patients in moderate HBV DNA group, and 46 patients in high HBV DNA group. The age, sex, PLT, ALT, and AST levels were comparable, while HBsAg level (4.4 log10 IU/mL vs. 4.7 log10 IU/mL vs. 4.8 log10 IU/mL, P < 0.001) showed an increasing trend in patients with low, moderate, and high HBV DNA levels. With regards to liver fibrosis, patients in low HBV DNA group had higher values of APRI (0.30 vs. 0.25 vs. 0.26, P = 0.056), FIB-4 (0.88 vs. 0.67 vs. 0.71, P = 0.034), and LSM (6.3 vs. 5.8 vs. 5.5, P = 0.814) than patients in moderate and high HBV DNA group (Table S4). In addition, we also compared the clinical features between HBeAg-positive CHB patients with normal ALT with relatively high HBV DNA levels with at least two measurements and those with only one-time measurement (Table S5). The results suggested that patients with at least two measurements had higher HBsAg (4.7 log10 IU/ml vs. 4.6 log10 IU/ml, P < 0.001) and HBV DNA (7.8 log10 IU/ml vs. 7.7 log10 IU/ml, P = 0.002) levels than those only one-time measurement, while age and liver fibrosis degree were comparable between two groups.

Discussion

In this multi-center study, we analyzed the association of HBV DNA levels with liver fibrosis in HBeAg-positive CHB patients with normal ALT with relatively high HBV DNA levels. The results indicated that patients with low HBV DNA level had more severe liver fibrosis compared to those with higher HBV DNA. A lower HBV DNA level was identified as a risk factor for significant liver fibrosis in HBeAg-positive CHB patients with normal ALT with relatively high HBV DNA levels.

The definition of IT phase is commonly based on serological markers including HBeAg positivity, normal ALT and high HBV DNA levels, which had minimal or no immune-mediated liver injury. Hui et al. analyzed 57 IT phase patients and 66.7% of patients had mild liver fibrosis, while none of patients had significant liver fibrosis. However, a growing body of evidence showed that although HBV-mediated immune response in IT phase is mild, substantial proportion of patients may have significant liver fibrosis. A meta-analysis, which included 9,377 CHB patients with IT phase underwent liver biopsy, revealed that nearly one third of patients had significant fibrosis or more severe fibrosis [16]. Yoo et al. reported that nearly 70% of patients who belonged to serological IT phase were not in true histologic IT phase [6]. Our previous study also demonstrated that over 30% of CHB patients with serological IT phase had significant liver fibrosis [17]. In addition, the long-term prognosis of CHB patients in the IT phase is generally favorable, with a low risk of disease progression [2, 3]. A meta-analysis revealed that HBeAg-positive CHB patients in the untreated IT phase and those in the antiviral-treated immune active phase had comparable clinical outcomes, including the development of HCC and death [18]. On the contrary, Kim et al. found that untreated CHB patients with IT phase had higher risk of HCC and death/transplantation than treated immune-active phase patients [4]. However, the mean age of IT phase patients was 38 years in this study and many patients need antiviral treatment according to current guidelines [4].

The inconsistent results of histological change and prognosis in IT phase patients may be due to the discrepancies of clinical features in previous studies, especially different HBV DNA levels. Xie et al. reported that 6.7 log10 IU/mL was the optimal threshold value of HBV DNA to identify significant fibrosis, and no patient had significant fibrosis in HBeAg positive CHB patients with HBV DNA > 8.5 log10 IU/mL [19]. Our previous study also found that patients with low HBV DNA level (5–7 log10 IU/mL) had higher proportion of significant inflammation in CHB patients with normal ALT [20]. Another study reported that HBV DNA levels of 6–7 log10 IU/mL in HBeAg positive CHB patients with normal ALT had a higher risk of HCC than patients with higher HBV DNA levels [21]. In the present study, we also demonstrated that HBV DNA levels were negatively associated with liver fibrosis, suggesting that lower HBV DNA levels may be associated with high risk of significant liver fibrosis in HBeAg-positive CHB patients with normal ALT with relatively high HBV DNA levels. However, high level of HBV DNA has always been regarded as a stimulative factor of adverse outcomes in patients with CHB [10, 11]. The potential mechanism behind the contradictory results of HBV DNA impacts on disease progression in CHB patients remains unclear. HBV variants may be one of the main causes of adverse outcomes in CHB patients with IT phase, including liver fibrosis, cirrhosis, and HCC [22, 23]. Yuen et al. found that basal core promoter and hepatitis B X gene variants were independently associated with lower levels of HBV DNA in IT phase patients, and increased HBV diversity was related to older age and lower HBV DNA [9]. In addition, patients with low HBV DNA levels may exist activated anti-HBV immune response, as reflected by higher ALT, AST, ALP, GGT, and Tbil levels in these patients in the present study. Therefore, patients with low HBV DNA might not be actually IT phase, who were more likely immune active phase but with normal ALT, or in the phase changing from IT to immune active phase. Liver biopsy is required to identify patients with significant histological change and initiate antiviral therapy to prevent adverse outcomes in IT phase patients with low HBV DNA levels.

Given the significant association between HBV DNA level and liver fibrosis in early phase of HBV infection, reconsideration of threshold value of HBV DNA is necessary to the definition of serological IT phase. The definition of IT phase as high HBV DNA of more than 106 IU/ml in AASLD guideline is challenged according our results and previous studies [2]. Although higher HBV DNA of 107 IU/ml for IT phase is defined in European Association for the Study of the Liver guideline, patients with HBV DNA of 107-108 IU/ml remain had more severe liver fibrosis than patients with HBV DNA ≥ 108 IU/ml in this study [3]. Patients with lower HBV DNA levels may be not in the “true” IT phase of CHB. Thus, the optimal threshold value of HBV DNA for the definition of IT phase needs to be confirmed in future study.

Several limitations need to be considered for this study. First, the majority of patients before study entry had a single-time point measurement in this study. Patients with low HBV DNA may be progressive toward the immune clearance phase. However, as a sensitive analysis, patients with at least two tests taken more than three months apart within a 1-year period were included and similar results were found. Second, we did not compare the longitudinal progression of liver fibrosis among patients with different HBV DNA levels due to the retrospective design. In addition, the difference of disease progression in patients HBeAg-positive CHB patients with normal ALT with relatively high HBV DNA levels by a single-time test and at least two tests were unclear. Thus, the results need validation by further prospective and longitudinal studies. Third, the degree of liver fibrosis was largely based on noninvasive measurements and most patients were lack of liver biopsy data. However, a sensitive analysis showed similar results in patients underwent liver biopsy. Fourth, we did not analyze the association between HBsAg and liver fibrosis because quantitative data of HBsAg levels were not available in a substantial proportion (17.7%) of patients. Last, HBV genotype data were not available and the HBV mutations were not detected in our study. Thus, the association of HBV genotypes and viral diversity with HBV DNA levels and liver fibrosis progression requires further investigation.

In conclusion, lower HBV DNA level was associated with more severe liver fibrosis in HBeAg-positive CHB patients with normal ALT with relatively high HBV DNA levels, especially for patients older than 30 years. Since a greater proportion of significant fibrosis was observed in HBeAg-positive CHB patients with normal ALT and lower HBV DNA levels, especially in older age groups, these subjects should adhere to the guidelines’ suggestion to receive fibrosis assessment to identify who is eligible for antiviral therapy.

Data availability

The data that support the study findings are available upon reasonable request from the corresponding authors (RH and CW).

Abbreviations

ALP:

alkaline phosphatase

ALT:

alanine transaminase

APRI:

AST to PLT ratio index

AST:

aspartate aminotransferase

CHB:

chronic hepatitis B

CI:

confidence interval

FIB-4:

fibrosis index based on 4 factors

HBV:

hepatitis B virus

HBeAg:

hepatitis B e antigen

HBsAg:

hepatitis B surface antigen

HCC:

hepatocellular carcinoma

IQR:

interquartile

IT:

immune-tolerate

GGT:

gamma-glutamyl transpeptidase

OR:

odds ratio

PLT:

platelet

Tbil:

total bilirubin

ULN:

upper limits of normal

References

  1. Jeng WJ, Papatheodoridis GV, Lok ASF, Hepatitis. B Lancet. 2023;401:1039–52.

    Article  CAS  PubMed  Google Scholar 

  2. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–99.

    Article  PubMed  Google Scholar 

  3. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, European Association for the study of the liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–98.

    Article  Google Scholar 

  4. Kim GA, Lim YS, Han S, Choi J, Shim JH, Kim KM, et al. High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B. Gut. 2018;67:945–52.

    Article  CAS  PubMed  Google Scholar 

  5. Li Z, Yang D, Ge Y, Song S, Lv Q, Ye Y. Histologic changes in immune-tolerant patients with chronic hepatitis B: a systematic review and meta-analysis. Sci Rep. 2023;13:469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yoo JJ, Park SY, Moon JE, Lee YR, Lee HA, Lee J et al. The long-term prognosis and the need for histologic assessment in chronic hepatitis B in serological immune-tolerant phase. Clin Mol Hepatol 2023.

  7. Andreani T, Serfaty L, Mohand D, Dernaika S, Wendum D, Chazouillères O, et al. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome. Clin Gastroenterol Hepatol. 2007;5:636–41.

    Article  PubMed  Google Scholar 

  8. Kawanaka M, Nishino K, Kawamoto H, Haruma K, Hepatitis B. Who should be treated?-managing patients with chronic hepatitis B during the immune-tolerant and immunoactive phases. World J Gastroenterol. 2021;27:7497–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yuen L, Revill PA, Rosenberg G, Wagner J, Littlejohn M, Bayliss J, et al. HBV variants are common in the immune-tolerant phase of chronic hepatitis B. J Viral Hepat. 2020;27:1061–70.

    Article  CAS  PubMed  Google Scholar 

  10. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73.

    Article  CAS  PubMed  Google Scholar 

  11. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678–86.

    Article  PubMed  Google Scholar 

  12. Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol. 1991;13:372–4.

    Article  CAS  PubMed  Google Scholar 

  13. Wai C-T, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–26.

    Article  PubMed  Google Scholar 

  14. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–25.

    Article  CAS  PubMed  Google Scholar 

  15. Kao JH, Hu TH, Jia J, Kurosaki M, Lim YS, Lin HC, et al. East Asia expert opinion on treatment initiation for chronic hepatitis B. Aliment Pharmacol Ther. 2020;52:1540–50.

    Article  CAS  PubMed  Google Scholar 

  16. Hui CK, Leung N, Yuen ST, Zhang HY, Leung KW, Lu L, et al. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology. 2007;46:395–401.

    Article  PubMed  Google Scholar 

  17. Wang J, Yan X, Zhu L, Liu J, Qiu Y, Li Y, et al. Significant histological disease of patients with chronic hepatitis B virus infection in the grey zone. Aliment Pharmacol Ther. 2023;57:464–74.

    Article  CAS  PubMed  Google Scholar 

  18. Lee HA, Kim SU, Seo YS, Ahn SH, Rim CH. Comparable outcomes between immune-tolerant and active phases in noncirrhotic chronic hepatitis B: a meta-analysis. Hepatol Commun. 2023;7:e0011.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Xie Q, Hu X, Zhang Y, Jiang X, Li X, Li J. Decreasing hepatitis B viral load is associated with a risk of significant liver fibrosis in hepatitis B e antigen positive chronic hepatitis B. J Med Virol. 2014;86:1828–37.

    Article  CAS  PubMed  Google Scholar 

  20. Liu J, Wang J, Yan X, Xue R, Zhan J, Jiang S, et al. Presence of Liver inflammation in Asian patients with chronic Hepatitis B with Normal ALT and detectable HBV DNA in absence of liver fibrosis. Hepatol Commun. 2022;6:855–66.

    Article  CAS  PubMed  Google Scholar 

  21. Kim GA, Han S, Choi GH, Choi J, Lim YS. Moderate levels of serum hepatitis B virus DNA are associated with the highest risk of hepatocellular carcinoma in chronic hepatitis B patients. Aliment Pharmacol Ther. 2020;51:1169–79.

    Article  CAS  PubMed  Google Scholar 

  22. Tseng TC, Liu CJ, Yang HC, Chen CL, Yang WT, Tsai C-S, et al. Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers. Gut. 2015;64:292–302.

    Article  CAS  PubMed  Google Scholar 

  23. Liao Y, Hu X, Chen J, Cai B, Tang J, Ying B, et al. Precore mutation of hepatitis B virus may contribute to hepatocellular carcinoma risk: evidence from an updated meta-analysis. PLoS ONE. 2012;7:e38394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Dr. Rui Huang wishes to acknowledge the supported from Nanjing Medical Science and Technique Development Foundation (JQX21002 and QRX17121), Natural Science Foundation of Jiangsu Province (BK20211004), and Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (2022-LCYJ-MS-07). Dr. Jian Wang wishes to acknowledge the support from the National Natural Science Fund (82300719), Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (2021-LCYJ-PY-43) and Nanjing Medical Science and Technique Development Foundation (YKK21067). Dr. Jie Li wishes to acknowledge the support from the National Natural Science Fund (81970545 and 82170609), Natural Science Foundation of Shandong Province (Major Project) (ZR2020KH006) and Ji’nan Science and Technology Development Project (2020190790). Dr. Li Zhu wishes to acknowledge the support from the Clinical Disease Diagnosis and Treatment Technology Foundation of Suzhou (LCZX202117).

Author information

Author notes

  1. Jian Wang, Li Zhu, Zhiyi Zhang and Shaoqiu Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Infectious Diseases, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China

    Jian Wang, Shaoqiu Zhang, Jiacheng Liu, Shengxia Yin, Xin Tong, Jie Li, Chao Wu & Rui Huang

  2. Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China

    Jian Wang, Yuxin Chen, Shengxia Yin, Xin Tong, Jie Li, Chao Wu & Rui Huang

  3. Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China

    Li Zhu & Chuanwu Zhu

  4. Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China

    Zhiyi Zhang, Fei Cao, Tao Fan, Ye Xiong, Jie Li, Chao Wu & Rui Huang

  5. Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China

    Yifan Pan, Yuanyuan Li & Rui Huang

  6. Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu, China

    Chao Jiang & Rui Huang

  7. Department of Clinical Laboratory, Huai’an No. 4 People’s Hospital, Huai’an, Jiangsu, China

    Xingxiang Liu

Authors
  1. Jian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhiyi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shaoqiu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yifan Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuanyuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fei Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tao Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ye Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jiacheng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yuxin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shengxia Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xin Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Chuanwu Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Xingxiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Chao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Rui Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to this study at different levels. All authors read and approved the final version. Study concept and design (Rui Huang, Jian Wang, Jie Li and Chao Wu); acquisition of data (Zhiyi Zhang, Yifan Pan, Yuanyuan Li, Jiacheng Liu, Yuxin Chen, Shengxia Yin, Xin Tong, Cao Fei, Chao Jiang, Tao Fan, Ye Xiong, Xingxiang Liu, Chuanwu Zhu); statistical analysis and interpretation of data (Jian Wang, Zhiyi Zhang, Li Zhu, Shaoqiu Zhang); drafting of the manuscript (Jian Wang, Li Zhu, Zhiyi Zhang); critical revision of the manuscript for important intellectual content (Rui Huang, Chao Wu).

Corresponding authors

Correspondence to Jie Li, Chao Wu or Rui Huang.

Ethics declarations

Ethics approval and consent to participate

The study protocol was approved by the Internal Review Board of Nanjing Drum Tower Hospital (IRB number: 2008022) and adhered to the ethical guidelines of the Declaration of Helsinki. A waiver of informed consent was granted by the ethics committees due to a retrospective design. This study was registered under ClinicalTrials.gov (NCT03097952).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, J., Zhu, L., Zhang, Z. et al. Lower HBV DNA level is associated with more severe liver fibrosis in HBeAg-positive chronic hepatitis B with normal alanine transaminase. Virol J 21, 127 (2024). https://doi.org/10.1186/s12985-024-02368-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12985-024-02368-0

Keywords

Virology Journal

ISSN: 1743-422X