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. 2014 Feb 13;9(2):e89046.
doi: 10.1371/journal.pone.0089046. eCollection 2014.

Analysis of hepatitis B virus intrahepatic covalently closed circular DNA and serum viral markers in treatment-naive patients with acute and chronic HBV infection

Weijie Li  1 , Jingmin Zhao  2 , Zhengsheng Zou  3 , Yan Liu  3 , Baosen Li  3 , Ying Sun  3 , Xiaodong Li  3 , Shuhong Liu  2 , Shaoping Cai  3 , Weiming Yao, Shaojie Xin  3 , Fengmin Lu  4 , Dongping Xu  1
Affiliations

Analysis of hepatitis B virus intrahepatic covalently closed circular DNA and serum viral markers in treatment-naive patients with acute and chronic HBV infection

Weijie Li et al. PLoS One. .

Erratum in

  • PLoS One.2014 Apr;9(4):e96382. Yao, Weimin [corrected to Yao, Weiming]

Abstract

Background: This study aimed to investigate the relationships of intrahepatic cccDNA with serum HBsAg and with HBV DNA in treatment-naive patients throughout acute and chronic HBV infection.

Methods: A total of 120 patients who had a liver biopsy were enrolled, including 19 with acute hepatitis B (AHB), and 101 patients with chronic HBV infection (CHB) of whom were 10 in immune-tolerant (IT) phase, 59 in immune-clearance (IC) phase, 8 in low-replicative (LR) phase, and 24 in HBeAg-negative hepatitis (ENH) phase. Intrahepatic cccDNA, serum HBsAg and serum HBV DNA levels were comparatively analyzed.

Results: The median intrahepatic cccDNA levels were 0.18 4.80, 3.81, 0.22 and 0.97 copies/cell for patients with AHB, CHB-IT, CHB-IC, CHB-LR, and CHB-ENH, respectively. In AHB patients, intrahepatic cccDNA was positively correlated with serum HBsAg (r = 0.665, P = 0.003), as well as serum HBV DNA (r = 0.536, P = 0.022). In CHB patients, intrahepatic cccDNA was positively correlated with serum HBsAg in the IC phase (r = 0.392, P = 0.005), and with serum HBV DNA in the IC phase (r = 0.301, P = 0.036) and ENH phase (r = 0.588, P = 0.013). HBV replicative efficiency, defined as the ratio of serum HBV DNA to intrahepatic cccDNA, was obviously lower in AHB and CHB-LR patients than in CHB-IT, CHB-IC and CHB-ENH patients (0.70 and 0.53 vs. 1.12, 1.09 and 0.99, P<0.001, values were logarithmic transformed for analysis). In CHB-IC patients, HBV replicative efficiency was positively correlated with histological activity index of liver inflammation (r = 0.308, P = 0.009).

Conclusion: Serum HBsAg and HBV DNA levels may reflect the amount of active intrahepatic cccDNA in treatment-naive AHB and CHB-IC patients. Reduced intrahepatic cccDNA and HBV replicative efficiency may imply effective immune control of HBV infection.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Comparison of intrahepatic (IH) HBV cccDNA levels among patients with different clinical presentations.
The horizontal lines illustrate the 25th, 50th, and 75th percentiles of the cccDNA levels. Symbols * and ** represent P value less than 0.01 and 0.05, respectively. AHB, acute hepatitis B; CHB, chronic HBV infection; IT, immune-tolerant; IC, immune-clearance; LR, low-replicative; ENH, HBeAg-negative hepatitis.
Figure 2
Figure 2. Quantitation of serum HBsAg for 120 HBV-infected patients with different clinical presentations.
The distribution of serum HBsAg level across the study population (A). Comparison of serum HBsAg levels among patients with different clinical presentations (B). Symbol ** represent P value less than 0.01.
Figure 3
Figure 3. Analysis of correlation between intrahepatic (IH) HBV cccDNA and serum HBV markers for 19 patients with acute hepatitis B.
Correlation between intrahepatic HBV cccDNA level and serum HBsAg level (A). Correlation between intrahepatic HBV cccDNA level and serum HBV DNA level (B).
Figure 4
Figure 4. Overall analysis of correlation between intrahepatic (IH) HBV cccDNA and serum HBV markers across 101 patients with chronic HBV infection.
Correlation between IH cccDNA level and serum HBsAg level (A). Correlation between IH cccDNA level and serum HBV DNA level (B).
Figure 5
Figure 5. Phase-categorized analysis of correlation between intrahepatic (IH) HBV cccDNA level and serum HBsAg level for patients with chronic HBV infection.
Analysis for 10 patients in immune-tolerant phase (A). Analysis for 59 patients in immune-clearance phase (B). Analysis for 8 patients in low-replicative phase (C). Analysis for 24 patients in HBeAg-negative hepatitis phase (D).
Figure 6
Figure 6. Phase-categorized analysis of correlation between intrahepatic (IH) HBV cccDNA level and serum HBV DNA level for patients with chronic HBV infection in different phases.
Analysis for 10 patients in immune-tolerant phase (A). Analysis for 59 patients in immune-clearance phase (B). Analysis for 8 patients in low-replicative phase (C). Analysis for 24 patients in HBeAg-negative hepatitis phase (D).
Figure 7
Figure 7. Monitoring of serum HBsAg and HBV DNA levels in patients with acute hepatitis B.
Dynamical change of serum HBsAg level (A). Dynamical change of serum HBV DNA level (B). Association of reductions between serum HBsAg level and HBV DNA level 14 days post patient admission (C).
Figure 8
Figure 8. Relationship of HBV replicative efficiency with histological activitiesin CHB-IC patients.
Correlation between HBV replicative efficiency and histological grade of active inflammation (A). Correlation between HBV replicative efficiency and histological stage of fibrosis(B).
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