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Editorial
肝内动力学共价闭合环状DNA和血清乙型肝炎表面抗原在抗病毒治疗慢性乙型肝炎的教训
实验和临床研究
Kinetics of Intrahepatic Covalently Closed Circular DNA and Serum Hepatitis B Surface Antigen During Antiviral Therapy for Chronic Hepatitis B: Lessons From
Experimental and Clinical Studies
FABIEN ZOULIM, MD, PhD
BARBARA TESTONI, PhD
FANNY LEBOSSÉ, MD
INSERM U1052
and Hospices Civils de Lyon
and Lyon University
Lyon, France
Extracts
In a newly infected cell, cccDNA formation results from the
transport of relaxed circular DNA into the nucleus of hepatocytes
and a series of biochemical reactions that lead to the
formation of this episomal form of viral DNA. cccDNA is
bound to histones and organized as a viral minichromosome.
Its transcriptional activity is regulated by epigenetic mechanisms9
(Figure 1). The pool of cccDNA initially is amplified and
then maintained by the recycling of nucleocapsid to the nucleus
of chronically infected cells. NUCs, which inhibit the viral
polymerase activity, do not inhibit the initial formation of
cccDNA in newly infected cells.10 However, a decrease of the
total amount of intrahepatic cccDNA was observed during
long-term therapy as a consequence of the inhibition of the
intracellular recycling pathway11–13 (Figure 1). Furthermore, it
was shown that hepatocyte turnover during chronic hepatitis B
may contribute to dilution of cccDNA because it is lost by cell
division11,14 (Figure 1). There is currently no commercially available
assay for the quantification of cccDNA, which still requires
a liver biopsy and access to frozen tissue. This is one of the
reasons why investigators have examined whether the quantification
of serum HBsAg might be a noninvasive surrogate
marker. Indeed, several assays are commercially available for the
quantification of serum HBsAg. HBsAg is part of the small,
middle, and large envelope proteins and is found in the envelope
of infectious virions (ie, Dane particles) and subviral particles.
HBsAg expression from the Pre-S/S gene can originate
either from viral cccDNA and/or from viral sequences integrated
in the host genome15 (Figure 1).
In this study, Wong et al8 had access to paired liver biopsy
samples taken at baseline and after 1 year of therapy from a
large group of 124 patients who were treated with 1 of the 5
NUCs (lamivudine, adefovir, entecavir, telbivudine, or clevudine).
Among the 117 patients who did not develop resistance,
the evaluation of viral suppression showed an average reduction
of approximately 0.2 log10 IU/mL in HBsAg, 5 log10 IU/mL in
serum level of hepatitis B virus (HBV) DNA, 2 log10 copies/cell
in intrahepatic total HBV DNA, and 1 log10 copies/cell in
cccDNA. Although 88 of 117 patients (75%) had undetectable
serum levels of HBV DNA (12 IU/mL), all had detectable
levels of HBsAg, and only 5 (4%) had undetectable levels of
cccDNA. Patients with greater reductions in levels of cccDNA
had greater reductions in HBsAg, but these reductions did not
reach statistically significant correlations.
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发表于 2013-8-17 20:42
