Bowden Scott, Locarnini Stephen, Chang Ting-Tsung, Chao You-Chen, Han Kwang-Hyub, Gish Robert G, de Man Robert A, Yu Miao, Llamoso Cyril, Tang Hong
Scott Bowden, Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory, Victoria 3000, Australia.
World J Gastroenterol. 2015 Apr 21;21(15):4644-51. doi: 10.3748/wjg.v21.i15.4644.
To investigate the reduction in hepatitis B virus (HBV) covalently closed-circular DNA (cccDNA) with entecavir (ETV) or lamivudine (LAM).
This analysis included patients who had participated in the randomized Phase III study ETV-022 comparing ETV vs LAM in nucleos(t)ide-naive, HBeAg-positive patients. Patients received ETV (0.5 mg daily) or LAM (100 mg daily) for a minimum of 52 wk. Patients were eligible to participate in this sub-study if they had paired biopsies at baseline and week 48 with evaluable measurements for hepatic HBV cccDNA and total hepatic HBV DNA. The main objective was to compare changes in hepatic HBV cccDNA and total hepatic HBV DNA at week 48 of ETV or LAM treatment, which was a secondary endpoint of study ETV-022. Additional post hoc analyses included linear regression analyses to assess associations of baseline levels and on-treatment changes of cccDNA with other baseline factors [sex, age, serum HBV DNA, alanine aminotransferase (ALT), Knodell necroinflammatory score, Ishak fibrosis score, total hepatic HBV DNA, and HBV genotype], or on-treatment factors (changes from baseline at week 48 in serum HBV DNA, ALT, Knodell necroinflammatory score, Ishak fibrosis score, total hepatic HBV DNA, and HBeAg loss at week 48).
Overall, 305 patients (ETV = 159; LAM = 146) of ETV-022 had paired baseline and week 48 liver biopsies with evaluable measurements for hepatic HBV cccDNA and total hepatic HBV DNA, and were included in this analysis. Baseline demographics and disease characteristics were comparable between the two arms. After 48 wk, ETV resulted in significantly greater reductions in hepatic HBV cccDNA [-0.9 log10 copies/human genome equivalent (HGEq) vs -0.7 log10 copies/HGEq; P = 0.0033] and total hepatic DNA levels (-2.1 log10 copies/HGEq vs -1.6 log10 copies/HGEq; P < 0.0001) than LAM. Virologic, biochemical, and histologic response rates at week 48 were also greater with ETV than with LAM. Baseline HBV cccDNA levels were positively associated with baseline levels of serum HBV DNA and total hepatic HBV DNA, and negatively associated with HBV genotype F. On-treatment changes in HBV cccDNA levels were negatively associated with baseline levels of serum HBV DNA and baseline ALT, and were positively associated with on-treatment changes in the levels of serum HBV DNA, total hepatic HBV DNA levels, and ALT, change in Knodell necroinflammatory score, and HBeAg loss.
Forty-eight weeks of ETV resulted in greater reductions in cccDNA and total hepatic HBV DNA than LAM, but long-term therapy may be needed for cccDNA elimination.
研究恩替卡韦（ETV）或拉米夫定（LAM）对乙肝病毒（HBV）共价闭合环状DNA（cccDNA）的降低作用。
本分析纳入了参与随机III期研究ETV - 022的患者，该研究在初治、HBeAg阳性患者中比较ETV与LAM。患者接受ETV（每日0.5 mg）或LAM（每日100 mg）治疗至少52周。如果患者在基线和第48周进行了配对活检，且肝内HBV cccDNA和肝内总HBV DNA测量值可评估，则有资格参与本亚研究。主要目的是比较ETV或LAM治疗第48周时肝内HBV cccDNA和肝内总HBV DNA的变化，这是研究ETV - 022的次要终点。额外的事后分析包括线性回归分析，以评估cccDNA的基线水平和治疗期间变化与其他基线因素[性别、年龄、血清HBV DNA、丙氨酸氨基转移酶（ALT）、Knodell坏死性炎症评分、Ishak纤维化评分、肝内总HBV DNA和HBV基因型]，或治疗因素（第48周时血清HBV DNA、ALT、Knodell坏死性炎症评分、Ishak纤维化评分、肝内总HBV DNA的基线变化以及第48周时HBeAg消失情况）之间的关联。
总体而言，ETV - 022研究中的305例患者（ETV组 = 159例；LAM组 = 146例）在基线和第48周进行了配对肝活检，且肝内HBV cccDNA和肝内总HBV DNA测量值可评估，纳入了本分析。两组基线人口统计学和疾病特征具有可比性。48周后，ETV导致肝内HBV cccDNA的降低幅度显著大于LAM（-0.9 log10拷贝/人类基因组当量（HGEq）对-0.7 log10拷贝/HGEq；P = 0.0033），肝内总DNA水平亦是如此（-2.1 log10拷贝/HGEq对-1.6 log10拷贝/HGEq；P < 0.0001）。第48周时，ETV的病毒学、生化和组织学应答率也高于LAM。基线HBV cccDNA水平与血清HBV DNA和肝内总HBV DNA的基线水平呈正相关，与HBV基因型F呈负相关。HBV cccDNA水平的治疗期间变化与血清HBV DNA和基线ALT的基线水平呈负相关，与血清HBV DNA水平、肝内总HBV DNA水平、ALT的治疗期间变化、Knodell坏死性炎症评分变化和HBeAg消失呈正相关。
48周的ETV治疗导致cccDNA和肝内总HBV DNA的降低幅度大于LAM，但可能需要长期治疗以消除cccDNA。
