阿德福韦酯对鸭乙肝病毒cccDNA的抗病毒作用研究

摘要

Objective To investigate the inhibition of adefovir dipivoxil (ADV ) against duck hepatitis B virus (DHBV ) cccDNA . Methods DHBV naturally infected Peikin ducks fed in Xi′an were used as the animal model and were treated orally with 10 mg · kg -1 of ADV daily for 30 days ,and 0 .5 mL of 0 .01 mol · L -1 PBS was used as the negative control .The levels of DHBV DNA in the peripheral blood were quantified at day 0 ,10 ,20 and 30 of the treatment and at day 15 after the termination of treat‐ment .The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were examined .Liver tissues of every duck in two groups were obtained by surgery ,and DHBV DNA and cccDNA were determined at day 30 of the treatment and at day 15 after the termination of treatment .Results The serum DHBV DNA levels in ADV treated ducks at day 10 ,20 and 30 of the treatment were significantly reduced as compared with those at baseline of treatment (P 0 .05) .At day 30 of the treatment and day 15 after the termination of treatment ,the inhibition ratio of cccDNA in ADV treated ducks were significantly reduced as compared with those in negative con‐trols ,suggesting that ADV can effectively inhibit the replication of DHBV cccDNA .No significant change between baseline and end of treatment was observed in ALT and AST in ADV treated ducks .Conclusion ADV can effectively inhibit the replication of DHBV ,particularly ,can make DHBV cccDNA decreased .However ,when the treatment was stopped ,there was a rebound in the levels of DHBV DNA and cccDNA ,indicating that ADV should be combined with other antiviral drugs in clinical treatment and be used long‐termly .%目的：探讨阿德福韦酯（ADV）对鸭乙肝病毒cccDNA的抑制作用。方法采用ADV（10 mg · kg－1· d－1）和0．01 mol · L －1 PBS（0．5 mL · kg －1· d－1）治疗感染鸭乙肝病毒（DHBV）的北京麻鸭。分别在治疗第0，10，20和30 d和停药15 d时，检测外周血DHBVDNA的载量和外周血AST和ALT水平。并分别于治疗前、治疗30 d和停药15 d分别通过手术、B超引导下的肝脏穿刺取鸭肝组织，检测DHBV DNA和DHBV cccDNA 载量。结果外周血DHBV DNA载量ADV 阳性药物组分别在治疗10，20和30 d均显著低于治疗基线（P＜0．05），并随着治疗时间延长，DHBV DNA呈下降趋势。停药15 d ，虽与治疗基线比较仍有显著性差异（P＜0．05），但病毒复制有反弹现象。在治疗20，30 d和停药15 d时，ADV治疗组均显著低于PBS阴性对照组（P＜0．05）。肝组织DHBV DNA载量，ADV阳性药物组治疗30 d时明显低于阴性对照和治疗基线（P＜0．05），但停药15 d后，肝组织中的DHBV DNA有所反弹，与治疗基线和阴性对照比均无显著性差异（P＞0．05）。肝组织DHBV cccDNA治疗抑制率在治疗30 d和停药15 d后，ADV阳性药物组均明显高于阴性对照（P＜0．05）。表明ADV可有效抑制DHBV cccDNA的复制，停药15 d后虽能够有效地维持抑制作用，但有所反弹。AST和ALT结果显示，ADV阳性药物组各时间点与基线之间，以及与PBS对照组之间均无统计学差异（P＞0．05）。结论 ADV可有效抑制DHBV DNA和cccDNA的复制。但停药后仍有反弹。提示临床ADV治疗 HBV应长期、联合用药，才能最终治愈乙肝。