Mason W S, Cullen J, Saputelli J, Wu T T, Liu C, London W T, Lustbader E, Schaffer P, O'Connell A P, Fourel I
Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
Hepatology. 1994 Feb;19(2):398-411.
This study was carried out to evaluate benefits and limitations of long-term therapy of hepatitis B virus infections with a nucleoside analog inhibitor of virus replication. The model we used was the domestic duck chronically infected with duck hepatitis B virus by in ovo infection. 2' Carbodeoxyguanosine was used as an inhibitor of viral DNA synthesis. In all animals examined there was a reduction in virus production during therapy. A dose of 2' carbodeoxyguanosine of 10 micrograms/kg every other day reduced the number of infected hepatocytes from greater than 95% to 25% to 50% in less than 3 mo, whereas a 10-fold higher dose produced a decline to less than 10%. Histological evaluation revealed mild to moderate liver injury in ducks receiving the higher dose of 2' carbodeoxyguanosine, suggesting that disappearance of infected hepatocytes may have been accelerated by a toxic effect of the drug. Drug treatment did not completely eliminate duck hepatitis B virus from any duck, and replication was restored in all hepatocytes within a few weeks to several months after antiviral therapy was terminated. Our results suggest that elimination of a chronic infection with a single inhibitor of replication may be difficult in a host that lacks an antiviral immune response capable of eliminating at least a portion of the infected hepatocytes and of ultimately producing antibodies capable of neutralizing residual virus.
本研究旨在评估使用核苷类似物病毒复制抑制剂对乙型肝炎病毒感染进行长期治疗的益处和局限性。我们使用的模型是通过卵内感染慢性感染鸭乙型肝炎病毒的家鸭。2'-碳脱氧鸟苷用作病毒DNA合成的抑制剂。在所有接受检查的动物中，治疗期间病毒产生量均有所减少。每隔一天给予10微克/千克的2'-碳脱氧鸟苷剂量，在不到3个月的时间内，感染肝细胞的数量从超过95%降至25%至50%，而剂量高出10倍则使感染肝细胞数量降至不到10%。组织学评估显示，接受较高剂量2'-碳脱氧鸟苷的鸭子出现轻度至中度肝损伤，这表明药物的毒性作用可能加速了感染肝细胞的消失。药物治疗未能使任何一只鸭子的鸭乙型肝炎病毒完全清除，并且在抗病毒治疗终止后的几周至几个月内，所有肝细胞中的病毒复制均得以恢复。我们的结果表明，在缺乏能够清除至少一部分感染肝细胞并最终产生能够中和残留病毒的抗体的抗病毒免疫反应的宿主中，使用单一复制抑制剂消除慢性感染可能很困难。
