Menne Stephan, Cote Paul J, Korba Brent E, Butler Scott D, George Andrea L, Tochkov Ilia A, Delaney William E, Xiong Shelly, Gerin John L, Tennant Bud C
Gastrointestinal Unit, Department of Clinical Sciences, College of Veterinary Medicine, Room C-2005 VMC, Cornell University, Ithaca, New York 14853, USA.
Antimicrob Agents Chemother. 2005 Jul;49(7):2720-8. doi: 10.1128/AAC.49.7.2720-2728.2005.
Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue approved for treatment of human immunodeficiency virus (HIV) infection. TDF also has been shown in vitro to inhibit replication of wild-type hepatitis B virus (HBV) and lamivudine-resistant HBV mutants and to inhibit lamivudine-resistant HBV in patients and HBV in patients coinfected with the HIV. Data on the in vivo efficacy of TDF against wild-type virus in non-HIV-coinfected or lamivudine-naïve chronic HBV-infected patients are lacking in the published literature. The antiviral effect of oral administration of TDF against chronic woodchuck hepatitis virus (WHV) infection, an established and predictive animal model for antiviral therapy, was evaluated in a placebo-controlled, dose-ranging study (doses, 0.5 to 15.0 mg/kg of body weight/day). Four weeks of once-daily treatment with TDF doses of 0.5, 1.5, or 5.0 mg/kg/day reduced serum WHV viremia significantly (0.2 to 1.5 log reduction from pretreatment level). No effects on the levels of anti-WHV core and anti-WHV surface antibodies in serum or on the concentrations of WHV RNA or WHV antigens in the liver of treated woodchucks were observed. Individual TDF-treated woodchucks demonstrated transient declines in WHV surface antigen serum antigenemia and, characteristically, these woodchucks also had transient declines in serum WHV viremia, intrahepatic WHV replication, and hepatic expression of WHV antigens. No evidence of toxicity was observed in any of the TDF-treated woodchucks. Following drug withdrawal there was prompt recrudescence of WHV viremia to pretreatment levels. It was concluded that oral administration of TDF for 4 weeks was safe and effective in the woodchuck model of chronic HBV infection.
富马酸替诺福韦二吡呋酯（TDF）是一种已获批准用于治疗人类免疫缺陷病毒（HIV）感染的核苷酸类似物。体外研究还表明，TDF可抑制野生型乙型肝炎病毒（HBV）及拉米夫定耐药HBV突变体的复制，并可抑制HIV合并感染患者体内的拉米夫定耐药HBV及HBV。已发表的文献中缺乏TDF对未合并HIV感染或未使用过拉米夫定的慢性HBV感染患者体内野生型病毒的体内疗效数据。在一项安慰剂对照、剂量范围研究（剂量为0.5至15.0mg/kg体重/天）中，评估了口服TDF对慢性土拨鼠肝炎病毒（WHV）感染（一种已确立的、可预测抗病毒治疗效果的动物模型）的抗病毒作用。每日一次给予0.5、1.5或5.0mg/kg/天的TDF治疗4周，可显著降低血清WHV病毒血症（较治疗前水平降低0.2至1.5个对数）。未观察到对治疗土拨鼠血清中抗WHV核心抗体和抗WHV表面抗体水平、肝脏中WHV RNA或WHV抗原浓度的影响。接受TDF治疗的个体土拨鼠显示WHV表面抗原血清抗原血症短暂下降，并且，这些土拨鼠的血清WHV病毒血症、肝内WHV复制及WHV抗原的肝脏表达也出现短暂下降。在任何接受TDF治疗的土拨鼠中均未观察到毒性证据。停药后，WHV病毒血症迅速复发至治疗前水平。得出的结论是，在慢性HBV感染的土拨鼠模型中，口服TDF 4周是安全有效的。
