AIDS THERAPIES IN ANIMAL RETROVIRUS MODELS

我们研究了治疗恒河猴的长期效果 30 mg/kg/天（R）-9-（2-膦酰基甲氧基丙基）腺嘌呤（PMPA） 给药后14天开始皮下注射 静脉感染SIV。 一种非常强的抗病毒作用， 在5只猴子中的3只中观察到。 经过7天的治疗， 血浆中的负荷平均降低了3.4 log， 7 x 106至2 x 103 SIV RNA拷贝/ml，相当于减少 的99.8%。 治疗28天后，血浆RNA水平 进一步降至可计量范围以下（<1 x 103）， 在治疗期间低或不可检测。 弱得多的 在另外两只猴子中观察到抗病毒效果， 治疗组仅降低了1.2 log，从平均1.6 x 107降至 1 x 106个RNA拷贝/ml，相当于减少93.7%。 治疗28天后，这2只猴的体重下降了2.1 log 平均值为1.6 x 105拷贝/ml，数值范围为1.6 x 104 至1 x 106（平均值= 3.03 x 105）。 治疗330天后，所有5只猴子都有不同程度的 骨质减少，5例中有4例血清磷水平降低， 碱性磷酸酶升高。 骨质减少持续进展， 血清磷仍然很低。 经过14个月的治疗， mg/kg/天的药代动力学评价显示， 治疗组的Cmax是正常值的1.8倍，AUC是正常值的2.1倍， 正常，t1/2为正常的1.7倍，清除率为51 正常 在448至469天后，3只猴子停止治疗。 天 血清磷水平迅速向正常水平上升， 从停药后13-21天开始。 一只猴子一直保持着很高的 整个治疗期间血浆病毒RNA水平和仅RNA水平 增加0.6 log，从6.4 x 104至2.6 x 105拷贝/ml，从63开始 停止后的几天。 但CD 4+细胞百分比下降， 从治疗后91天开始，从19%逐渐增加到6%， 停止. 另一只猴子表现出明显的渐进性增加， 停药后42天开始血浆病毒RNA， 的CD 4+细胞从36%下降到15%， 停止 在PBMC中检测不到的前病毒DNA， 112天后仍能检测到。 第三只猴子只表现出 血浆病毒RNA的小幅短暂增加56天后， 停止，沿着CD 4+细胞轻微一过性降低。 一系列放射学检查表明，骨密度开始下降， 增加至

We examined the long-term effects of treatment of rhesus monkeys with 30 mg/kg/day (R)-9-(2-phosphonylmethoxypropyl) adenine (PMPA) administered by subcutaneous injection beginning 14 days after intravenous infection with SIV. A very strong antiviral effect was observed in 3 of 5 monkeys. After only 7 days of treatment the virus burden in plasma had decreased an average of 3.4 logs, from a mean of 7 x 106 to 2 x 103 SIV RNA copies per ml, corresponding to a decrease of 99.8%. After 28 days of treatment, the levels of plasma RNA had decreased further below the quantifiable range (<1 x 103) and remained low or undetectable for the duration of treatment. A much weaker antiviral effect was observed in 2 other monkeys which after 7 days of treatment had decreases of only 1.2 logs, from a mean of 1.6 x 107 to 1 x 106 RNA copies per ml, corresponding to a decrease of 93.7%. After 28 days of treatment, these 2 monkeys had decreases of 2.1 logs to a mean of 1.6 x 105 copies per ml and values ranged from 1.6 x 104 to 1 x 106 (average = 3.03 x 105) for the duration of treatment. After 330 days of treatment all 5 monkeys had varying degrees of osteopenia and 4 of 5 had decreased levels of serum phophorus and increased alkaline phosphatase. Osteopenia continued to progress and serum phosphorus remained low. After 14 months of treatment with 30 mg/kg/day pharmacokinetic evaluation revealed that in the long-term treated group the Cmax was 1.8 times normal, the AUC was 2.1 times normal, the t1/2 was 1.7 times normal, and the clearance rate was 51% of normal. Treatment was stopped in 3 of the monkeys after 448 to 469 days. Serum phosphorus levels increased rapidly toward normal levels, beginning 13-21 days after cessation. One monkey had maintained high levels of plasma viral RNA throughout treatment and the RNA level only increased 0.6 log, from 6.4 x 104 to 2.6 x 105 copies/ml, beginning 63 days after cessation. However, the percentage of CD4+ cells decreased progressively from 19% to 6% beginning 91 days after treatment was stopped. Another monkey showed a marked progressive increase in plasma viral RNA beginning 42 days after cessation, and the percentage of CD4+ cells plunged from 36% to 15% beginning 84 days after cessation. Proviral DNA, which had been undetectable in PBMC, became consistently detectable after 112 days. The third monkey showed only a small transient increase in plasma viral RNA 56 days after cessation, along with a slight transient decrease in CD4+ cells. Serial radiologic examinations indicated that bone density began to increase towards