PHARMACOKINETICS AND ANTIVIRAL EFFECT OF T 20 ADMINISTERED TO HIV 1 ADULTS

据报道，目前批准的所有抗逆转录病毒药物都有耐药性，而且独特的毒性限制了它们的临床效果，这表明有必要开发新的、安全的和机械上不同的抗病毒药物来治疗艾滋病毒。研究试剂T-20是一个由36个氨基酸组成的合成肽。T-20是由自然产生的1-氨基酸残基组成的线性分子。T-20的主要序列来源于HIV-1 gp41跨膜糖蛋白中的一个天然基序(氨基酸残基643-678)。非临床作用机制研究结果表明，T-20通过与调节病毒与宿主细胞膜融合的gp41关键区域的结合，显示出对新生感染和细胞间病毒传播的有效和选择性的抑制。在啮齿动物和灵长类动物身上进行的非临床安全性研究表明，连续28天每天两次静脉注射T-20与任何临床或实验室毒性标志无关。这项试验将研究T-20的安全性、药代动力学和抗病毒活性。T-20通过连续皮下注射给HIV-1阳性的成年人，这些成年人的HIV-RNA水平超过5,000拷贝/毫升，并接受了包含2种核苷逆转录酶抑制剂和吲地那韦的3种药物抗病毒方案的治疗。在这项研究中，患者将随机接受连续皮下注射(CSI)的四种剂量水平的T-20或间歇皮下注射10天的一种剂量水平的治疗，然后他/她将通过CSI与奈韦拉平、奈非那韦和沙奎那韦一起接受T-20治疗约24周。

Teh observation that resistance has been reported for all of the currently approved antiretroviral HIV agents together with unique toxicities that limit their clinical effectivenss establishes a need for development of new, safe and mechanistically distinct antiviral agents for the treatment of HIV. The investigational agent, T-20 , is a 36-amino acid synthetic peptide. T-20 is a linear moecule composed of naturally occurring 1-amino acid residues. The pirmary sequence of T-20 was derived from a naturally occurring motif (amino acid residues 643-678) within gp41 transmembrane glycoprotein of HIV-1. The results of nonclinical mechanism of action studies indicate that T-20 exhibits potent and selective inhibition of de novo infection and cell to cell virus transmission by binding to a critical region of gp41 which regulates the fusion of virus to host cell membranes. Nonclinical safety studies conducted in rodents and primates indicate that the intravenous administration of T-20 twice daily for 28 consecutive days is not associated with any markers of either clinical or laboratory toxicity. This trial will be studying the safety, pharmacokinetics, and antiviral activity of T-20 given by continuous subcutaneous injection to HIV-1 positive adults with HIV-RNA levels greater than 5,000 copies/ml and who have been treated with a 3-drug antiviral regimen containing 2 nucleoside reverse transcriptase inhibitors and indinavir. During this study, the patient will be randomized to receive treatment with one of four dose levels of T-20 alone by continuous subcutaneous infusion (CSI) or one dose level by intermittent subcutaneous injection ten days and then he/she will receive T-20 by CSI along with nevirapine, nelfinavir, and saquinavir for approximately 24 weeks.