PHASE II SAFETY, PLASMA PHARMACOKINETICS & ANTIRETROVIRAL

在一项随机、多中心、开放标签的II期临床试验中评估了T-20的安全性、血浆药代动力学和抗病毒活性。T-20是一种36个氨基酸的肽，通过抑制gp 41介导的融合来阻断从头感染和细胞间病毒传播。 78名血浆HIV RNA值> 5，000拷贝/ml的患者在稳定或未接受ARV治疗的背景下被分配到6组，代表T-20剂量范围为12.5至200 mg/天。 T-20通过连续皮下输注或每日两次给药。皮下注射28天。 入组时，平均血浆HIV-RNA为5.0 log 10拷贝/ml，平均CD 4+计数为117个细胞/mm 3。 78例患者中有77例报告了抗逆转录病毒治疗经验（既往ARV的平均数量=9），98%的患者使用了蛋白酶抑制剂（既往PI的平均数量=3）。 在整个28天治疗期间，所有剂量的T-20均耐受良好。 未观察到治疗相关的3级或4级全身毒性。 2例患者因AE退出研究。 在大多数患者中观察到输注或注射部位的硬结和红斑。 通过连续输注和每日两次注射给药均观察到T-20的持续稳态血浆浓度（峰谷比<2）。 观察到血浆HIV RNA的剂量相关抑制。 各治疗组较基线的平均最大变化范围为-0.3至1.6 log 10拷贝/mL。 在基线病毒载量<100，000拷贝/mL的患者中，病毒载量抑制的幅度和持久性更大。 T-20代表了第一个安全有效的新型抗逆转录病毒药物，它能抑制gp 41的功能。 评估T-20联合治疗的长期安全性和持久性的进一步研究正在进行中。

The safety, plasma pharmacokinetics, and antiviral activity of T-20 were assessed in a randomized, multicenter, open-label phase 2 clinical trial. T-20 is a 36-amino acid peptide that blocks de novo infection and cell-to-cell virus transmission by inhibiting gp41-mediated fusion. 78 patients with plasma HIV RNA values >5,000 copies/ml on a background of either stable or no ARV therapy were assigned to 6 groups representing T-20 doses ranging from 12.5 to 200 mg/day. T-20 was given by continuous subcutaneous infusion or by b.i.d. subcutaneous injection for 28 days. At entry, mean plasma HIV-RNA was 5.0 log10 copies/ml and mean CD4+ count was 117 cells/mm3. 77 of 78 patients reported antiretroviral experience (mean number of prior ARV's=9) and 98% were protease inhibitor experienced (mean number of prior PI's=3). T-20 was well tolerated at all doses throughout the 28-day treatment period. No treatment-related Grade 3 or 4 systemic toxicities were observed. Two patients withdrew due to AE's. Induration and erythema at the site of infusion or injection were seen in most patients. Sustained steady-state plasma concentrations of T-20 (peak-to-trough ratio <2) were observed both for administration by continuous infusion and by twice-daily injection. A dose-related suppression of plasma HIV RNA was observed. The average maximum change from baseline ranged from -0.3 to 1.6 log10 copies/mL across the treatment groups. The magnitude and durability of viral load suppression was greated in patients with baseline viral load <100,000 copies/mL. T-20 represents the first member of a safe and potent new class of antiretroviral agents that inhibit the function of gp41. Further studies to assess the long-term safety and durability of T-20 in combination therapy are in progress.