PHASE II SAFETY, PLASMA PHARMACOKINETICS & ANTIRETROVIRAL

T-20的安全性、血浆药代动力学和抗病毒活性在一项随机、多中心、开放标签的2期临床试验中进行了评估。T-20是一种由36个氨基酸组成的肽，通过抑制gp41介导的融合来阻断新发感染和细胞间病毒传播。78例血浆HIV RNA值为50 000拷贝/ml的患者在稳定或未接受ARV治疗的背景下被分为6组，T-20剂量为12.5至200 mg/天。T-20连续皮下输注或静脉注射28天。入组时，平均血浆HIV-RNA为5.0 log10拷贝/ml，平均CD4+计数为117个细胞/mm3。78例患者中有77例报告了抗逆转录病毒治疗（平均既往ARV次数=9），98%的患者经历了蛋白酶抑制剂治疗（平均既往PI次数=3）。在整个28天的治疗期间，T-20在所有剂量下都具有良好的耐受性。未观察到与治疗相关的3级或4级全身毒性。2例患者因AE退出手术。大多数患者在输注或注射部位出现硬化和红斑。连续输注和每日两次注射均可观察到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。各治疗组与基线的平均最大变化范围为-0.3至1.6 log10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是抑制gp41功能的一种安全有效的新型抗逆转录病毒药物的首个成员。进一步评估T-20联合治疗的长期安全性和持久性的研究正在进行中。

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.