Lalezari Jacob P, DeJesus Edwin, Northfelt Donald W, Richmond Gary, Wolfe Peter, Haubrich Richard, Henry David, Powderly William, Becker Stephen, Thompson Melanie, Valentine Fred, Wright David, Carlson Margrit, Riddler Sharon, Haas Frances F, DeMasi Ralph, Sista Prokash R, Salgo Miklos, Delehanty John
Quest Clinical Research and Mount Zion Hospital/UCSF, San Francisco, Calif., USA.
Antivir Ther. 2003 Aug;8(4):279-87.
Enfuvirtide is a novel antiretroviral that blocks HIV-1 cell fusion and viral entry. This Phase II, controlled, open-label, randomized, multicentre dose-ranging trial explored the safety, antiviral activity and pharmacokinetics of enfuvirtide, administered by subcutaneous (s.c.) injection, in 71 HIV-1-infected, protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive adults for 48 weeks. Study participants were randomized to receive enfuvirtide at a deliverable dose of 45, 67.5 or 90 mg twice daily; the 45 mg twice daily dose required 2 injections/day, while the higher doses required 4 injections/day. A background oral antiretroviral (ARV) regimen of abacavir (300 mg twice daily), amprenavir (1200 mg twice daily), ritonavir (200 mg twice daily) and efavirenz (600 mg once daily) was provided with enfuvirtide. A control group received the background ARV regimen alone. All potential participants underwent an HIV genotype at screen to ensure a homogenous population and to exclude patients with evidence of genotypic resistance to NNRTIs. Overall, the tolerability of the combination of abacavir, amprenavir, ritonavir, efavirenz and enfuvirtide was generally comparable to control through 48 weeks. No enfuvirtide dose-dependent adverse events (AEs) were observed across treatment groups. Injection site reactions (ISRs) occurred at least once in 68.5% of the enfuvirtide-treated population, and most ISRs were mild to moderate in severity, with no apparent dose relationship. Excluding ISRs, the most common treatment-emergent AEs were nausea, diarrhoea, dizziness and fatigue; with no clinically significant differences in the incidence of AEs observed between the control and enfuvirtide groups. Each treatment group benefited from ARV therapy, with a trend of increasing antiviral and immunological activity associated with increasing enfuvirtide dose. At 48 weeks, the median HIV-1 RNA change from baseline for the ITT population was -2.24 log10 copies/ml for the combined enfuvirtide groups compared with -1.87 log10 copies/ml for the control group. In addition, 54.9% of patients in the enfuvirtide group achieved HIV-1 RNA < or = 400 copies/ml versus 36.8% of patients in the control group. These results indicate that enfuvirtide has a favourable safety profile and is a promising new antiviral agent for HIV-infected patients who have been on previously failing ARV regimens.
恩夫韦肽是一种新型抗逆转录病毒药物，可阻断HIV-1细胞融合及病毒进入。这项II期、对照、开放标签、随机、多中心剂量范围试验，对71名感染HIV-1、有蛋白酶抑制剂治疗史且未使用过非核苷类逆转录酶抑制剂（NNRTI）的成人，皮下注射恩夫韦肽48周，探讨其安全性、抗病毒活性及药代动力学。研究参与者被随机分配，接受每日两次、可给药剂量为45、67.5或90毫克的恩夫韦肽；每日两次45毫克的剂量每天需注射2次，而较高剂量则每天需注射4次。恩夫韦肽与阿巴卡韦（每日两次300毫克）、安普那韦（每日两次1200毫克）、利托那韦（每日两次200毫克）和依非韦伦（每日一次600毫克）的背景口服抗逆转录病毒（ARV）方案联合使用。对照组仅接受背景ARV方案。所有潜在参与者在筛查时均进行HIV基因型检测，以确保人群同质，并排除有NNRTI基因型耐药证据的患者。总体而言，阿巴卡韦、安普那韦、利托那韦、依非韦伦和恩夫韦肽联合使用的耐受性在48周内总体上与对照组相当。各治疗组均未观察到恩夫韦肽剂量依赖性不良事件（AE）。68.5%接受恩夫韦肽治疗的人群至少发生过一次注射部位反应（ISR），且大多数ISR严重程度为轻至中度，无明显剂量关系。排除ISR后，最常见的治疗中出现的AE为恶心、腹泻、头晕和疲劳；对照组和恩夫韦肽组之间观察到的AE发生率无临床显著差异。各治疗组均从ARV治疗中获益，抗病毒和免疫活性有随恩夫韦肽剂量增加而增加的趋势。在48周时，ITT人群中联合恩夫韦肽组的HIV-1 RNA相对于基线的变化中位数为-2.24 log10拷贝/毫升，而对照组为-1.87 log10拷贝/毫升。此外，恩夫韦肽组54.9%的患者HIV-1 RNA≤400拷贝/毫升，而对照组为36.8%。这些结果表明，恩夫韦肽具有良好的安全性，对于之前使用ARV方案治疗失败的HIV感染患者而言，是一种有前景的新型抗病毒药物。
