Schooley R T, Clumeck N, Haubrich R, Thompson M, Danner S A, van Der Ende M E, Sereni D, Antunes F, Blake D, Myers R E, Tisdale M, Millard J, Mustafa N, Nacci P
Division of Infectious Diseases, Health Sciences Center, University of Colorado, Denver, USA.
Antivir Ther. 2001 Jun;6(2):89-96.
To evaluate the antiretroviral activity and safety of multiple escalating doses of amprenavir administered alone, and in combination with abacavir in HIV-1-infected adults.
Sixty-two HIV-1-infected subjects were enrolled in a multicentre, open-label, non-randomized, dose-escalating trial.
Subjects were assigned to one of six dose groups and received amprenavir 300 mg twice daily, 300 mg three times daily, 900, 1050, or 1,200 mg twice daily for 4 weeks. One dose group received amprenavir 900 mg twice daily in combination with abacavir 300 mg twice daily for 4 weeks. Antiretroviral activity was assessed by measuring changes from baseline in plasma HIV-1 RNA levels and CD4 cell counts. Safety was evaluated by monitoring clinical adverse events and changes in laboratory values. Genotypic and phenotypic analyses were performed using ABI sequencing and the recombinant virus assay, respectively.
At week 4, amprenavir monotherapy (900, 1,050, or 1,200 mg twice daily) resulted in marked decreases in plasma HIV-1 RNA levels (1.3-1.6 log10 copies/ml), and substantial increases in CD4 cell counts in the two dose groups who received 1,050 mg twice daily (118 x 10(6) cells/mm3) or 1,200 mg twice daily (114 x 10(6) cells/mm3). Amprenavir/abacavir resulted in median plasma HIV-1 RNA reductions of 1.8 log10 copies/ml, and median CD4 cell count increases of 138 x 10(6) cells/mm3. Amprenavir was reasonably well tolerated with few treatment-limiting adverse events. No known active site mutations associated with amprenavir resistance were selected in any of the dose groups, and no significant phenotypic resistance to amprenavir developed during 4 weeks of therapy.
The antiviral effect of amprenavir monotherapy increased with escalating doses, and all amprenavir doses were reasonably well tolerated over 4 weeks of therapy. Amprenavir/abacavir combination therapy elicited a potent antiviral effect. The three highest doses of amprenavir (900, 1,050 and 1,200 mg twice daily) were selected to design subsequent Phase II and III studies that confirmed the safety profile and efficacy of amprenavir in combination regimens and led to the approval of amprenavir in the USA in 1999.
评估单独使用多剂量递增的安普那韦以及安普那韦与阿巴卡韦联合使用对HIV-1感染成人的抗逆转录病毒活性和安全性。
62名HIV-1感染受试者参加了一项多中心、开放标签、非随机、剂量递增试验。
受试者被分配到六个剂量组之一，接受每日两次300毫克、每日三次300毫克、每日两次900、1050或1200毫克的安普那韦治疗，持续4周。一个剂量组接受每日两次900毫克安普那韦与每日两次300毫克阿巴卡韦联合治疗，持续4周。通过测量血浆HIV-1 RNA水平和CD4细胞计数相对于基线的变化来评估抗逆转录病毒活性。通过监测临床不良事件和实验室值变化来评估安全性。分别使用ABI测序和重组病毒试验进行基因型和表型分析。
在第4周时，安普那韦单药治疗（每日两次900、1050或1200毫克）导致血浆HIV-1 RNA水平显著下降（1.3 - 1.6 log10拷贝/毫升），并且在接受每日两次1050毫克（118×10⁶细胞/立方毫米）或每日两次1200毫克（114×10⁶细胞/立方毫米）的两个剂量组中，CD4细胞计数大幅增加。安普那韦/阿巴卡韦使血浆HIV-1 RNA中位数降低1.8 log10拷贝/毫升，CD4细胞计数中位数增加138×10⁶细胞/立方毫米。安普那韦耐受性良好，几乎没有限制治疗的不良事件。在任何剂量组中均未检测到与安普那韦耐药相关的已知活性位点突变，并且在治疗4周期间未出现对安普那韦的显著表型耐药。
安普那韦单药治疗的抗病毒效果随剂量增加而增强，并且在4周治疗期间所有安普那韦剂量耐受性良好。安普那韦/阿巴卡韦联合治疗产生了强大的抗病毒效果。选择安普那韦的三个最高剂量（每日两次900、1050和1200毫克）来设计后续的II期和III期研究，这些研究证实了安普那韦在联合治疗方案中的安全性和疗效，并导致安普那韦于1999年在美国获批。
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