A dose-ranging study to evaluate the antiretroviral activity and safety ofamprenavir alone and in combination with abacavir in HIV-infected adults with limited antiretroviral experience

Objective: To evaluate the antiretroviral activity and safety of multiple e scalating doses of amprenavir administered alone, and in combination with a bacavir in HIV-1-infected adults. Design: Sixty-two HIV-1-infected subjects were enrolled in a multicentre, o pen-label, non-randomized, dose-escalating trial. Methods: Subjects were assigned to one of six dose groups and received ampr enavir 300 mg twice daily, 300 mg three times daily, 900, 1050, or 1200 mg twice daily for 4 weeks. One dose group received amprenavir 900 mg twice da ily in combination with abacavir 300 mg twice daily for 4 weeks. Antiretrov iral activity was assessed by measuring changes from baseline in plasma HIV -1 RNA levels and CD4 cell counts. Safety was evaluated by monitoring clini cal adverse events and changes in laboratory values. Genotypic and phenotyp ic analyses were performed using ABI sequencing and the recombinant virus a ssay, respectively. Results: At week 4, amprenavir monotherapy (900, 1050, or 1200 mg twice dai ly) resulted in marked decreases in plasma HIV-1 RNA levels (1.3-1.6 log(10 ) copies/ml), and substantial increases in CD4 cell counts in the two dose groups who received 1050 mg twice daily (118x10(6) cells/mm(3)) or 1200 mg twice daily (114x10(6) cells/mm(3)). Amprenavir/abacavir resulted in median plasma HIV-1 RNA reductions of 1.8 log(10) copies/ml, and median CD4 cell count increases of 138x10(6) cells/mm(3). Amprenavir was reasonably well to lerated with few treatment-limiting adverse events. No known active site mu tations associated with amprenavir resistance were selected in any of the d ose groups, and no significant phenotypic resistance to amprenavir develope d during 4 weeks of therapy. Conclusions: The antiviral effect of amprenavir monotherapy increased with escalating doses, and all amprenavir doses were reasonably well tolerated o ver 4 weeks of therapy. Amprenavir/abacavir combination therapy elicited a potent antiviral effect. The three highest doses of amprenavir (900, 1050 a nd 1200 mg twice daily) were selected to design subsequent Phase II and III studies that confirmed the safety profile and efficacy of amprenavir in co mbination regimens and led to the approval of amprenavir in the USA in 1999 .