A DOSE-RANGING STUDY TO EVALUATE THE SAFETY AND EFFICACY OF ABACAVIR ALONE OR IN COMBINATION WITH ZIDOVUDINE AND LAMIVUDINE IN ANTIRETROVIRAL TREATMENT NAIVE SUBJECTS

Objective: To compare antiretroviral efficacy, safety and tolerance of three dosing regimens of the novel nucleoside reverse transcriptase i nhibitor, abacavir (1592U89) over 23 weeks and its efficacy in open-la bel combination with zidovudine and lamivudine. Design: Sixty HIV-1-in fected antiretroviral therapy naive subjects (entry criteria; CD4+ cel l count greater than or equal to 100 cells/mm(3), plasma HIV-1 RNA gre ater than or equal to 30 000 copies/ml), randomized into 20 subjects p er cohort received 100, 300 or 600 mg abacavir twice daily. Subjects s uccessfully completing 24 weeks' randomized therapy could switch to op en label therapy abacavir, zidovudine, lamivudine at 300, 300 and 150 mg twice daily, respectively) for a further 24 weeks of study, as coul d subjects meeting one or more switch criteria. Methods: Subjects were assessed for antiretroviral activity by measuring changes in plasma H IV-1 RNA load and CD4+ cell counts. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses. Results : At week 4, subjects receiving 300 or 600 mg abacavir twice daily had greater reductions in plasma HIV-1 RNA (median changes -1.55 and -1.6 1 log(10) copies/ml, respectively); differences (P = 0.007 and P less than or equal to 0.001, respectively) than subjects receiving 100 mg a bacavir twice daily (median change, -0.63 log(10) copies/ml). Differen ces between the 300 and 600 mg twice daily groups were not clinically or statistically significant. At 24 weeks, analysis showed a median ch ange in plasma HIV-1 RNA of -0.70 and -1.30 log(10) copies/ml in the 3 00 and 600 mg twice daily groups, respectively. During the open label phase In which zidovudine/lamivudine was added to 300 mp abacavir twic e daily, a further median reduction in plasma HIV-1 RNA of 1.74 log(10 ) copies/ml was seen. At 48 weeks pooled data from all abacavir-treate d subjects showed a sustained reduction in plasma HIV-1 RNA of 2.8 log (10) copies/ml; 65% and 43% of subjects had less than or equal to 400 and less than or equal to 50 HIV-1 RNA copies/ml, respectively, and a further median increase of 111 CD4+ cells/mm(3) were seen. Abacavir wa s generally well tolerated with few clinically significant adverse eve nts. Two subjects (3.3%) developed hypersensitivity reactions to abaca vir. There were no differences between the groups with regard tu serio us adverse events. Conclusions: In terms of antiretroviral therapy nai ve subjects;, treatment with 300 or 600 mg abacavir twice daily was st atistically superior to a 100 mg twice daily dose at 4 weeks. Combinat ions therapy containing abacavir-zidovudine-lamivudine was a highly ef fective antiretroviral regimen, resulting in substantial reductions in plasma HIV-1 RNA which may be comparable to combinations containing p rotease inhibitors. Abacavir was generally tolerated. (C) 1998 Lippinc ott Williams & Wilkins