ACTG 320 was designed to compare the clinical efficacy and safety of the three-drug regimen of IDV in combination with either ZDV (or d4T) plus 3TC with the double nucleoside regimen of ADV (or d4T) plus 3TC in ADV experienced subjects with CD4 cell counts < 200/mm3. 1,156 subjects were randomized to this study over one year and were followed for a median period of 38 weeks. The loss to follow-up rate in this study was low (5%), and the overall premature treatment discontinuation rate was moderate (20%), and lower than that seen in other ACTG studies of similar subject populations. This study demonstrated the clear clinical superiority of IDV+ADV (or d4T)+3TC over ADV (or d4T)+3TC in the population studied. The overall rate of progression to AIDS or death was reduced from 11% to 6% by the three-drug combination reflecting a 50% reduction in hazard. This result was statistically significant (p=0.001) and led to the DSMB's recommendation that the study be terminated early. The rate of disease progression in the stratum defined by a CD4 cell count < 50/mm3 was also significantly reduced from 20% to 11% in the double vs. triple drug combination, respectively (p=0.005), with a concordant trend seen in the 50-200 CD4 cell/mm3 stratum. Although the latter did not reach statistical significance, most likely because of the low number of events recorded, the hazard ratios for the overall study and the two CD4 cell strata were very similar (0.50, 0.49 and 0.51, respectively), indicating a similar treatment effect across the study population. The ACTG 320 study results demonstrate that an indinavir-nucleoside analogue triple drug regimen confers clinical benefit compared to dual nucleoside analogue therapy in patients with advanced HIV disease. It should be noted that the clinical benefit of indinavir was seen when compared to a control arm in which patients were naive to at least one of the two nucleoside analog agents. Taken together with the results from the Abbott-sponsored 247 trial of ritonavir and the Hoffmann-LaRoche sponsored NV14256 trial of saquinavir, it is increasingly clear that more potent therapies, represented currently by protease inhibitor containing 3 drug regimens, are preferred in subjects with more advanced disease.
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