ACTG 347 was a phase II trial which compared the investigational protease inhibitor, 141W94/VX-478 alone with 141W94/VX-478 plus ZDV/3TC in patients who had >50 CD4 cells/mL, greater than 5,000 copies/mL HIV-1 RNA, and no prior treatment history with a protease inhibitor or 3TC. The rationale was based on in vitro data that suggested the plasma protein-adjusted through levels of 141W94/VX-478 would be up to 15 times the expected IC90 of most isolates. Additional clinical data suggested that monotherapy with this protease inhibitor was durable for at least 28 days. The primary objective of the study was to determine the proportion of patients who had reached and sustained an undetectable level, defined as less than 500 copies/mL, of plasma HIV-1 RNA up to week 24. The primary endpoint of the study was detectability (greater than 500 copies/mL) of plasma HIV-1 RNA on two consecutive occasions four weeks apart between 12-24 weeks of study therapy. The results of the plasma HIV-1 RNA concentrations were reported to the sites in real time. An interim review had been initially scheduled to occur after one half of the patients enrolled had received study medication for 12 weeks. However, it was noted early in the study that a few of the patients were experiencing rebounds in their plasma HIV-1 concentrations. Because of this the Team decided to create a category of virologic failure that could occur as early as week 8. On July 1, 1997, Version 3.0 was finalized and included the definition for virologic failure, """"""""a confirmed (two values 4 weeks apart) plasma HIV-1 RNA that meets any of the criteria: 1) at least one log10 above the nadir (minimum increase must be to greater than 5000 copies/mL) at any time; 2) greater than the baseline value at any time; and 3) greater than 500 copies/mL after 16 weeks of continuous treatment with the study regimen"""""""". The number of evaluable subjects in each arm are 37 for monotherapy and 39 for triple therapy. All nine of the subjects that have met the criteria for virologic failure had been assigned to the 141W94/VX-478 monotherapy arm. These correspond to the number of subjects for which RNA is available through week 4. The difference between the two groups is significant at the level p=0.0009 by Fisher's Exact Test. As of July 17, 1997, there were an additional 15 subjects with unconfirmed virologic failure (confirmation at 4 weeks has not yet been performed): 10 of these from the monotherapy arm, and 5 from the triple therapy arm. When the analysis was performed with the combined confirmed plus unconfirmed failures, the difference between the two groups including 19 of 37 in the monotherapy arm and 5 of 39 in the triple drug therapy arm, was significant at the level of p=0.0004 by Fisher's Exact Test. The study treatments were reasonably well tolerated. Three patients receiving monotherapy and four triple therapy experienced a severe laboratory abnormality, mainly elevations in hepatic transaminase levels. Three patients discontinued study medication because of a related adverse event.
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