AIDS Clinical Trials Group protocol 194 is a placebo- controlled, randomized study to evaluate the short-term virologic effect of continuing ZDV, switching to ddI, or adding ddI in ZDV-resistant HIV-1 seropositive subjects with CD4 counts 100-300/microliter following greater than 1 yr prior ZDV therapy. The trial has accrued 81 subjects thus far; median pre-study duration of ZDV use was 2.6 yrs (25- 75% range 1.9-3.6 yrs). Median absolute baseline CD4 count was 187/microliter (136-241/microliter). To date, of 31 persons evaluated, 34% had a sensitive baseline ZDV phenotype (IC50 less than or equal to 0.1 micromolar) by the ACTG/DOD consensus assay, 34% were intermediate (0.1-1.0 micromolar), and 32% showed resistance (greater than or equal to 1.0 micromolar). For a subset (n= 23) of these patients, the occurrence of a mutation at pol codon 215 was associated with ZDV IC50 greater than or equal to 1.0 micromolar; genotypes were 35% wildtype, 30% mutant 215 codon, and 35% mixed. SI occurred in 11/20 of assayed baseline isolates, but did not appear more often with resistant isolates. IC50 showed no significant correlation with baseline viral load by quantitative HIV-RNA (n=23, bDNA assay) or p24 antigen (n=31). This ongoing trial shows high- level resistance at study entry for one-third of subjects who had received over 2 years of prior ZDV. ZDV susceptibility may not correlate with HIV-RNA, p24 antigen, or SI phenotype.

Drug Resistance, Microbial/*GENETICS HIV-1/*DRUG EFFECTS/ENZYMOLOGY/GENETICS Mutagenesis, Site-Directed Mutation RNA-Directed DNA Polymerase/GENETICS Zidovudine/*PHARMACOLOGY ABSTRACT

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