DRUG-COMBINATIONS AND EFFECT PARAMETERS OF ZIDOVUDINE, STAVUDINE, ANDNEVIRAPINE IN STANDARDIZED DRUG-SENSITIVE AND RESISTANT HIV TYPE-1 STRAINS

Reference strains of HIV-1 from the NIH AIDS Research and Reference Re agent Program, including wildtype IIIB, G762-3, and AZT resistant with RT 215T --> Y (G910-11/AZT); 67D --> N, 70K --> R, 215T --> F, 219K - -> Q (G691-2/AZT); as well as nevirapine (NEV) resistant with 181Y --> C (N119/NEV); and 103K --> N, 181Y --> C (A17/NEV), were subjected to quantitative parametric efficacy analysis using AZT, stavudine (D4T), and nevirapine (NEV) singly or in combinations in MT4 or MT2 cells. T he median-effect principle and combination index (CI) method of Chou-T alalay (see Ref. 26) have been used, which take into account both the potency (D-m value or EC(50)) and the shape of the dose-effect curve ( m value). Under standardized assay conditions, G910-11 and G691-2 stra ins showed 600- and 7800-fold resistance to AZT, and N119 and A17 stra ins showed 3600- and 1000-fold resistance to NEV at the EC(50) level, respectively. AZT-resistant strains exhibited slight cross-resistance to D4T. Computerized analysis indicates that IIIB gave sigmoidal dose- effect curves (m = 2.8, 3.4, and 3.1 for AZT, D4T, and NEV, respective ly) whereas drug-resistant strains showed negative sigmoidicity toward the corresponding AZT or NEV, with m = 0.27-0.73. Therefore, the degr ees of drug resistance are drastically different at classic EC(50) and at therapeutically more relevant EC(95) levels (ranging from severalf old to several log orders). Combinations of AZT + NEV and AZT + NEV D4T showed synergism against IIIB, G762-3 (wild type) and A17/NEV, G91 0-11/AZT strains. D4T + NEV and AZT + D4T showed nearly additive or mo derate antagonism. Synergism or additive effect leads to a favorable d ose-reduction index (DRI). The present study on RT inhibitors provides quantitative assessment of the combinations of AZT, NEV, and D4T agai nst HIV infections involving drug-sensitive and drug-resistant HIVs.