Drug Combinations and Effect Parameters of Zidovudine, Stavudine, and Nevirapine in Standardized Drug-Sensitive and Resistant HIV Type 1 Strains*

Publisher Website
Google Scholar
Abstract
Reference strains of HIV-1 from the NIH AIDS Research and Reference Reagent Program, including wild-type HIB, 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. The median-effect principle and combination index (CI) method of Chou-Talalay (see Ref. 26) have been used, which take into account both the potency (Dm value or EC50) and the shape of the dose–effect curve (m value). Under standardized assay conditions, G910-11 and G691-2 strains showed 600- and 7800-fold resistance to AZT, and N119 and A17 strains showed 3600- and 1000-fold resistance to NEV at the EC50 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, respectively) whereas drug-resistant strains showed negative sigmoidicity toward the corresponding AZT or NEV, with m = 0.27–0.73. Therefore, the degrees of drug resistance are drastically different at classic EC50 and at therapeutically more relevant EC95 levels (ranging from severalfold to several log orders). Combinations of AZT + NEV and AZT + NEV + D4T showed synergism against IIIB, G762-3 (wild type) and A17/NEV, G910-11/AZT strains. D4T + NEV and AZT + D4T showed nearly additive or moderate antagonism. Synergism or additive effect leads to a favorable dose-reduction index (DRI). The present study on RT inhibitors provides quantitative assessment of the combinations of AZT, NEV, and D4T against HIV infections involving drug-sensitive and drug-resistant HIVs.