Potentiation of inhibition of wild-type and mutant human immunodeficiency virus type 1 reverse transcriptases by combinations of nonnucleoside inhibitors and D- and L-(beta)-dideoxynucleoside triphosphate analogs

Combinations of reverse transcriptase (RT) inhibitors are currently used in anti-human immunodeficiency virus therapy in order to prevent or delay the emergence of resistant virus and to improve the efficacy against viral enz ymes carrying resistance mutations. Drug-drug interactions can result in ei ther positive (additive or synergistic inhibition) or adverse (antagonistic interaction, synergistic toxicity) effects. Elucidation of the nature of d rug interaction would help to rationalize the choice of antiretroviral agen ts to be used in combination. In this study, different combinations of nucl eoside and nonnucleoside inhibitors, including D- and L-(beta)-deoxy- and - dideoxynucleoside triphosphate analogues, have been tested in in vitro RT a ssays against either recombinant wild-type RT or RT bearing clinically rele vant nonnucleoside inhibitor resistance mutations (L1001, K103N, Y1811), an d the nature of the interaction (either synergistic or antagonistic) of the se associations was evaluated, The results showed that (i) synergy of a com bination was not always equally influenced by the individual agents utilize d, (ii) a synergistic combination could improve the sensitivity profile of a drug-resistant mutant enzyme to the single agents utilized, (iii) L-(beta )-enantiomers of nucleoside RT inhibitors were synergistic when combined wi th nonnucleoside RT inhibitors, and (iv) inter- and intracombination compar isons of the relative potencies of each drug could be used to highlight the different contributions of each drug to the observed synergy.