High level of virologic failure was observed in HIV patients receiving combinations of tenofovir (TFV), lamivudine (3TC) combined with either abacavir (ABC) or didanosine (ddI). To investigate the pharmacologic mechanisms involve with the virologic failures, a comprehensive study was undertaken to evaluate the intracellular concentration of the active moiety (ddNTP) of these respective nucleoside analogs.; Triple nucleoside combinations were tested at physiological concentrations revealed reductions of 5 to 33% of the respective ddNTP. In vitro studies evaluating TFV and ABC in a concentration dependent manner showed a reduction of 40% and 30% in intracellular CBV-TP and TFV-DP. Similar findings were demonstrated with TFV and ddI, where 40% and 25% reduction in ddATP and TFV-DP, respectively, was detected. The level of dATP and dGTP, endogenous nucleotides, were increased by 2.4- and 2.7-fold, respectively, when cells were treated with 20 µM TFV, which can dilute the effect of ddNTP.; The expression of MRP2 and MRP4 were increased in cells serially passaged in either ABC or TFV, which correlated with cellular viability in the presence of high concentrations of nucleosides. Moreover, these cells had significantly lower level of ddNTP accumulation as compared to the wild type counterparts.; A clinical study was undertaken to evaluate whether the in vitro findings were also observed in humans. The combination of ABC and TDF resulted in a 2-fold increase in intracellular TFV-DP in patients receiving the combination of ABC and TFV as compared to TDF alone. Increases in TFV-DP may be attributed to higher plasma level of TFV, which was detected in the second phase of this study. A 4-fold increase in CBV-TP was detected three of nine patients, while the other six (6/9) had a 41% reduction. The degree of CBV-TP reduction is consistent with what is seen in vitro.; These findings suggest that cellular adaptive are critical in reducing intracellular levels of nucleoside analogs and their corresponding ddNTP, which may increase risk of virologic failures. The underlying pharmacological mechanisms may include but are not limited to, the competitive inhibition of anabolic enzymes, increase expression of efflux transporters and increase dATP and dGTP, where the resultant effect is reduced antiviral activity. Advisors/Committee Members: Burckart, Gilbert J. (Committee Chair), Louie, Stan (Committee Member), Shen, Wei-Chiang (Committee Member), D'Argenio, David (Committee Member), Wang, Clay C. C. (Committee Member).