Why Did the Once-Daily Nucleoside Reverse Transcriptase Inhibitor-Only Combination Regimens Fail?
Much attention has been focused on the possible causes of the unacceptably high early virologic failure rates in the once-daily NRTI-only combination regimens described previously. Major possibilities have included unexpected pharmacokinetic drug interactions, an unexpected adverse pharmacodynamic interaction (ie, antagonism), inadequate concentrations of the drugs involved throughout the 24-hour dosing interval, and a low genetic barrier to resistance combined with inadequate drug concentrations. Pharmacokinetic drug interactions are unlikely to explain these early treatment failures. Studies of interactions between tenofovir and abacavir107 and tenofovir and lamivudine42 show no significant pharmacokinetic interactions involving altered plasma concentrations of the parent drug. Although a systemic interaction exists between tenofovir and didanosine, resulting in an approximately 44% mean increase in the didanosine AUC when the 2 drugs are coadministered, this interaction does not exp
