The effect of polyvalent cations on bictegravir exposures administered under various dosing conditions (i.e. fasted vs. fed and simultaneous vs. staggered administration) was evaluated in healthy volunteers (n=14/cohort). Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF; 50/200/25 mg) was administered simultaneously under fasted or fed conditions, with/without maximum strength antacid (aluminium hydroxide 1600 mg, magnesium hydroxide 1600 mg, simethicone 160 mg), calcium carbonate (1200 mg) or ferrous fumarate (324 mg). Additionally, the effect of staggering B/F/TAF ± 2 hours from maximum strength antacid under fasted conditions was evaluated. B/F/TAF co-administered simultaneously with certain cations (antacid, ferrous fumarate) under fasted conditions substantially reduced bictegravir exposures by 63-79%. Under fed conditions, bictegravir exposures were reduced modestly (47%) with antacid and were unaffected by ferrous fumarate or calcium carbonate supplements. When B/F/TAF was administered in the fasted state 2 hours after antacid, mean bictegravir exposures were reduced by 52% but remain projected to be substantially above the protein adjusted IC95 (IQ = 7.7) and above the lower IQ values associated with efficacy in the B/F/TAF registrational trials (lowest observed IQ = 4.7). Bictegravir exposures were not affected by B/F/TAF fasted administration 2 hours before antacid. The high IQ values and associated efficacy of bictegravir& in the B/F/TAF registrational trials supports its flexible use in patients using polyvalent cation containing antacids/supplements through co-administration either simultaneously fed or fasted when staggered ± 2 hours.