Background
The high potency and genetic barrier of BIC/TAF/FTC (BETAF), and the long-half lives of their components could allow for longer than once-daily dosing (OD) with low risk of developing resistance mutations. We assessed the feasibility of reducing BETAF OD to 3 (3W), 2 (2W), or 1 (1W) doses per week.
Methods
Pilot randomized controlled trial (Clinicaltrials.gov NCT05602506). Consecutive PWH on BETAF OD ≥6 months with plasma HIV RNA (VL) <50 c/mL, CD4 cells >350/µL, no resistance mutations to BETAF drugs, and no active hepatitis B or C were randomized (n=10 per arm) to: OD, 3W (Mon-Wed-Fri), 2W (Tue-Fri), or 1W (Wed) with visits at baseline, 4, 12, 24, 36, and 48 weeks. Primary endpoints were VL <50 c/mL (Snapshot ITT-exposed population) at 12 and 48 weeks. Individuals with viral failure (confirmed VL ≥50 c/mL) underwent genotypic resistance testing and were switched to OD up to 48 weeks. We measured ultrasensitive VL; total, defective and intact HIV reservoir (IPDA); CD4 and CD8 cells; hsCRP and IL-6; and plasma and intracellular trough drug levels at baseline, 12, and 48 weeks. The stopping rule was >30% viral failure in any of the dose reduction arms.
Results
One person withdraw consent at baseline (OD). Two persons prematurely discontinued the study due to their own decision, both at 12 weeks (OD, and 1W). Three persons had confirmed VL >50 c/mL: 2 in 1W (both at 4 weeks, VL 780 and 29800 c/mL, no resistance mutations); and 1 in 3W (at 12 weeks, VL 60 c/mL, not amplified) but all returned to <50 c/mL on switching to OD as pre-scheduled. PWH with VL <50 c/mL (Snapshot ITT-exposed population) at 12 and 48 weeks were: OD, 9 (100%) and 8 (89%); 3W, 9 (90%) and 10 (100%); 2W, 10 (100%) and 10 (100%); 1W, 10 (100%) and 9 (90%). There were no significant differences in ultrasensitive VL, HIV reservoir, CD4 or CD8 cells, and hsCRP or IL-6 among arms. Although trough plasma and intracellular drug levels significantly decreased in 3W, 2W, and 1W relative to OD at 12 and 48 weeks, mean trough levels at 12 and 48 weeks in 3W and 2W, but not in 1W, were generally above the known inhibitory concentrations (Table).
Conclusions
In virally suppressed PWH on BETAF OD, the strategy of reducing the BETAF OD dose to 3W, 2W, or 1W for 48 weeks was safe, well tolerated, and effective as compared with continuing OD. Consistent with subtherapeutic drug levels, the risk of viral failure was higher with 1W than with 2W or 3W; there was no emergent resistance and viral control was regained upon switching to OD.
Table or Figure
