1448 - Forgiveness of BIC/FTC/TAF: In Vitro Simulations of Intermittent Poor Adherence Find Limited HIV-1 Breakthrough and High Barrier to Resistance

Background: Short lapses in adherence to ARVs can lead to virologic failure and emergence of resistance. Previous in vitro studies of regimen “forgiveness” simulated drug exposures of perfect adherence or short-term suboptimal adherence with bictegravir+emtricitabine+tenofovir alafenamide (BIC+FTC+TAF) and with dolutegravir and lamivudine (DTG+3TC). Here, viral breakthrough (VB) and resistance development were evaluated under alternating high and low drug exposures simulating variable adherence levels.

Methods: Wild-type HIV-1 (IIIb)-infected MT-2 cells were exposed to drug combinations and monitored for VB. Experiments alternated between high and low drug concentrations of either BIC+FTC+TAF or DTG+3TC (Table 1). Drug concentrations for each regimen were determined using human plasma-free adjusted clinical trough concentrations (C_min), at simulated C_min after missing 2 or 4 consecutive doses (C_min-2 and C_min-4) based on drug half-lives. Emergent HIV-1 were genotyped by deep sequencing and a 2% threshold.

Results: In these experiments, constant drug concentrations corresponding to full adherence (C_min) did not lead to VB. Using C_min concentrations for one week followed by constant C_min-2 exposures for 4 weeks, DTG+3TC had VB and emergence of M184V/I in reverse transcriptase (RT) but there was no VB for BIC+FTC+TAF. Using alternating drug exposures of C_min (weeks 1 and 3) and C_min-2 or C_min -4 (weeks 2, 4, and 5), VB was not observed with BIC+FTC+TAF, and VB was decreased or delayed with DTG+3TC compared to DTG+3TC held at C_min-2 or C_min-4. Resistance development was observed in some cultures with VB: 1 culture with BIC+FTC+TAF had G163R in IN and 19 cultures with DTG+3TC had INSTI and RT resistance including 10 with M184V/I.Table 1. Summary of Breakthrough Frequency and Resistance Development


Conclusion: BIC+FTC+TAF has high in vitro forgiveness and consistent protection against emergence of drug resistance during simulations of short lapses in adherence. Higher DTG+3TC exposure, whether constant or intermittent, was better at preventing or delaying VB than lower DTG+3TC exposures, but DTG+3TC was less forgiving than BIC+FTC+TAF. Prevention of viral replication and resistance development is necessary to maintain lifelong viral suppression, particularly in the real world where drug adherence is often imperfect.