Mulato A, Acosta R, Chang S, et al. - Following are identified as barriers to lifelong HIV-1 suppression by antiretrovirals: poor adherence and drug resistance. Regimens with higher tolerance to missed doses (forgiveness) are suggested to be beneficial to patients. In vitro experiments monitoring viral breakthrough (VB) and resistance development were performed to model short-term nonadherence. Drug exposures at full adherence or suboptimal adherence to bictegravir+emtricitabine+tenofovir alafenamide (BIC+FTC+TAF) or dolutegravir + lamivudine (DTG+3TC) are simulated in HIV breakthrough experiments. Infection with wild-type or low frequency M184V HIV-1 was induced in MT-2 cells, followed by their exposure to drug combinations, monitoring for VB, and deep sequencing of rebound virus. Per in vitro VB results, the BIC/FTC/TAF triple therapy regimen is linked with high potency, long half-lives, and antiviral synergy that may protect from viral rebound and resistance development after short-term lapses in drug adherence.