Simulating HIV Breakthrough and Resistance Development During Variable Adherence to Antiretroviral Treatment

Background: Barriers to lifelong HIV-1 suppression by antiretrovirals include poor adherence and drug resistance; regimens with higher tolerance to missed doses (forgiveness) would be beneficial to patients. To model short-term nonadherence, in vitro experiments monitoring viral breakthrough (VB) and resistance development were conducted.

Methods: HIV breakthrough experiments simulated drug exposures at full adherence or suboptimal adherence to bictegravir+emtricitabine+tenofovir alafenamide (BIC+FTC+TAF) or dolutegravir + lamivudine (DTG+3TC). MT-2 cells were infected with wild-type or low frequency M184V HIV-1, exposed to drug combinations, monitored for VB, and rebound virus was deep sequenced. Drug concentrations were determined using human plasma-free adjusted clinical trough concentrations (Cmin), at simulated Cmin after missing 1 to 3 consecutive doses (Cmin - 1 or Cmin - 2, and Cmin - 3) based on drug or active metabolite half-lives.

Results: Cultures infected with wild-type or low frequency M184V HIV-1 showed no VB with BIC+FTC+TAF at drug concentrations corresponding to Cmin, Cmin - 1, or Cmin - 2 but breakthrough did occur in 26 of 36 cultures at Cmin - 3, where the M184V variant emerged in one culture. Experiments using DTG + 3TC prevented most breakthrough at Cmin concentrations (9/60 had breakthrough) but showed more breakthroughs as drug concentrations decreased (up to 36/36) and variants associated with resistance to both drugs emerged in some cases.

Conclusions: These in vitro VB results suggest that the high potency, long half-lives, and antiviral synergy provided by the BIC/FTC/TAF triple therapy regimen may protect from viral rebound and resistance development after short-term lapses in drug adherence.