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

Area of Science:

• Virology
• Pharmacology
• Infectious Diseases

Background:

• Antiretroviral therapy (ART) for HIV-1 requires lifelong adherence for viral suppression.
• Poor adherence and drug resistance are major barriers to effective HIV-1 treatment.
• Regimens with greater forgiveness for missed doses are needed to improve patient outcomes.

Purpose of the Study:

• To evaluate the in vitro impact of short-term nonadherence on viral breakthrough (VB) and resistance development.
• To compare the forgiveness of two common HIV-1 ART regimens: bictegravir/emtricitabine/tenofovir alafenamide (BIC+FTC+TAF) and dolutegravir/lamivudine (DTG+3TC).

Main Methods:

• Simulated short-term nonadherence by exposing HIV-1 infected MT-2 cells to ART drug concentrations representing 1 to 3 missed doses.
• Monitored viral breakthrough and resistance emergence using deep sequencing of rebound virus.
• Used human plasma-free adjusted clinical trough concentrations (Cmin) and drug half-lives to model adherence scenarios.

Main Results:

• BIC+FTC+TAF prevented viral breakthrough at simulated Cmin, Cmin-1, and Cmin-2 concentrations, with breakthrough only occurring at Cmin-3 in some cases.
• DTG+3TC showed minimal breakthrough at Cmin but increased significantly with lower drug concentrations, leading to resistance emergence.
• The M184V HIV-1 variant emerged in one culture treated with BIC+FTC+TAF at Cmin-3, while DTG+3TC showed resistance development to both drugs.

Conclusions:

• The in vitro data suggest BIC+FTC+TAF provides robust protection against viral rebound and resistance following short-term adherence lapses.
• The high potency, long half-lives, and synergistic action of BIC+FTC+TAF contribute to its enhanced forgiveness.
• These findings highlight the potential clinical benefit of BIC+FTC+TAF in patients with adherence challenges.