Abstract
In HIV-1-infected patients, virological failure can occur as a consequence of the mutations that accumulate in the viral genome that allow replication to continue in the presence of antiretrovirals (ARVs). The development of treatment-emergent resistance to an ARV can limit a patient's options for future therapy, prompting the need for ARV regimens that are resilient to the emergence of resistance. The genetic barrier to resistance refers to the number of mutations in an ARV's therapeutic target that are required to confer a clinically meaningful loss of susceptibility to the drug. The emergence of resistance can be affected by pharmacological aspects of the ARV, including its structure, inhibitory quotient, therapeutic index, and pharmacokinetic characteristics. Dolutegravir (DTG) has demonstrated a high barrier to resistance, including when used in a two-drug regimen (2DR) with lamivudine (3TC). In the GEMINI-1 and GEMINI-2 studies, DTG +3TC was noninferior to DTG + emtricitabine/tenofovir disoproxil fumarate in treatment-naive participants, with similar proportions achieving HIV-1 RNA <50 copies/mL through 96 weeks. Furthermore, in the TANGO study, virological suppression was maintained at 48 weeks after switching to DTG +3TC from a tenofovir alafenamide (TAF)-based regimen compared with continuing a TAF-based regimen. Most other 2DRs with successful outcomes compared with three-drug regimens have been based on protease inhibitors (PIs); however, this class is associated with adverse metabolic effects and drug–drug interactions. In this review, we discuss the barrier to resistance in the context of a 2DR in which a boosted PI is replaced with DTG +3TC.
Highlights
Virological failure in HIV-1-infected patients can be associated with emergence of antiretroviral (ARV) drug resistance, narrowing options for future therapy.[1]
Several two-drug regimens (2DRs) have been compared with three-drug regimens (3DRs) in clinical studies, most of which examined regimens based on boosted protease inhibitors (PIs).[7,8,9]
PIs demonstrate a high barrier to resistance,[10,11,12] they are associated with metabolic adverse effects and substantial drug–drug interactions compared with other ARV classes.[13,14]
Summary
Virological failure in HIV-1-infected patients can be associated with emergence of antiretroviral (ARV) drug resistance, narrowing options for future therapy.[1]. Studies evaluating INSTI-based 2DRs include the NEAT001, PROGRESS, and SECOND-LINE studies, which all examined 2DRs composed of a ritonavir-boosted PI + RAL.[48,50,51] In each of these studies, the 2DR demonstrated noninferior efficacy compared with the 3DR; mutations associated with RAL resistance emerged in participants who developed virological failure while receiving the 2DR. DTG is a strong candidate for 2DRs based on phase III trials demonstrating its high barrier to resistance.[15,18,22,23,52] In the GEMINI-1 and GEMINI-2 studies, virological suppression with the 2DR DTG +3TC was noninferior to that of the 3DR DTG + TDF/FTC as first-line treatment.[15] Viral suppression (HIV-1 RNA
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