Perspectives on the Barrier to Resistance for Dolutegravir + Lamivudine, a Two-Drug Antiretroviral Therapy for HIV-1 Infection

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.

Transmitted drug resistance among HIV-1 drug-naïve patients in Greece

“…The efficacy and tolerability of DTG/3TC was comparable to the guideline-recommended three-drug regimen of DTG plus tenofovir disoproxil fumarate and FTC. Thus, DTG/3TC holds much promise to be used as initial therapy for HIV ART-naïve patients, also taking into account the high genetic barrier to resistance of DTG when used in a two-drug regimen with 3TC (Chan and Ly, 2019;Fida et al, 2019;Scott, 2020;Boffito et al, 2020). Other NRTI-associated mutations detected in the present study included the T215 revertant mutations and M41L, which are selected by thymidine analogs, a class of drugs no longer used in current therapeutic regimens (Mazzuti et al, 2020).…”

HIV-1 elite controllers present a high frequency of activated regulatory T and Th17 cells

“…Activation levels were lower among cART-treated patients than VCs, pointing to the undeniable positive effect of cART. In the last decades, drugs with higher genetic barriers and new regimens have been developed [69], bypassing drug resistance issues, improving the survival and quality of life of infected individuals [70][71][72] and decreasing transmission rates [73,74], which supports the expansion of cART coverage and early initiation. In this context, antiretroviral therapy could improve immunological health in viremic controllers, lowering activation levels as observed in cART individuals.…”

Virologic outcomes of switching to dolutegravir functional mono- or dual therapy with a non-cytosine nucleoside analog: a retrospective study of treatment-experienced, patients living with HIV

“…This suggests that DTG monotherapy and certain 2-drug DCRs may be ‘less forgiving’ regarding the risk of resistance development in the setting of VF. This has important implications in real-world settings where a multitude of factors including patient characteristics, disease characteristics and other social and clinical barriers may contribute to higher rates of VF than is observed in randomized clinical trials [ 8 ]. Given the increased use of DCRs globally with several low- and middle-income countries (LMICs) switching to the use of DTG-based therapy as first-and-second line regimens in response to increasing non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance [ 9 – 12 ], real-world studies to evaluate non-traditional combinations of DTG with other antiretroviral (ARV) drugs would be useful to provide further information about the efficacy and barrier to resistance of this second-generation integrase strand transfer inhibitor (INSTI).…”