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

Authors
  • Boffito, Marta1
  • Waters, Laura2
  • Cahn, Pedro3
  • Paredes, Roger4
  • Koteff, Justin5
  • Van Wyk, Jean6
  • Vincent, Tia6
  • Demarest, James5
  • Adkison, Kimberly6
  • Quercia, Romina6
  • 1 Chelsea and Westminister Hospital, London, United Kingdom. , (United Kingdom)
  • 2 Mortimer Market Centre, London, United Kingdom. , (United Kingdom)
  • 3 Fundación Huésped, Buenos Aires, Argentina. , (Argentina)
  • 4 Hospital Germans Trias i Pujol, Catalonia, Spain. , (Spain)
  • 5 ViiV Healthcare, Research Triangle Park, North Carolina.
  • 6 ViiV Healthcare, Brentford, United Kingdom. , (United Kingdom)
Type
Published Article
Journal
AIDS Research and Human Retroviruses
Publisher
Mary Ann Liebert
Publication Date
Oct 21, 2019
Identifiers
DOI: 10.1089/AID.2019.0171
PMID: 31507204
Source
Medline
Keywords
Language
English
License
Unknown

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.

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