Short Communication: Dolutegravir-Based Regimens Are Active in Integrase Strand Transfer Inhibitor-Naive Patients with Nucleoside Reverse Transcriptase Inhibitor Resistance

AIDS Res Hum Retroviruses. 2018 Apr;34(4):343-346. doi: 10.1089/AID.2017.0184. Epub 2018 Mar 22.

Abstract

In the SAILING study, dolutegravir demonstrated superior virologic efficacy compared with raltegravir in treatment-experienced, integrase strand transfer inhibitor (INSTI)-naive patients with HIV-1 who harbored resistance to ≥2 antiretroviral drug classes. Significantly fewer dolutegravir-treated patients demonstrated virologic failure with treatment-emergent resistance than raltegravir-treated patients through 48 weeks. Investigator-selected background therapy (ISBT) included at least one fully active agent, selected on the basis of resistance analysis. Genotypic and phenotypic resistance testing were performed on baseline and time-of-failure samples from patients with protocol-defined virologic failure (PDVF). A post hoc analysis of SAILING (N = 715; 354 dolutegravir, 361 raltegravir) assessed efficacy in subpopulations defined by ISBT activity, resistance profiles, and treatment history. When ISBT contained only nucleoside reverse transcriptase inhibitors (NRTIs), PDVF occurred in 0% (0/32) of dolutegravir-treated patients and 21.9% (7/32) of raltegravir-treated patients (p = .005). In patients harboring M184 V whose ISBT contained lamivudine or emtricitabine plus a second NRTI, 0% (0/13) of dolutegravir- and 33.3% (4/12) of raltegravir-treated patients (p = .026) experienced PDVF. Among patients receiving protease inhibitor (PI)-containing ISBT, 6.0% (18/300) of dolutegravir-treated patients versus 11.8% (36/305) of raltegravir-treated patients (p = .012) experienced PDVF. Darunavir/ritonavir was part of ISBT in 130 dolutegravir-treated patients and 145 raltegravir-treated patients; 6 (4.6%) and 12 (8.3%), respectively, experienced PDVF (difference -3.7%; 95% confidence interval: -10.1% to 2.5%; p = .256). There was no or less virologic failure in treatment-experienced, INSTI-naive subjects receiving dolutegravir versus raltegravir, even when the ISBT was suboptimal or NRTI resistance was present at baseline. These findings are not explained by the use of PI/ritonavir-containing ISBT.

Keywords: HIV-1; antiretroviral resistance; combination antiretroviral therapy; dolutegravir; integrase inhibitor; raltegravir.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiretroviral Therapy, Highly Active / methods
  • Clinical Trials, Phase III as Topic
  • Drug Resistance, Viral / drug effects*
  • Drug Resistance, Viral / genetics
  • Genotype
  • HIV Infections / drug therapy*
  • HIV Integrase Inhibitors / therapeutic use*
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Heterocyclic Compounds, 3-Ring / therapeutic use*
  • Humans
  • Mutation
  • Oxazines
  • Piperazines
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use
  • Pyridones
  • Raltegravir Potassium / pharmacology
  • Raltegravir Potassium / therapeutic use
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Reverse Transcriptase Inhibitors / therapeutic use

Substances

  • HIV Integrase Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Oxazines
  • Piperazines
  • Protease Inhibitors
  • Pyridones
  • Reverse Transcriptase Inhibitors
  • Raltegravir Potassium
  • dolutegravir