Absence of HIV-1 Drug Resistance Mutations Supports the Use of Dolutegravir in Uganda

AIDS Res Hum Retroviruses. 2018 May;34(5):404-414. doi: 10.1089/AID.2017.0205. Epub 2018 Feb 26.

Abstract

To screen for drug resistance and possible treatment with Dolutegravir (DTG) in treatment-naive patients and those experiencing virologic failure during first-, second-, and third-line combined antiretroviral therapy (cART) in Uganda. Samples from 417 patients in Uganda were analyzed for predicted drug resistance upon failing a first- (N = 158), second- (N = 121), or third-line [all 51 involving Raltegravir (RAL)] treatment regimen. HIV-1 pol gene was amplified and sequenced from plasma samples. Drug susceptibility was interpreted using the Stanford HIV database algorithm and SCUEAL was used for HIV-1 subtyping. Frequency of resistance to nucleoside reverse transcriptase inhibitors (NRTIs) (95%) and non-NRTI (NNRTI, 96%) was high in first-line treatment failures. Despite lack of NNRTI-based treatment for years, NNRTI resistance remained stable in 55% of patients failing second-line or third-line treatment, and was also at 10% in treatment-naive Ugandans. DTG resistance (n = 366) was not observed in treatment-naive individuals or individuals failing first- and second-line cART, and only found in two patients failing third-line cART, while 47% of the latter had RAL- and Elvitegravir-resistant HIV-1. Secondary mutations associated with DTG resistance were found in 2%-10% of patients failing third-line cART. Of 14 drugs currently available for cART in Uganda, resistance was readily observed to all antiretroviral drugs (except for DTG) in Ugandan patients failing first-, second-, or even third-line treatment regimens. The high NNRTI resistance in first-line treatment in Uganda even among treatment-naive patients calls for the use of DTG to reach the UNAIDS 90:90:90 goals.

Keywords: HIV drug resistance; Uganda; dolutegravir; integrase inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Resistance, Viral*
  • Female
  • Genotype
  • HIV Infections / drug therapy*
  • HIV Infections / virology*
  • HIV Integrase Inhibitors / pharmacology
  • HIV Integrase Inhibitors / therapeutic use*
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Heterocyclic Compounds, 3-Ring / therapeutic use*
  • Humans
  • Male
  • Mutation, Missense*
  • Oxazines
  • Piperazines
  • Pyridones
  • Retrospective Studies
  • Sequence Analysis, DNA
  • Uganda
  • pol Gene Products, Human Immunodeficiency Virus / genetics

Substances

  • HIV Integrase Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Oxazines
  • Piperazines
  • Pyridones
  • pol Gene Products, Human Immunodeficiency Virus
  • dolutegravir