title: Discordant predictions of residual activity could impact dolutegravir prescription upon raltegravir failure.
abstract: BACKGROUND
  Dolutegravir is approved for the treatment of HIV-1 patients exposed to other integrase inhibitors, but the decision to use dolutegravir in this setting should be informed by drug resistance testing.
  
  
  OBJECTIVE
  This study determined the extent of disagreement in predicted residual dolutegravir activity after raltegravir use, and identified individual mutational patterns for which uncertainty exists among HIV-1 expert systems.
  
  
  METHODS
  Mutation patterns were classified in raltegravir signature pathways including positions 143, 148 and 155, and interpreted into clinically informative resistance levels using genotypic drug resistance interpretation systems ANRS v24, HIVdb v7.0 and Rega v9.1.0, and instructions of dolutegravir use as approved by the Food and Drug Administration and the European Medicines Agency.
  
  
  RESULTS
  In 216HIV-1 patients failing raltegravir-therapy, 87% patients displayed mutations associated with resistance towards integrase inhibitors. A total of 141 unique mutational patterns were observed, with N155H (25.4%), Q148H (16.2%) and Y143R (8.3%) the most prevalent signature mutations. The Q148 pathway occurred almost exclusively in HIV-1 subtype B viruses. Concordances in predicted dolutegravir susceptibility scores among 5 systems were obtained in 57.8% of patients, and concordant intermediate resistant and concordant resistant scores were only observed in 6.5% and 0.9% of patients, respectively. However, systems individually scored higher levels of dolutegravir intermediate resistance and resistance, ranging from 4.2% to 10.2% and from 14.8% to 22.7% of patients, respectively. A consensus on interpreting the extent of residual activity was lacking in 34.7% of patients and was highly resistance pathway-specific.
  
  
  CONCLUSIONS
  Dolutegravir may potentially be effective in the majority of HIV-1 patients failing raltegravir, but concern over the uncertainty in predicted residual activity could withhold clinicians from prescribing dolutegravir during its clinical assessment.
authors: KU Leuven - University of Leuven, Department Microbiology and Immunology, Rega Institute for Medical Research, B-3000 Leuven, Belgium. Electronic address: kristof.theys@rega.kuleuven.be.
authors: Kristof
authors: K
authors: Theys
authors: Global Health and Tropical Medicine, International Public Health and Biostatistics, Institute for Hygiene and Tropical Medicine, Universidade NOVA de Lisboa, Lisbon, Portugal.
authors: Ana
authors: A
authors: Abecasis
authors: KU Leuven - University of Leuven, Department Microbiology and Immunology, Rega Institute for Medical Research, B-3000 Leuven, Belgium; Artificial Intelligence Lab, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors: Pieter
authors: P
authors: Libin
authors: LMCBM, SPC, HEM - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal; Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Superior de Ciências da Saúde Egas Moniz, Monte de Caparica, Portugal.
authors: Perpe Tua
authors: PT
authors: Gomes
authors: LMCBM, SPC, HEM - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.
authors: Joaquim
authors: J
authors: Cabanas
authors: KU Leuven - University of Leuven, Department Microbiology and Immunology, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
authors: Ricardo J
authors: RJ
authors: Camacho
authors: KU Leuven - University of Leuven, Department Microbiology and Immunology, Rega Institute for Medical Research, B-3000 Leuven, Belgium; University Hospitals Leuven, AIDS Reference Laboratory, Herestraat 49, 3000 Leuven, Belgium.
authors: Kristel
authors: K
authors: Van Laethem
mesh_terms: D000066491:Clinical Decision-Making; D011307:Drug Prescriptions; D024882:Drug Resistance, Viral / Q000187:drug effects; D005838:Genotype; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010078:Oxazines; D010879:Piperazines; D011379:Prognosis; D011728:Pyridones; D017211:Treatment Failure; D016896:Treatment Outcome; D000099226:Dolutegravir
chemical_list: D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir
keywords: HIV-1; dolutegravir; integrase; interpretation; resistance; treatment