title: Sub-Epidemics Explain Localized High Prevalence of Reduced Susceptibility to Rilpivirine in Treatment-Naive HIV-1-Infected Patients: Subtype and Geographic Compartmentalization of Baseline Resistance Mutations.
abstract: OBJECTIVE
  The latest nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV) is indicated for human immunodeficiency virus type-1 (HIV-1) patients initiating antiretroviral treatment, but the extent of genotypic RPV resistance in treatment-naive patients outside clinical trials is poorly defined.
  
  
  METHODS
  This retrospective observational study of clinical data from Belgium and Portugal evaluates genotypic information from HIV-1 drug-naive patients obtained for the purpose of drug resistance testing. Rilpivirine resistance-associated mutations (RPV-RAMs) were defined based on clinical trials, phenotypic studies, and expert-based resistance algorithms. Viral susceptibility to RPV alone and to the single-tablet regimen was estimated using expert-based resistance algorithms.
  
  
  RESULTS
  In 4,631 HIV-1 treatment-naive patients infected with diverse HIV-1 subtypes, major RPV-RAMs were detected in 4.6%, while complete viral susceptibility to RPV was estimated in 95% of patients. Subtype C- and F1-infected patients displayed the highest levels of reduced viral susceptibility at baseline, respectively 13.2% and 9.3%, mainly due to subtype- and geographic-dependent occurrence of RPV-RAMs E138A and A98G as natural polymorphisms. Strikingly, a founder effect in Portugal resulted in a 138A prevalence of 13.2% in local subtype C-infected treatment-naive patients. The presence of transmitted drug resistance did not impact our estimates.
  
  
  CONCLUSIONS
  RPV is the first HIV-1 inhibitor for which, in the absence of transmitted drug resistance, intermediate or high-level genotypic resistance can be detected in treatment-naive patients. The extent of RPV susceptibility in treatment-naive patients differs depending on the HIV-1 subtype and dynamics of local compartmentalized epidemics. The highest prevalence of reduced susceptibility was found to be 15.7% in Portuguese subtype C-infected treatment-naive patients. In this context, even in the absence of transmitted HIV-1 drug resistance (TDR), drug resistance testing at baseline should be considered extremely important before starting treatment with this NNRTI.
authors.affiliation: 1 Clinical and Epidemiological Virology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven - University of Leuven , Leuven, Belgium .
authors.forename: Kristof
authors.initials: K
authors.lastname: Theys
authors.affiliation: 1 Clinical and Epidemiological Virology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven - University of Leuven , Leuven, Belgium .|2 AIDS Reference Laboratory, University Hospitals Leuven , Leuven, Belgium .
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Laethem
authors.affiliation: 3 LMCBM, SPC, HEM - Centro Hospitalar de Lisboa Ocidental , Lisbon, Portugal .|4 Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Superior de Ciências da Saúde Sul , Caparica, Portugal .
authors.forename: Perpetua
authors.initials: P
authors.lastname: Gomes
authors.affiliation: 1 Clinical and Epidemiological Virology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven - University of Leuven , Leuven, Belgium .
authors.forename: Guy
authors.initials: G
authors.lastname: Baele
authors.affiliation: 5 Global Health and Tropical Medicine, Institute for Hygiene and Tropical Medicine , Universidade NOVA de Lisboa, Lisbon, Portugal .|6 Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Basic Sciences Department, Universidad del Rosario , Bogotá, Colombia .
authors.forename: Andrea-Clemencia
authors.initials: AC
authors.lastname: Pineda-Peña
authors.affiliation: 1 Clinical and Epidemiological Virology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven - University of Leuven , Leuven, Belgium .|5 Global Health and Tropical Medicine, Institute for Hygiene and Tropical Medicine , Universidade NOVA de Lisboa, Lisbon, Portugal .
authors.forename: Anne-Mieke
authors.initials: AM
authors.lastname: Vandamme
authors.affiliation: 1 Clinical and Epidemiological Virology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven - University of Leuven , Leuven, Belgium .
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Camacho
authors.affiliation: 5 Global Health and Tropical Medicine, Institute for Hygiene and Tropical Medicine , Universidade NOVA de Lisboa, Lisbon, Portugal .
authors.forename: Ana B
authors.initials: AB
authors.lastname: Abecasis
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D001530:Belgium / Q000453:epidemiology; D024882:Drug Resistance, Viral / Q000235:genetics*; D018703:Founder Effect; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011174:Portugal / Q000453:epidemiology; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D000068696:Rilpivirine / Q000627:therapeutic use*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D000068696:Rilpivirine