title: Predicted residual activity of rilpivirine in HIV-1 infected patients failing therapy including NNRTIs efavirenz or nevirapine.
abstract: Rilpivirine is a second-generation nonnucleoside reverse-transcriptase inhibitor (NNRTI) currently indicated for first-line therapy, but its clinical benefit for HIV-1 infected patients failing first-generation NNRTIs is largely undefined. This study quantified the extent of genotypic rilpivirine resistance in viral isolates from 1212 patients upon failure of efavirenz- or nevirapine-containing antiretroviral treatment, of whom more than respectively 80% and 90% showed high-level genotypic resistance to the failing NNRTI. Of all study patients, 47% showed a rilpivirine resistance-associated mutation (RPV-RAM), whereas preserved residual rilpivirine activity was predicted in half of the patients by three genotypic drug resistance interpretation algorithms. An NNRTI-dependent impact on rilpivirine resistance was detected. Compared with the use of nevirapine, the use of efavirenz was associated with a 32% lower risk of having a RPV-RAM and a 50% lower risk of predicted reduced rilpivirine susceptibility. Most prevalent RPV-RAMs after nevirapine experience were Y181C and H221Y, whereas L100I+K103N, Y188L and K101E occurred most in efavirenz-experienced patients. Predicted rilpivirine activity was not affected by HIV-1 subtype, although frequency of individual mutations differed across subtypes. In conclusion, this genotypic resistance analysis strongly suggests that the latest NNRTI, rilpivirine, may retain activity in a large proportion of HIV-1 patients in whom resistance failed while they were on an efavirenz- or nevirapine-containing regimen, and may present an attractive option for second-line treatment given its good safety profile and dosing convenience. However, prospective clinical studies assessing the effectiveness of rilpivirine for NNRTI-experienced patients are warranted to validate knowledge derived from genotypic and phenotypic drug resistance studies.
authors.affiliation: KU Leuven, University of Leuven, Department Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium. Electronic address: kristof.theys@rega.kuleuven.be.
authors.forename: K
authors.initials: K
authors.lastname: Theys
authors.affiliation: KU Leuven, University of Leuven, Department Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium; Centro de Malária e outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical e Unidade de Microbiologia, Universidade Nova de Lisboa, Lisbon, Portugal.
authors.forename: R J
authors.initials: RJ
authors.lastname: Camacho
authors.affiliation: Centro de Malária e outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical e Unidade de Microbiologia, Universidade Nova de Lisboa, Lisbon, Portugal; Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal; Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Superior de Ciências da Saúde Sul, Caparica, Portugal.
authors.forename: P
authors.initials: P
authors.lastname: Gomes
authors.affiliation: KU Leuven, University of Leuven, Department Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium; Centro de Malária e outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical e Unidade de Microbiologia, Universidade Nova de Lisboa, Lisbon, Portugal.
authors.forename: A M
authors.initials: AM
authors.lastname: Vandamme
authors.affiliation: KU Leuven, University of Leuven, Department Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium; Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: S Y
authors.initials: SY
authors.lastname: Rhee
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D048588:Benzoxazines / Q000627:therapeutic use*; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense; D019829:Nevirapine / Q000627:therapeutic use*; D000068696:Rilpivirine / Q000627:therapeutic use*; D017211:Treatment Failure
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D019829:Nevirapine; D000068696:Rilpivirine; C098320:efavirenz
keywords: Activity; HIV; mutation; resistance; therapy