title: Highly multidrug-resistant HIV: clonal analysis and therapeutic strategies.
abstract: OBJECTIVE
  There are today HIV-infected patients in therapeutic impasses because of highly multidrug-resistant (HMDR) viruses. We studied the distribution of resistance mutations at clonal level, and we analysed the therapeutic strategies used in such cases to achieve undetectable viraemia.
  
  
  METHODS
  The HMDR profile was defined as a genotypic sensitivity score (GSS) ≤ 1.5 for etravirine and raltegravir with full resistance to darunavir. About 30 clones per gene and per patient were sequenced. Virtual phenotypes were determined. Efficacy of therapeutic strategies was evaluated by follow-up of viral loads, CD4 cell counts and trough concentrations of drugs.
  
  
  RESULTS
  Among 1310 patients on treatment and with genotypic resistance testing, 25 (2%) were resistant to darunavir and 11 (0.8%) had an HMDR profile. Five-hundred clones could be analysed for four of them. HMDR profiles were harboured by the great majority of clones and all resistance mutations were located on the same strains for all genes. Despite this and a regimen with a GSS <2.0 in three patients, they achieved a viraemia <20 copies/mL. These results were obtained using different strategies: high doses of drugs; combination of antiretrovirals with full or intermediate susceptibility, such as tipranavir, etravirine or maraviroc; and use of alternative compounds, such as foscarnet or interferon.
  
  
  CONCLUSIONS
  Patients with HMDR HIV were uncommon, but, in such cases, all resistance mutations were borne on the same majority strains. In this study, tipranavir was the only protease inhibitor with full or intermediate susceptibility. Despite very limited therapeutic options, an undetectable viraemia can be achieved by combining different strategies.
authors.affiliation: Université Pierre et Marie Curie, Paris 6, France.
authors.forename: Eve
authors.initials: E
authors.lastname: Todesco
authors.forename: Sophie
authors.initials: S
authors.lastname: Sayon
authors.forename: Slim
authors.initials: S
authors.lastname: Fourati
authors.forename: Roland
authors.initials: R
authors.lastname: Tubiana
authors.forename: Anne
authors.initials: A
authors.lastname: Simon
authors.forename: Nadine
authors.initials: N
authors.lastname: Ktorza
authors.forename: Luminita
authors.initials: L
authors.lastname: Schneider
authors.forename: Gilles
authors.initials: G
authors.lastname: Peytavin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Malet
authors.forename: Peter
authors.initials: P
authors.lastname: Van den Eede
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
authors.forename: Anne-Genevieve
authors.initials: AG
authors.lastname: Marcelin
authors.forename: Marc
authors.initials: M
authors.lastname: Wirden
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D024921:Drug Resistance, Multiple, Viral; D005838:Genotype; D006678:HIV / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D019380:Anti-HIV Agents
keywords: HIV resistance; darunavir; dolutegravir; maraviroc; salvage therapy; tipranavir