title: Virological and pharmacological factors associated with virological response to salvage therapy after an 8-week of treatment interruption in a context of very advanced HIV disease (GigHAART ANRS 097).
abstract: Both highly potent antiretroviral drug rescue multi therapy and treatment interruption (TI) have been suggested to be effective in HIV-1 infected-patients with multiple treatment failure. GigHAART-ANRS 097 was the only randomized trial during which an 8-week TI was beneficial in heavily pre-treated patients with multi-drug resistant virus on resuming a multiple-drug salvage regimen. The aim of this study was to analyze virological and pharmacological factors associated with a virological response. Clonal resistance analysis showed that although the viral population was highly mutated and nearly monoclonal at baseline, the 8-week interruption therapy allowed the re-emergence of more susceptible quasispecies to the subsequent salvage therapy, which were not detected by classical genotypic resistance testing. The fact that not every viral clone harbored all resistance viral mutations could explain a part of the virological response to a six to eight drug regimen for patients enrolled in the TI group. This phenomenon was associated with a transient virological response after the use of a GigHAART therapy, but was followed by the re-emergence of baseline resistance pattern and acquisition of additional mutations in patients failing this strategy. A combined factor of protease inhibitor (PI) concentration and genotypic score, expressed as a genotypic inhibitory quotient (GIQ), was used to assess the importance of genotypic resistance and plasma drug levels in the rate of response to multiple PI combination. The GIQ of each PI used in the regimen was not associated with virological success. However, the sum of PI GIQs was predictive of a virological response. These results suggest that pharmacological enhancement might overcome viral resistance and that there is some benefit in adding the activity of several boosted-PIs to improve the response to a salvage regimen.
authors.affiliation: Department of Virology, Pitié-Salpêtrière Hospital-Paris, Paris, France. constance.delaugerre@nck.ap-hop-paris.fr
authors.forename: Constance
authors.initials: C
authors.lastname: Delaugerre
authors.forename: Gilles
authors.initials: G
authors.lastname: Peytavin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dominguez
authors.forename: Anne-Genevieve
authors.initials: AG
authors.lastname: Marcelin
authors.forename: Claudine
authors.initials: C
authors.lastname: Duvivier
authors.forename: Karine
authors.initials: K
authors.lastname: Gourlain
authors.forename: Bahia
authors.initials: B
authors.lastname: Amellal
authors.forename: Mayeule
authors.initials: M
authors.lastname: Legrand
authors.forename: François
authors.initials: F
authors.lastname: Raffi
authors.forename: Dominique
authors.initials: D
authors.lastname: Costagliola
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D016333:HIV Protease / Q000235:genetics; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009154:Mutation; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D016879:Salvage Therapy; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D016333:HIV Protease