title: Dolutegravir in HIV-2-Infected Patients With Resistant Virus to First-line Integrase Inhibitors From the French Named Patient Program.
abstract: BACKGROUND
  Dolutegravir has shown in vitro activity against human immunodeficiency virus type 2 (HIV-2). We report safety and efficacy data of regimens containing dolutegravir (50 mg twice daily) in antiretroviral-experienced, HIV-2-infected patients.
  
  
  METHODS
  HIV-2-infected patients experiencing virological failure to raltegravir received dolutegravir with optimized background antiretroviral combinations within the French Named Patient Program (NPP). Plasma HIV-2 RNA (pVL) was assessed at time of dolutegravir initiation (baseline), month 3, and month 6. Antiretroviral trough plasma concentrations (C12h) were determined using liquid chromatography coupled with tandem mass spectrometry.
  
  
  RESULTS
  Thirteen HIV-2-infected-patients, with a median duration of 15 years' infection and given 16 previous antiretroviral regimens, were included in NPP. Median follow-up was 9 months (min-max, 3-15 months). Median baseline pVL and CD4 cell count were 9544 copies/mL (inter quartile range [IQR], 3096-23 120 copies/mL) and 100 cells/µL (IQR, 77-171 cells/µL), respectively. Available integrase genotypic resistance patterns were Y143C/G/H/R (n = 5), Q148R/K (n = 2), and N155H (n = 4). Optimized background antiretroviral regimens conferring a genotypic sensitivity score ≤2 in 10 patients included nucleoside reverse transcriptase inhibitors associated with darunavir/ritonavir (n = 12), saquinavir/ritonavir (n = 2), and maraviroc (n = 3). At months 3 and 6, pVL was undetectable in 6 of 13 and 4 of 12 patients, respectively, and median CD4 count was 161 (101-188) cells/µL and 167 (135-1353) cells/µL, respectively. Median dolutegravir C12h was 4086 (1756-5717 ng/mL) ng/mL in 9 patients. No serious events were notified except 1 death from progressive multifocal leukoencephalopathy at month 4.
  
  
  CONCLUSIONS
  Optimized dolutegravir-containing antiretroviral regimens supported by good plasma exposure provide a substantial initial efficacy rate for salvage therapy in heavily antiretroviral-experienced HIV-2-infected patients with virus harboring resistance to first-generation integrase inhibitors. Larger numbers of patients and longer follow-up are needed to confirm these findings.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité INSERM, IAME, UMR 1137 Laboratoire de Virologie.
authors.forename: Diane
authors.initials: D
authors.lastname: Descamps
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité INSERM, IAME, UMR 1137 Laboratoire de Pharmaco-Toxicologie, AP-HP, Hôpital Bichat-Claude Bernard.
authors.forename: Gilles
authors.initials: G
authors.lastname: Peytavin
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité INSERM, IAME, UMR 1137 Laboratoire de Virologie.
authors.forename: Benoit
authors.initials: B
authors.lastname: Visseaux
authors.affiliation: Service des Maladies Infectieuses et Tropicales, AP-HP, Hôpital Pitié-Salpêtrière Pierre Louis Institute of Epidemiology and Public Health, Sorbonne University, UPMC, INSERM UMR-S1136.
authors.forename: Roland
authors.initials: R
authors.lastname: Tubiana
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité INSERM, IAME, UMR 1137 Laboratoire de Virologie.
authors.forename: Florence
authors.initials: F
authors.lastname: Damond
authors.affiliation: Service des Maladies Infectieuses et Tropicales, AP-HP, Hôpital Saint-Antoine, Paris.
authors.forename: Pauline
authors.initials: P
authors.lastname: Campa
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité INSERM, IAME, UMR 1137 Laboratoire de Virologie.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Charpentier
authors.affiliation: Service des Maladies Infectieuses et Tropicales, Hôpital Delafontaine, Saint-Denis.
authors.forename: Marie-Aude
authors.initials: MA
authors.lastname: Khuong-Josses
authors.affiliation: Service de Maladies Infectieuses et Tropicales, AP-HP, Hôpital Necker, Centre d'Infectiologie Necker-Pasteur, Université Paris Descartes, Sorbonne Paris Cité IHU Imagine.
authors.forename: Claudine
authors.initials: C
authors.lastname: Duvivier
authors.affiliation: Service d'Immunologie Clinique, AP-HP, Hôpital Européen Georges Pompidou, Paris.
authors.forename: Marina
authors.initials: M
authors.lastname: Karmochkine
authors.affiliation: ViiV Healthcare, Marly le Roi.
authors.forename: Tuna
authors.initials: T
authors.lastname: Lukiana
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité INSERM, IAME, UMR 1137 Service de Maladies Infectieuses et Tropicales, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Matheron
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D002853:Chromatography, Liquid; D024882:Drug Resistance, Viral; D005260:Female; D005602:France; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015498:HIV-2 / Q000187:drug effects* / Q000302:isolation & purification; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D010949:Plasma / Q000737:chemistry / Q000821:virology; D011728:Pyridones; D012367:RNA, Viral / Q000097:blood; D016879:Salvage Therapy / Q000009:adverse effects / Q000379:methods; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome; D019562:Viral Load; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; D000099226:Dolutegravir
keywords: HIV-2; dolutegravir; drug resistance mutations; integrase