title: Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study.
abstract: BACKGROUND
  Dolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance.
  
  
  METHODS
  ING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516.
  
  
  RESULTS
  Analysis included 715 patients (354 dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7·4%, 95% CI 0·7 to 14·2); superiority of dolutegravir versus raltegravir was then concluded (p=0·03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on dolutegravir (four vs 17 patients; adjusted difference -3·7%, 95% CI -6·1 to -1·2; p=0·003). Adverse event frequencies were similar across groups; the most commonly reported events for dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] dolutegravir, 14 [4%] raltegravir).
  
  
  CONCLUSIONS
  Once-daily dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group.
  
  
  BACKGROUND
  ViiV Healthcare.
authors.affiliation: Fundacion Huesped, Buenos Aires, Argentina. pcahn@huesped.org.ar
authors.forename: Pedro
authors.initials: P
authors.lastname: Cahn
authors.forename: Anton L
authors.initials: AL
authors.lastname: Pozniak
authors.forename: Horacio
authors.initials: H
authors.lastname: Mingrone
authors.forename: Andrey
authors.initials: A
authors.lastname: Shuldyakov
authors.forename: Carlos
authors.initials: C
authors.lastname: Brites
authors.forename: Jaime F
authors.initials: JF
authors.lastname: Andrade-Villanueva
authors.forename: Gary
authors.initials: G
authors.lastname: Richmond
authors.forename: Carlos Beltran
authors.initials: CB
authors.lastname: Buendia
authors.forename: Jan
authors.initials: J
authors.lastname: Fourie
authors.forename: Moti
authors.initials: M
authors.lastname: Ramgopal
authors.forename: Debbie
authors.initials: D
authors.lastname: Hagins
authors.forename: Franco
authors.initials: F
authors.lastname: Felizarta
authors.forename: Jose
authors.initials: J
authors.lastname: Madruga
authors.forename: Tania
authors.initials: T
authors.lastname: Reuter
authors.forename: Tamara
authors.initials: T
authors.lastname: Newman
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Small
authors.forename: John
authors.initials: J
authors.lastname: Lombaard
authors.forename: Beatriz
authors.initials: B
authors.lastname: Grinsztejn
authors.forename: David
authors.initials: D
authors.lastname: Dorey
authors.forename: Mark
authors.initials: M
authors.lastname: Underwood
authors.forename: Sandy
authors.initials: S
authors.lastname: Griffith
authors.forename: Sherene
authors.initials: S
authors.lastname: Min
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones / Q000008:administration & dosage* / Q000009:adverse effects; D012367:RNA, Viral / Q000378:metabolism; D000068898:Raltegravir Potassium; D016896:Treatment Outcome; D019562:Viral Load; D000099226:Dolutegravir
chemical_list: D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011760:Pyrrolidinones; D012367:RNA, Viral; D000068898:Raltegravir Potassium; D000099226:Dolutegravir