title: Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial.
abstract: BACKGROUND
  Twice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data suggesting efficacy of once-daily raltegravir and because adherence is often improved with once-daily dosing, we aimed to compare these dosing schedules.
  
  
  METHODS
  In our international, double-blind, randomised, phase 3 non-inferiority study, we enrolled antiretroviral-naive patients with HIV RNA loads of more than 5000 copies per mL and no baseline resistance to tenofovir or emtricitabine at 83 centres worldwide. We randomly allocated patients (1:1) by use of a computer-generated sequence to receive raltegravir once daily (two 400 mg tablets taken together every 24 h), or twice daily (one 400 mg tablet every 12 h), both in combination with once-daily co-formulated tenofovir 300 mg plus emtricitabine 150 mg. The primary outcome was virological response at 48 weeks (viral RNA loads <50 copies per mL) in patients who received at least one dose of study drug, counting non-completers as failure. We assessed non-inferiority in terms of the proportion of patients in both treatment groups who achieved the primary outcome, with a non-inferiority margin of -10%. This study is registered with ClinicalTrials.gov, number NCT00745823.
  
  
  RESULTS
  From Oct 15, 2008, to Nov 2, 2009, we randomly allocated 775 patients, of whom 382 (99%) of 386 patients in the once-daily group and 388 (99%) of 389 in the twice-daily group received at least one dose of study drug. At baseline, 304 (39%) of 770 treated patients had viral loads of more than 100,000 copies per mL and 188 (24%) had CD4 cell counts of fewer than 200 cells per μL. 318 (83%) of 382 patients in the once-daily group had virological response compared with 343 (89%) of 386 in the twice-daily group (difference -5·7%, 95% CI -10·7 to -0·83; p=0·044). Serious adverse events were reported in 26 (7%) of 382 once-daily recipients and 40 (10%) of 388 twice-daily recipients, and adverse events leading to discontinuation occurred in four (1%) patients in each group.
  
  
  CONCLUSIONS
  Despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing.
  
  
  BACKGROUND
  Merck.
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Eron
authors.forename: Jürgen K
authors.initials: JK
authors.lastname: Rockstroh
authors.forename: Jacques
authors.initials: J
authors.lastname: Reynes
authors.forename: Jaime
authors.initials: J
authors.lastname: Andrade-Villanueva
authors.forename: Jose Valdez
authors.initials: JV
authors.lastname: Ramalho-Madruga
authors.forename: Linda-Gail
authors.initials: LG
authors.lastname: Bekker
authors.forename: Benjamin
authors.initials: B
authors.lastname: Young
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Gatell-Artigas
authors.forename: Jose R
authors.initials: JR
authors.lastname: Arribas
authors.forename: Mark
authors.initials: M
authors.lastname: Nelson
authors.forename: Havilland
authors.initials: H
authors.lastname: Campbell
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Rodgers
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Rizk
authors.forename: Larissa
authors.initials: L
authors.lastname: Wenning
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Daria
authors.initials: D
authors.lastname: Hazuda
authors.forename: Mark J
authors.initials: MJ
authors.lastname: DiNubile
authors.forename: Randi
authors.initials: R
authors.lastname: Leavitt
authors.forename: Robin
authors.initials: R
authors.lastname: Isaacs
authors.forename: Michael N
authors.initials: MN
authors.lastname: Robertson
authors.forename: Peter
authors.initials: P
authors.lastname: Sklar
authors.forename: Bach-Yen
authors.initials: BY
authors.lastname: Nguyen
mesh_terms: D000328:Adult; D000368:Aged; D018791:CD4 Lymphocyte Count; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011760:Pyrrolidinones / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068898:Raltegravir Potassium; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult
chemical_list: D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium