title: Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials.
abstract: BACKGROUND
  To reduce lipid abnormalities and other side-effects associated with antiretroviral regimens containing lopinavir-ritonavir, patients might want to switch one or more components of their regimen. We compared substitution of raltegravir for lopinavir-ritonavir with continuation of lopinavir-ritonavir in HIV-infected patients with stable viral suppression on lopinavir-ritonavir-based combination therapy.
  
  
  METHODS
  The SWITCHMRK 1 and 2 studies were multicentre, double-blind, double-dummy, phase 3, randomised controlled trials. HIV-infected patients aged 18 years or older were eligible if they had documented viral RNA (vRNA) concentration below the limit of assay quantification for at least 3 months while on a lopinavir-ritonavir-based regimen. 707 eligible patients were randomly allocated by interactive voice response system in a 1:1 ratio to switch from lopinavir-ritonavir to raltegravir (400 mg twice daily; n=353) or to remain on lopinavir-ritonavir (two 200 mg/50 mg tablets twice daily; n=354), while continuing background therapy consisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors. Primary endpoints were the mean percentage change in serum lipid concentrations from baseline to week 12; the proportion of patients with vRNA concentration less than 50 copies per mL at week 24 (with all treated patients who did not complete the study counted as failures) with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks. Analyses were done according to protocol. These trials are registered with ClinicalTrials.gov, numbers NCT00443703 and NCT00443729.
  
  
  RESULTS
  702 patients received at least one dose of study drug and were included in the efficacy and safety analyses for the combined trials (raltegravir, n=350; lopinavir-ritonavir, n=352). Percentage changes in lipid concentrations from baseline to week 12 were significantly greater (p<0.0001) in the raltegravir group than in the lopinavir-ritonavir group in each study, yielding combined results for total cholesterol -12.6%vs 1.0%, non-HDL cholesterol -15.0%vs 2.6%, and triglycerides -42.2%vs 6.2%. At week 24, 293 (84.4%, 95% CI 80.2-88.1) of 347 patients in the raltegravir group had vRNA concentration less than 50 copies per mL compared with 319 (90.6%, 87.1-93.5) of 352 patients in the lopinavir-ritonavir group (treatment difference -6.2%, -11.2 to -1.3). Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups. There were no serious drug-related adverse events or deaths. The only drug-related clinical adverse event of moderate to severe intensity reported in 1% or more of either treatment group was diarrhoea, which occurred in ten patients in the lopinavir-ritonavir group (3%) and no patients in the raltegravir group. The studies were terminated at week 24 because of lower than expected virological efficacy in the raltegravir group compared with the lopinavir-ritonavir group.
  
  
  CONCLUSIONS
  Although switching to raltegravir was associated with greater reductions in serum lipid concentrations than was continuation of lopinavir-ritonavir, efficacy results did not establish non-inferiority of raltegravir to lopinavir-ritonavir.
  
  
  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: Benjamin
authors.initials: B
authors.lastname: Young
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.forename: Michael
authors.initials: M
authors.lastname: Youle
authors.forename: Edwin
authors.initials: E
authors.lastname: Dejesus
authors.forename: Jaime
authors.initials: J
authors.lastname: Andrade-Villanueva
authors.forename: Cassy
authors.initials: C
authors.lastname: Workman
authors.forename: Roberto
authors.initials: R
authors.lastname: Zajdenverg
authors.forename: Gerd
authors.initials: G
authors.lastname: Fätkenheuer
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Berger
authors.forename: Princy N
authors.initials: PN
authors.lastname: Kumar
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Rodgers
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Shaughnessy
authors.forename: Monica L
authors.initials: ML
authors.lastname: Walker
authors.forename: Richard J O
authors.initials: RJ
authors.lastname: Barnard
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dinubile
authors.forename: Bach-Yen
authors.initials: BY
authors.lastname: Nguyen
authors.forename: Randi
authors.initials: R
authors.lastname: Leavitt
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.forename: Peter
authors.initials: P
authors.lastname: Sklar
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D011744:Pyrimidinones / Q000009:adverse effects / Q000627:therapeutic use*; D011760:Pyrrolidinones / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood / Q000187:drug effects; D000068898:Raltegravir Potassium; D019438:Ritonavir / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014766:Viremia / Q000503:physiopathology / Q000821:virology
chemical_list: D019380:Anti-HIV Agents; D008078:Cholesterol, LDL; D011744:Pyrimidinones; D011760:Pyrrolidinones; D012367:RNA, Viral; D061466:Lopinavir; D000068898:Raltegravir Potassium; D019438:Ritonavir