title: Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.
abstract: BACKGROUND
  We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed.
  
  
  METHODS
  We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure.
  
  
  RESULTS
  Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations.
  
  
  CONCLUSIONS
  When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)
authors.affiliation: National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney.
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.forename: Roy T
authors.initials: RT
authors.lastname: Steigbigel
authors.forename: Jose M
authors.initials: JM
authors.lastname: Gatell
authors.forename: Jurgen K
authors.initials: JK
authors.lastname: Rockstroh
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.forename: Patrick
authors.initials: P
authors.lastname: Yeni
authors.forename: Adriano
authors.initials: A
authors.lastname: Lazzarin
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Princy N
authors.initials: PN
authors.lastname: Kumar
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Eron
authors.forename: Mauro
authors.initials: M
authors.lastname: Schechter
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.forename: Mona R
authors.initials: MR
authors.lastname: Loutfy
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Lennox
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Joshua
authors.initials: J
authors.lastname: Chen
authors.forename: Desmond M
authors.initials: DM
authors.lastname: Ryan
authors.forename: Rand R
authors.initials: RR
authors.lastname: Rhodes
authors.forename: John A
authors.initials: JA
authors.lastname: Killar
authors.forename: Lucinda R
authors.initials: LR
authors.lastname: Gilde
authors.forename: Kim M
authors.initials: KM
authors.lastname: Strohmaier
authors.forename: Anne R
authors.initials: AR
authors.lastname: Meibohm
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nessly
authors.forename: Mark J
authors.initials: MJ
authors.lastname: DiNubile
authors.forename: Robin D
authors.initials: RD
authors.lastname: Isaacs
authors.forename: Hedy
authors.initials: H
authors.lastname: Teppler
authors.forename: Bach-Yen
authors.initials: BY
authors.lastname: Nguyen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018791:CD4 Lymphocyte Count; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009930:Organic Chemicals / Q000009:adverse effects / Q000627:therapeutic use*; D010641:Phenotype; D011760:Pyrrolidinones; D012367:RNA, Viral / Q000097:blood; D000068898:Raltegravir Potassium; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D019428:HIV Integrase Inhibitors; D009930:Organic Chemicals; D011760:Pyrrolidinones; D012367:RNA, Viral; D000068898:Raltegravir Potassium; D019427:HIV Integrase