title: Integrase inhibitor versus protease inhibitor based regimen for HIV-1 infected women (WAVES): a randomised, controlled, double-blind, phase 3 study.
abstract: Women are under-represented in HIV antiretroviral therapy (ART) studies. Guidelines for selection of ART as initial therapy in patients with HIV-1 infection do not contain sex-specific treatment. We aimed to assess the safety and efficacy of the single tablet integrase inhibitor regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate compared with a boosted protease inhibitor regimen of ritonavir-boosted atazanavir with emtricitabine and tenofovir disoproxil fumarate.
  
  
  
  In this international, randomised, controlled, double-blind, phase 3 study (Women AntiretroViral Efficacy and Safety study [WAVES]), we recruited treatment-naive HIV-infected women with an estimated creatinine clearance of 70 mL/min or higher from 80 centres in 11 countries. Women were randomly assigned (1:1) to receive elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (integrase inhibitor regimen) or ritonavir-boosted atazanavir with emtricitabine and tenofovir disoproxil fumarate (protease inhibitor based regimen); regimens were masked with matching placebos. Randomisation was done by a computer-generated allocation sequence (block size four) and was stratified by HIV-1 RNA viral load and race. Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary efficacy and safety analyses. The main outcome was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by US Food and Drug Administration snapshot algorithm (prespecified non-inferiority margin of 12%). This study is registered with ClinicalTrials.gov, number NCT01705574.
  
  
  
  Between Nov 28, 2012, and March 12, 2014, 575 women were enrolled. 289 were randomly assigned to receive the integrase inhibitor regimen and 286 to receive the protease inhibitor based regimen. 252 (87%) women in the integrase inhibitor group had plasma HIV-1 RNA less than 50 copies per mL at week 48 compared with 231 (81%) women in the protease inhibitor group (adjusted difference 6·5%; 95% CI 0·4-12·6). No participant had virological failure with resistance in the integrase inhibitor group compared with three participants ([1%]; all Met184Val/Ile) in the protease inhibitor group. 19 women in the protease inhibitor group discontinued because of adverse events compared with five in the integrase inhibitor group.
  
  
  
  WAVES shows that clinical trials of ART regimens in global and diverse populations of treatment-naive women are possible. The findings support guidelines recommending integrase inhibitor based regimens in first-line antiretroviral therapy.
  
  
  
  Gilead Sciences.
authors: Thomas Jefferson University, Philadelphia, PA, USA.
authors: Kathleen
authors: K
authors: Squires
authors: Joint Clinical Research Centre, Clinical Research, Kampala, Uganda.
authors: Cissy
authors: C
authors: Kityo
authors: West Virginia University, Morgantown, WV, USA.
authors: Sally
authors: S
authors: Hodder
authors: Royal Free Hospital, Hampstead, London, UK.
authors: Margaret
authors: M
authors: Johnson
authors: Regional Clinic in Infectious Hospital, St Petersburg, Russia.
authors: Evgeny
authors: E
authors: Voronin
authors: Chatham County Health Department, Savannah, GA, USA.
authors: Debbie
authors: D
authors: Hagins
authors: HIV-NAT, Thai Red Cross AIDS Research Center and Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors: Anchalee
authors: A
authors: Avihingsanon
authors: Zona Universitaria/IDEV, Santo Domingo, Dominican Republic.
authors: Ellen
authors: E
authors: Koenig
authors: Gilead Sciences, Foster City, CA, USA.
authors: Shuping
authors: S
authors: Jiang
authors: Gilead Sciences, Foster City, CA, USA.
authors: Kirsten
authors: K
authors: White
authors: Gilead Sciences, Foster City, CA, USA.
authors: Andrew
authors: A
authors: Cheng
authors: Gilead Sciences, Foster City, CA, USA.
authors: Javier
authors: J
authors: Szwarcberg
authors: Gilead Sciences, Foster City, CA, USA. Electronic address: huyen.cao@gilead.com.
authors: Huyen
authors: H
authors: Cao
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D000069446:Atazanavir Sulfate / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000069547:Cobicistat / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004311:Double-Blind Method; D000068679:Emtricitabine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007391:International Cooperation; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000068698:Tenofovir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D019562:Viral Load
chemical_list: D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D015363:Quinolones; D012367:RNA, Viral; C509700:elvitegravir; D000069446:Atazanavir Sulfate; D000068698:Tenofovir; D000068679:Emtricitabine; D000069547:Cobicistat; D019438:Ritonavir