title: Bone mineral density and inflammatory and bone biomarkers after darunavir-ritonavir combined with either raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial.
abstract: BACKGROUND
  Osteopenia, osteoporosis, and low bone mineral density are frequent in patients with HIV. We assessed the 96 week loss of bone mineral density associated with a nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI)-sparing regimen.
  
  
  METHODS
  Antiretroviral-naive adults with HIV were enrolled in 78 clinical sites in 15 European countries into a randomised (1:1), open-label, non-inferiority trial (NEAT001/ANRS143) assessing the efficacy and safety of darunavir (800 mg once per day) and ritonavir (100 mg once per day) plus either raltegravir (400 mg twice per day; NtRTI-sparing regimen) or tenofovir (245 mg once per day) and emtricitabine (200 mg once per day; standard regimen). For this bone-health substudy, 20 of the original sites in six countries participated, and any patient enrolled at one of these sites who met the following criteria was eligible: plasma viral loads greater than 1000 HIV RNA copies per mL and CD4 cell counts of fewer than 500 cells per μL, except in those with symptomatic HIV infection. Exclusion criteria included treatment for malignant disease, testing positive for hepatitis B virus surface antigen, pregnancy, creatinine clearance less than 60 mL per min, treatment for osteoporosis, systemic steroids, or oestrogen-replacement therapy. The two primary endpoints were the mean percentage changes in lumbar spine and total hip bone mineral density at week 48, assessed by dual energy x-ray absorptiometry (DXA) scans. We did the analysis with an intention-to-treat-exposed approach with antiretroviral modifications ignored. The parent trial is registered with ClinicalTrials.gov, number NCT01066962, and is closed to new participants.
  
  
  RESULTS
  Between Aug 2, 2010, and April 18, 2011, we recruited 146 patients to the substudy, 70 assigned to the NtRTI-sparing regimen and 76 to the standard regimen. DXA data were available for 129, 121 and 107 patients at baseline, 48 and 96 weeks respectively. At week 48, the mean percentage loss in bone mineral density in the lumbar spine was greater in the standard group than in the NtRTI-sparing group (mean percentage change -2.49% vs -1.00%, mean percentage difference -1.49, 95% CI -2.94 to -0.04; p=0.046). Total hip bone mineral density loss was similarly greater at week 48 in the standard group than in the NtRTI-sparing group (mean percentage change -3.30% vs -0.73%; mean percentage difference -2.57, 95% CI -3.75 to -1.35; p<0.0001). Seven new fractures occurred during the trial (two in the NtRTI-sparing group and five in the standard group).
  
  
  CONCLUSIONS
  A raltegravir-based regimen was associated with significantly less loss of bone mineral density than a standard regimen containing tenofovir disoproxil fumarate, and might be a treatment option for patients at high risk of osteopenia or osteoporosis who are not suitable for NtRTIs such as abacavir or tenofovir alafenamide.
  
  
  BACKGROUND
  The European Union Sixth Framework Programme, Inserm-ANRS, Ministerio de Sanidad y Asuntos Sociales de España, Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories.
authors.affiliation: Department of Internal Medicine, Hospital Universitario La Paz, Idipaz, Madrid, Spain. Electronic address: jose.bernardino@salud.madrid.org.
authors.forename: Jose I
authors.initials: JI
authors.lastname: Bernardino
authors.affiliation: University College London, London, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mocroft
authors.affiliation: School of Medicine, University College Dublin, Dublin, Ireland.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Mallon
authors.affiliation: University Bordeaux, ISPED, Centre Inserm U897-Epidemiologie-Biostatistique, Bordeaux, France.
authors.forename: Cedrick
authors.initials: C
authors.lastname: Wallet
authors.affiliation: Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Gerstoft
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Russell
authors.affiliation: Department of Global Health and Division of Infectious Diseases, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Reiss
authors.affiliation: Hospital Pitie-Salpetriere UPMC University Paris 06, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.affiliation: Saint Pierre University Hospital Brussels, Brussels, Belgium.
authors.forename: Stephane
authors.initials: S
authors.lastname: De Wit
authors.affiliation: University Bordeaux, ISPED, Centre Inserm U897-Epidemiologie-Biostatistique, Bordeaux, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Richert
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Abdel
authors.initials: A
authors.lastname: Babiker
authors.affiliation: Laboratory Medicine Department, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Buño
authors.affiliation: Vita-Salute San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Castagna
authors.affiliation: Department of Infectious and Tropical Diseases, Hôpital Saint-Antoine, AP-HP and INSERM UMR_S 1136, Paris, France.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Girard
authors.affiliation: University Bordeaux, ISPED, Centre Inserm U897-Epidemiologie-Biostatistique, Bordeaux, France.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Chene
authors.affiliation: College of Professors of Infectious and Tropical Diseases, Paris, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Raffi
authors.affiliation: Department of Internal Medicine, Hospital Universitario La Paz, Idipaz, Madrid, Spain.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Arribas
mesh_terms: D015502:Absorptiometry, Photon; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects*; D001851:Bone Diseases, Metabolic / Q000139:chemically induced* / Q000453:epidemiology / Q000503:physiopathology; D018791:CD4 Lymphocyte Count; D015897:Comorbidity; D000069454:Darunavir / Q000008:administration & dosage / Q000009:adverse effects; D004359:Drug Therapy, Combination; D000068679:Emtricitabine / Q000008:administration & dosage / Q000009:adverse effects; D005060:Europe / Q000453:epidemiology; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D010022:Osteopetrosis / Q000139:chemically induced* / Q000453:epidemiology / Q000503:physiopathology; D000068898:Raltegravir Potassium / Q000008:administration & dosage / Q000009:adverse effects; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects; D000068698:Tenofovir / Q000008:administration & dosage / Q000009:adverse effects; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D000068898:Raltegravir Potassium; D000068698:Tenofovir; D000068679:Emtricitabine; D019438:Ritonavir; D000069454:Darunavir