title: Effect of therapeutic intensification followed by HIV DNA prime and rAd5 boost vaccination on HIV-specific immunity and HIV reservoir (EraMune 02): a multicentre randomised clinical trial.
abstract: BACKGROUND
  Achievement of a cure for HIV infection might need reactivation of latent virus and improvement of HIV-specific immunity. As an initial step, in this trial we assessed the effect of antiretroviral therapy intensification and immune modulation with a DNA prime and recombinant adenovirus 5 (rAd5) boost vaccine.
  
  
  METHODS
  In this multicentre, randomised, open-label, non-comparative, phase 2 clinical trial, we enrolled eligible adults 18-70 years of age with chronic HIV-1 infection on suppressive antiretroviral therapy with current CD4 count of at least 350 cells per μL and HIV DNA between 10 and 1000 copies per 10(6) peripheral blood mononuclear cells. After an 8 week lead-in of antiretroviral intensification therapy (standard dose raltegravir and dose-adjusted maraviroc based on baseline antiretroviral therapy), patients were randomly assigned (1:1) to receive antiretroviral therapy intensification alone or intensification plus injections of HIV DNA prime vaccine (4 mg VRC-HIVDNA016-00-VP) at weeks 8, 12, and 16, followed by HIV rAd5 boost vaccine (10(10) particle units of VRC-HIVADV014-00-VP) at week 32. Randomisation was computer generated in permuted blocks of six and was stratified by study site. The primary endpoint was a 0·5 log10 or greater decrease in HIV DNA in peripheral blood mononuclear cells at week 56. This study is registered with ClinicalTrials.gov, number NCT00976404.
  
  
  RESULTS
  Between Nov 29, 2010, and Oct 28, 2011, we enrolled 28 eligible patients from three academic HIV clinics in the USA. After the 8 week lead-in of antiretroviral intensification therapy, 14 patients were randomly assigned to continue antiretroviral therapy intensification alone and 14 to intensification plus vaccine. Enrolled participants had median CD4 count of 636 cells per μL, median HIV DNA 170 copies per 10(6) peripheral blood mononuclear cells, and duration of antiretroviral therapy of 13 years. The median amount of HIV DNA did not change significantly between baseline and week 56 in the antiretroviral therapy intensification plus vaccine group. One participant in the antiretroviral therapy intensification alone group reached the primary endpoint, with 0·55 log10 decrease in HIV DNA in peripheral blood mononuclear cells. Both treatments were well tolerated. No severe or systemic reactions to vaccination occurred, and five serious adverse events were recorded during the study, most of which resolved spontaneously or were judged unrelated to study treatments.
  
  
  CONCLUSIONS
  Antiretroviral therapy intensification followed by DNA prime and rAd5 boost vaccine did not significantly increase HIV expression or reduce the latent HIV reservoir. A multifaceted approach that includes stronger activators of HIV expression and novel immune modulators will probably be needed to reduce the latent HIV reservoir and allow for long-term control in patients off antiretroviral therapy.
  
  
  BACKGROUND
  Objectif Recherche Vaccin SIDA (ORVACS).
authors.affiliation: Center for Global Health and Division of Infectious Diseases, Northwestern University, Chicago, IL, USA. Electronic address: c-achenbach@northwestern.edu.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Achenbach
authors.affiliation: INSERM, UMRS 943, Paris, France; UPMC University of Paris 06, UMRS 943, Paris, France.
authors.forename: Lambert
authors.initials: L
authors.lastname: Assoumou
authors.affiliation: HIV/AIDS Division, San Francisco General Hospital and University of California San Francisco, San Francisco, CA, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Division of Infectious Diseases, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Wilkin
authors.affiliation: Center for Global Health and Division of Infectious Diseases, Northwestern University, Chicago, IL, USA.
authors.forename: Baiba
authors.initials: B
authors.lastname: Berzins
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Casazza
authors.affiliation: INSERM, UMRS 943, Paris, France; UPMC University of Paris 06, UMRS 943, Paris, France; Department of Virology, AP-HP Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Sidonie
authors.initials: S
authors.lastname: Lambert-Niclot
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.affiliation: INSERM, UMRS 943, Paris, France; UPMC University of Paris 06, UMRS 943, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Costagliola
authors.affiliation: INSERM, UMRS 943, Paris, France; UPMC University of Paris 06, UMRS 943, Paris, France; Department of Virology, AP-HP Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
authors.affiliation: INSERM, UMRS 943, Paris, France; UPMC University of Paris 06, UMRS 943, Paris, France; Department of Infectious Diseases, AP-HP Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.affiliation: INSERM, UMRS 943, Paris, France; UPMC University of Paris 06, UMRS 943, Paris, France; Department of Immunology, AP-HP Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Autran
authors.affiliation: Center for Global Health and Division of Infectious Diseases, Northwestern University, Chicago, IL, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Murphy
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000276:immunology; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D018791:CD4 Lymphocyte Count; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D007117:Immunization, Secondary; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology; D019562:Viral Load; D055815:Young Adult
chemical_list: D016915:AIDS Vaccines; D019380:Anti-HIV Agents; D019444:Vaccines, DNA