title: Combined effect of Vacc-4x, recombinant human granulocyte macrophage colony-stimulating factor vaccination, and romidepsin on the HIV-1 reservoir (REDUC): a single-arm, phase 1B/2A trial.
abstract: Immune priming before reversal of latency might be a component of a functional HIV cure. To assess this concept, we assessed if therapeutic HIV immunisation followed by latency reversal would affect measures of viral transcription, plasma viraemia, and reservoir size in patients with HIV on suppressive antiretroviral therapy.
  
  
  
  In this single-arm, phase 1B/2A trial, we recruited adults treated at the Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark (aged ≥18 years) with successfully treated HIV-1 with plasma RNA loads of less than 50 copies per mL for the previous year and CD4 counts of at least 500 cells per μL. Exclusion criteria included CD4 counts of less than 200 cells per μL within the past 2 years, active hepatitis B or C infections, and clinically significant cardiac disease, including QTc prolongation. Participants received six therapeutic intradermal HIV-1 immunisations with 12 mg/mL Vacc-4x and 0·6 mg/mL rhuGM-CSF over 12 weeks (at 0 weeks, 1 week, 2 weeks, 3 weeks, 11 weeks, and 12 weeks) before receiving 5 mg/m(2) intravenous romidepsin once a week for 3 weeks. This procedure was followed by analytical treatment interruption. Coprimary outcomes were changes in copies of HIV-1 DNA (total and integrated) per million CD4 T cells and infectious units per million (IUPM) resting memory CD4 T cells established by viral outgrowth, assessed in all patients receiving at least one dose of active treatment with assessable data. We assessed total HIV-1 DNA at screening, before romidepsin treatment, and 6 weeks after romidepsin treatment. We assessed integrated viral DNA at baseline, before romidepsin treatment, and 8 weeks after romidepsin treatment. We assessed IUPM at screening, 2 weeks before romidepsin treatment, and 6 weeks after romidepsin treatment. This trial is registered at ClinicalTrials.gov, number NCT02092116.
  
  
  
  Between May 19, 2014, and Oct 8, 2014, we enrolled 20 individuals, of whom 17 completed all Vacc-4x and rhuGM-CSF administrations and romidepsin infusions. 16 of 17 had assessable total HIV-1 DNA, 15 of 17 had assessable integrated HIV-1 DNA, and six of 17 had assessable IUPM at baseline and at one or more timepoints after study treatment. Total HIV-1 DNA declined from screening to 6 weeks after romidepsin treatment (mean reduction 39·7%, 95% CI -59·7 to -11·5; p=0·012). The decrease in integrated HIV-1 DNA from baseline to 8 weeks after romidepsin treatment was not significant (19·2%, -38·6 to 6·3; p=0·123). Among the six assessable participants, the mean reduction in IUPM from screening to 6 weeks after romidepsin treatment was 38·0% (95% CI -67·0 to -8·0; p=0·019). Of 141 adverse events, 134 (95%) were grade 1 and seven (5%) were grade 2-3.
  
  
  
  This in-vivo combinatorial approach provides the first evidence for the feasibility of a combined shock and kill strategy, but also emphasises that further optimisation of this strategy is needed to achieve a sizeable effect on the latent reservoir that will translate into clinically measurable benefits for people living with HIV-1.
  
  
  
  Bionor Pharma, the Research Council of Norway, and SkatteFUNN.
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address: steffenleth@gmail.com.
authors.forename: Steffen
authors.initials: S
authors.lastname: Leth
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Mariane H
authors.initials: MH
authors.lastname: Schleimann
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Nissen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Jesper F
authors.initials: JF
authors.lastname: Højen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Olesen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Mette E
authors.initials: ME
authors.lastname: Graversen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Sofie
authors.initials: S
authors.lastname: Jørgensen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Anne Sofie
authors.initials: AS
authors.lastname: Kjær
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Denton
authors.affiliation: Bionor Pharma, Oslo, Norway.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Mørk
authors.affiliation: Bionor Pharma, Oslo, Norway.
authors.forename: Maja A
authors.initials: MA
authors.lastname: Sommerfelt
authors.affiliation: Bionor Pharma, Oslo, Norway.
authors.forename: Kim
authors.initials: K
authors.lastname: Krogsgaard
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rasmussen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address: olesoega@rm.dk.
authors.forename: Ole Schmeltz
authors.initials: OS
authors.lastname: Søgaard
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000276:Adjuvants, Immunologic; D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004279:DNA, Viral / Q000097:blood; D047630:Depsipeptides / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy* / Q000628:therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007115:Immunization Schedule; D007156:Immunologic Memory; D007271:Injections, Intradermal; D008297:Male; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D014611:Vaccination; D019562:Viral Load; D017735:Virus Latency; D055815:Young Adult
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D004279:DNA, Viral; D047630:Depsipeptides; D011994:Recombinant Proteins; C494182:Vacc-4x; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C087123:romidepsin