title: Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial.
abstract: BACKGROUND
  Activating the expression of latent virus is an approach that might form part of an HIV cure. We assessed the ability of the histone deacetylase inhibitor panobinostat to disrupt HIV-1 latency and the safety of this strategy.
  
  
  METHODS
  In this phase 1/2 clinical trial, we included aviraemic adults with HIV treated at Aarhus University Hospital, Denmark. Participants received oral panobinostat (20 mg) three times per week every other week for 8 weeks while maintaining combination antiretroviral therapy. The primary outcome was change from baseline of cell-associated unspliced HIV RNA. Secondary endpoints were safety, plasma HIV RNA, total and integrated HIV DNA, infectious units per million CD4 T cells, and time to viral rebound during an optional analytical treatment interruption of antiretroviral therapy. This trial is registered with ClinicalTrial.gov, number NCT01680094.
  
  
  RESULTS
  We enrolled 15 patients. The level of cell-associated unspliced HIV RNA increased significantly at all timepoints when patients were taking panobinostat (p < 0·0001). The median maximum increase in cell-associated unspliced HIV RNA during panobinostat treatment was 3·5-fold (range 2·1-14·4). Panobinostat induced plasma viraemia with an odds ratio of 10·5 (95% CI 2·2-50·3; p = 0·0002) compared with baseline. We recorded a transient decrease in total HIV DNA, but no cohort-wide reduction in total HIV DNA, integrated HIV DNA, or infectious units per million. Nine patients participated in the analytical treatment interruption, median time to viral rebound was 17 days (range 14-56). Panobinostat was well tolerated. 45 adverse events were reported, but only 16 (all grade 1) were presumed related to panobinostat.
  
  
  CONCLUSIONS
  Panobinostat effectively disrupts HIV latency in vivo and is a promising candidate for future combination clinical trials aimed at HIV eradication. However, panobinostat did not reduce the number of latently infected cells and this approach may need to be combined with others to significantly affect the latent HIV reservoir.
  
  
  BACKGROUND
  The Danish Council for Strategic Research and Aarhus University.
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Denmark. Electronic address: thomrasm@rm.dk.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rasmussen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Denmark.
authors.forename: Christel R
authors.initials: CR
authors.lastname: Brinkmann
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Olesen
authors.affiliation: Department of Clinical Immunology, Aarhus University Hospital, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Erikstrup
authors.affiliation: Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC, Australia.
authors.forename: Ajantha
authors.initials: A
authors.lastname: Solomon
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Denmark.
authors.forename: Anni
authors.initials: A
authors.lastname: Winckelmann
authors.affiliation: Westmead Millennium Institute for Medical Research, University of Sydney, Westmead, NSW, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Palmer
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Dinarello
authors.affiliation: Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA; Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Buzon
authors.affiliation: Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA; Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.affiliation: Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC, Australia; Centre for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia.
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Denmark.
authors.forename: Ole S
authors.initials: OS
authors.lastname: Søgaard