title: Bryostatin-1 for latent virus reactivation in HIV-infected patients on antiretroviral therapy.
abstract: The protein kinase C (PKC) agonist bryostatin-1 has shown significant ex-vivo potency to revert HIV-1 latency, compared with other latency reversing agents (LRA). The safety of this candidate LRA remains to be proven in treated HIV-1-infected patients.
  
  
  
  In this pilot, double-blind phase I clinical-trial (NCT 02269605), we included aviraemic HIV-1-infected patients on triple antiretroviral therapy to evaluate the effects of two different single doses of bryostatin-1 (10 or 20 μg/m) compared with placebo.
  
  
  
  Twelve patients were included, four in each arm. Bryostatin-1 was well tolerated in all participants. Two patients in the 20 μg/m arm developed grade 1 headache and myalgia. No detectable increases of cell-associated unspliced (CA-US) HIV-1-RNA were observed in any study arm, nor differences in HIV-1 mRNA dynamics between arms (P = 0.44). The frequency of samples with low-level viraemia did not differ between arms and low-level viraemia did not correlate with CA-US HIV-1-RNA levels (P = 0.676). No changes were detected on protein kinase C (PKC) activity and in biomarkers of inflammation (sCD14 and interleukin-6) in any study arm. After the single dose of bryostatin-1, plasma concentrations were under detection limits in all the patients in the 10 μg/m arm, and below 50 pg/ml (0.05 nmol/l) in those in the 20 μg/m arm.
  
  
  
  Bryostatin-1 was safe at the single doses administered. However, the drug did not show any effect on PKC activity or on the transcription of latent HIV, probably due to low plasma concentrations. This study will inform next trials aimed at assessing higher doses, multiple dosing schedules or combination studies with synergistic drugs.
authors.affiliation: aDepartment of Infectious Diseases bDepartment of Biochemistry Research, Ramón y Cajal University Hospital, Alcalá University and IRYCIS cCEMBIO, San Pablo CEU University, Madrid dDepartment of Cell Biology, Physiology and Immunology, Maimonides Biomedical Research Institute of Córdoba, Reina Sofía University Hospital, University of Córdoba eMolecular ImmunoBiology Laboratory, Gregorio Marañón University Hospital, IISGM, CIBER-BBN, Madrid, Spain fAphios Corporation, Boston, Massachusetts, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gutiérrez
authors.forename: Sergio
authors.initials: S
authors.lastname: Serrano-Villar
authors.forename: Nadia
authors.initials: N
authors.lastname: Madrid-Elena
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Pérez-Elías
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Martín
authors.forename: Coral
authors.initials: C
authors.lastname: Barbas
authors.forename: Javier
authors.initials: J
authors.lastname: Ruipérez
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Muñoz-Fernández
authors.forename: Trevor
authors.initials: T
authors.lastname: Castor
authors.forename: Santiago
authors.initials: S
authors.lastname: Moreno
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D054713:Bryostatins / Q000008:administration & dosage* / Q000009:adverse effects*; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D020536:Enzyme Activators / Q000008:administration & dosage* / Q000009:adverse effects*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010919:Placebos / Q000008:administration & dosage; D016896:Treatment Outcome; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D044966:Anti-Retroviral Agents; D054713:Bryostatins; D020536:Enzyme Activators; D010919:Placebos; C046785:bryostatin 1