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Bryostatin-1 for latent virus reactivation in HIV-infected patients on antiretroviral therapy

Gutiérrez, Carolina; Serrano-Villar, Sergio; Madrid-Elena, Nadia; Pérez-Elías, Maria J.; Martín, Maria Elena; Barbas, Coral; Ruipérez, Javier; Muñoz, Eduardo; Muñoz-Fernández, Maria Angeles; Castor, Trevor; Moreno, Santiago

doi: 10.1097/QAD.0000000000001064
Clinical Science

Objective: 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.

Methods: 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/m2) compared with placebo.

Results: Twelve patients were included, four in each arm. Bryostatin-1 was well tolerated in all participants. Two patients in the 20 μg/m2 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/m2 arm, and below 50 pg/ml (0.05 nmol/l) in those in the 20 μg/m2 arm.

Conclusion: 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.

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.

Correspondence to Santiago Moreno, Department of Infectious Diseases, Hospital Universitario Ramón y Cajal, Carretera de Colmenar, Km. 9.100, 28034 Madrid, Spain. Tel: +0034 913 368 710; fax: +0034 913 368 792; e-mail:

Received 13 January, 2016

Revised 11 February, 2016

Accepted 11 February, 2016

Copyright © 2016 Wolters Kluwer Health, Inc.