Drugs

Tat Oyi

Drug Class: Therapeutic Vaccines Organization: Biosantech Phase of Development: I/IIa

(Compound details obtained from Treatment Action Group website,1 Biosantech website,2 and Retrovirology article3)

Pharmacology


Mechanism of Action: Therapeutic vaccine. Tat Oyi is a protein-based therapeutic HIV vaccine.1 Therapeutic vaccines are being investigated as an immunotherapeutic approach to correcting HIV-associated immune dysfunction, such as impaired dendritic cell (DC) responses to HIV and suboptimal adaptive immune responses (including HIV-specific T cell responses).4-7 A therapeutic vaccine may potentially increase the effectiveness of ART, simplify ART regimens, or allow for periodic structured treatment interruptions. A successful therapeutic vaccine would either completely eradicate the virus or improve an individual’s immune response sufficiently to suppress viral replication without ART. In either case, a therapeutic vaccine would help to circumvent a lifetime of ART.8

While the focus of therapeutic HIV vaccine study has been on the development of vaccines that induce cellular immune responses, the Tat Oyi vaccine is designed to generate antibodies that act against extracellular HIV Tat. The Tat Oyi vaccine is composed of a synthetic, full-length HIV Tat protein based on the Oyi strain of HIV-1.3,9,10 HIV Tat is a regulatory protein that primarily activates HIV gene expression in the host cell nucleus. It is also secreted by HIV-infected CD4 cells into the extracellular space, where it may not only protect HIV-infected cells by inhibiting cellular immune responses against HIV, but also activate latently infected cells. The Tat gene of the Oyi strain contains specific mutations not seen in Tat genes of other HIV strains. The Tat protein of the Oyi strain is unable to activate HIV transcription and has unique immunologic characteristics. The vaccine based on Tat Oyi induces the production of antibodies directed against conserved three-dimensional epitopes on Tat and has been shown to be capable of recognizing Tat variants from several different HIV-1 strains.3,9,11,12

Researchers suggest that the Tat Oyi vaccine may help individuals with HIV control viral load levels in the absence of ART and help with latent HIV reservoir reduction by supporting cytotoxic T lymphocyte (CTL) responses to infection. To this end, Tat Oyi’s potential has been evaluated in a Phase I/IIa trial (NCT01793818).2,3,11,13


Select Clinical Trials


Study Identifiers: EVATAT trial; NCT01793818
Sponsor: Biosantech
Phase: I/IIa
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety of three different doses of the Tat Oyi vaccine and the ability of the vaccine to control viral load levels after treatment interruption of ART.
Study Population:
  • Participants were adults with chronic HIV infection.
  • Participants had been on a three-drug ART regimen for at least 12 months and had maintained HIV RNA <40 copies/mL during that time. For the past 3 months, participants’ ART regimens had not changed.
  • Participants had CD4 counts >350 cells/mm3 and in the past 12 months had nadir CD4 counts >200 cells/mm3.1,3,13
Selected Study Results:


Adverse Events


In the EVATAT trial (NCT01793818), five out of 46 evaluable participants experienced a serious adverse event (SAE). Only one SAE (facial neuralgia), which occurred in one participant who received the lowest dose of the vaccine, was considered to be possibly related to the Tat Oyi vaccine. This event occurred 11 months after vaccination and lasted for 1 week. Two of the other SAEs that occurred during the study were considered unrelated to Tat Oyi vaccination, and the remaining two SAEs (tuberculosis and diarrhea) could not be clearly established as related to the vaccine.3 Injection site pain was also reported in several participants.9


Drug Interactions


The EVATAT trial (NCT01793818) did not identify any drug-drug interactions that were associated with the use of Tat Oyi.9,13


References


  1. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed April 25, 2019.
  2. Biosantech website. Research program Tat. http://biosantech-vih.fr/programme-de-recherche-tat/?lang=en. Accessed April 25, 2019.
  3. Loret EP, Darque A, Jouve E, et al. Intradermal injection of a Tat Oyi-based therapeutic HIV vaccine reduces of 1.5 log copies/mL the HIV RNA rebound median and no HIV DNA rebound following cART interruption in a Phase I/II randomized controlled clinical trial. Retrovirology. 2016;13. doi:10.1186/s12977-016-0251-3
  4. Lederman M, Rodriguez B, Sieg S. Immunopathogenesis of HIV Infection. In: Coffey S, Volberding P, eds. HIV InSite Knowledge Base. University of California San Francisco; 2004. http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-02-01-04. Accessed April 25, 2019.
  5. Miller E, Bhardwaj N. Advances in dendritic cell immunotherapies for HIV-1 infection. Expert Opin Biol Ther. 2014;14(11):1545-1549.
  6. Smith PL, Tanner H, Dalgleish A. Developments in HIV-1 immunotherapy and therapeutic vaccination. F1000Prime Rep. 2014;6(43). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047951/. Accessed April 25, 2019.
  7. Routy J-P, Boulassel M-R, Yassine-Diab B, et al. Immunologic activity and safety of autologous HIV RNA–electroporated dendritic cells in HIV-1 infected patients receiving antiretroviral therapy. Clin Immunol. 2010;134(2):140-147.
  8. Graziani GM, Angel JB. Evaluating the efficacy of therapeutic HIV vaccines through analytical treatment interruptions. J Int AIDS Soc. 2015;18(1):20497.
  9. Escaich S. Tat Oyi-based candidate therapeutic vaccine: a successful Phase 1 clinical trial in HIV-1 infected patients. Abstract presented at: International Conference on Retroviruses and Novel Drugs; June 8-9, 2015; Chicago, IL. https://retrovirus.conferenceseries.com/abstract/2015/tat-oyi-based-candidate-therapeutic-vaccine-a-successful-phase-1-clinical-trial-in-hiv-1-infected-patients. Accessed April 25, 2019.
  10. Jefferys R and Jacobson J. Therapeutic vaccines and immune-based therapies. CUREiculum: HIV/AIDS and cure basics – Module 12. PowerPoint presentation available on the AIDS Vaccine Advocacy Coalition (AVAC) website: http://www.avac.org/sites/default/files/u16/Theraeutic_Vaccine_Module_June.pptx. Accessed April 25, 2019.
  11. Watkins JD, Lancelot S, Campbell GR, et al. Watkins. Reservoir cells no longer detectable after a heterologous SHIV challenge with the synthetic HIV-1 Tat Oyi vaccine. Retrovirology. 2006;3:8. doi:10.1186/1742-4690-3-8
  12. Campbell GR and Loret EP. What does the structure-function relationship of the HIV-1 Tat protein teach us about developing an AIDS vaccine? Retrovirology. 2009;6:50. doi:10.1186/1742-4690-6-50
  13. Biosantech. Evaluation on seropositive patients of a synthetic vaccine targeting the HIV Tat protein. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 14, 2013. NLM Identifier: NCT01793818. https://clinicaltrials.gov/ct2/show/NCT01793818. Accessed April 25, 2019.


Last Reviewed: April 25, 2019