Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure

• ClinicalTrials.gov Identifier: NCT02961829
• Recruitment Status: Completed
• First Posted: November 11, 2016
• Last Update Posted: July 28, 2020
• Sponsor: Federal University of São Paulo
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo; Conselho Nacional de Desenvolvimento Científico e Tecnológico; ViiV Healthcare
• Information provided by (Responsible Party): Ricardo Sobhie Diaz, MD, PHD, Federal University of São Paulo

Tracking Information

• First Submitted Date: December 18, 2015
• First Posted Date: November 11, 2016
• Last Update Posted Date: July 28, 2020
• Actual Study Start Date: July 2015
• Actual Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 27, 2017)

• Ultrasensitive RNA Viral load, [ Time Frame: from baseline and every 4 weeks up to 48 weeks. ]
• Cell-associated HIV RNA [ Time Frame: from baseline and every 4 weeks up to 48 weeks. ]
• Episomal DNA [ Time Frame: from baseline and every 4 weeks up to 48 weeks ]
• specific HIV antibodies [ Time Frame: from baseline and every 4 weeks up to 48 weeks ]
• CD38 and HLA-DR on CD4 and CD8+ cells [ Time Frame: from baseline and every 4 weeks up to 48 weeks ]
• PBMC for env sequence evolution [ Time Frame: from baseline and every 4 weeks up to 48 weeks ]

Original Primary Outcome Measures (submitted: November 9, 2016)

• Ultrasensitive RNA Viral load, [ Time Frame: from baseline and every 4 weeks up to 48 weeks. ]
• Cell-associated HIV RNA [ Time Frame: from baseline and every 4 weeks up to 48 weeks. ]
• Epissomal DNA [ Time Frame: from baseline and every 4 weeks up to 48 weeks ]
• specific HIV antibodies [ Time Frame: from baseline and every 4 weeks up to 48 weeks ]
• CD38 and HLA-DR on CD4 and CD8+ cells [ Time Frame: from baseline and every 4 weeks up to 48 weeks ]
• PBMC for env sequence evolution [ Time Frame: from baseline and every 4 weeks up to 48 weeks ]

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure
• Official Title: Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure
• Brief Summary: It is becoming clear that a combination of interventions will be desirable to achieve HIV cure. Therefore the investigators propose a pilot proof of concept study, using combination of a number of different interventions for eradicating residual plasma viremia and decreasing HIV reservoirs. The investigators hypothesize that, (i) antiretroviral intensification using Maraviroc, and/or dolutegravir with (ii) Dendritic Cell vaccination using autologous HIV, and (iii) purging intervention using the Class III HDACs, Sirtuin-1, and (iv) decreasing the ratio of long-lived central memory (TCM)/transitional memory (TTM) CD4+ T-cells using Auranofin will provide a synergistic impact leading to a sterilizing cure of HIV infection. Results of this study may provide insightful evidence for planning the next steps using the more efficacious combination of intervention strategies towards HIV sterilizing cure.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Chronic Infection
• HIV

Intervention

• Drug: Maraviroc
  antiretroviral intensification
  Other Names:

  • Selzentry
  • Celsentri
• Drug: Dolutegravir
  antiretroviral intensification
  Other Name: Tivicay
• Biological: Dendritic Cell Vaccine
  Therapeutic vaccination
  Other Name: DC Vaccine
• Drug: Auranofin
  purging
  Other Name: Gold Salt
• Drug: Sirtuin Histone deacetylase inhibitor
  latency disruption
  Other Name: Nicotinamide

Study Arms

• No Intervention: Antiretroviral Treated (ART) Group
  Five patients will receive no further intervention this group (control group)
• Experimental: ART Intensification Group
  Five patients will receive antiretroviral intensification with maraviroc and dolutegravir for 48 weeks
  Interventions:

  • Drug: Maraviroc
  • Drug: Dolutegravir
• Experimental: ART Intensification + Nicotinamide Group
  Five patients will receive antiretroviral intensification with maraviroc and dolutegravir and the Sirtuin Histone deacetylase inhibitor nicotinamide for 48 weeks.
  Interventions:

  • Drug: Maraviroc
  • Drug: Dolutegravir
  • Drug: Sirtuin Histone deacetylase inhibitor
• Experimental: ART Intensification + Auranofin Group
  Five patients will receive antiretroviral intensification with maraviroc and dolutegravir for 48 weeks and the gold salt auranofin for 24 weeks.
  Interventions:

  • Drug: Maraviroc
  • Drug: Dolutegravir
  • Drug: Auranofin
• Experimental: ART Intensification + DC vaccine Group
  Five patients will receive antiretroviral intensification with dolutegravir and for 48 weeks, and dendritic cell vaccine.
  Interventions:

  • Drug: Dolutegravir
  • Biological: Dendritic Cell Vaccine
• Experimental: Multi Interventional Group
  Five patients will receive antiretroviral intensification with dolutegravir and the Sirtuin Histone deacetylase inhibitor nicotinamide for 48 weeks, and gold salt for 24 weeks and dendritic cell vaccine.
  Interventions:

  • Drug: Dolutegravir
  • Biological: Dendritic Cell Vaccine
  • Drug: Auranofin
  • Drug: Sirtuin Histone deacetylase inhibitor

Publications *

• de Almeida Baptista MV, da Silva LT, Samer S, Oshiro TM, Shytaj IL, Giron LB, Pena NM, Cruz N, Gosuen GC, Ferreira PRA, Cunha-Neto E, Galinskas J, Dias D, Sucupira MCA, de Almeida-Neto C, Salomao R, da Silva Duarte AJ, Janini LM, Hunter JR, Savarino A, Juliano MA, Diaz RS. Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical trial. AIDS Res Ther. 2022 Jan 12;19(1):2. doi: 10.1186/s12981-021-00426-z.
• Diaz RS, Shytaj IL, Giron LB, Obermaier B, Della Libera E Jr, Galinskas J, Dias D, Hunter J, Janini M, Gosuen G, Ferreira PA, Sucupira MC, Maricato J, Fackler O, Lusic M, Savarino A; SPARC Working Group. Potential impact of the antirheumatic agent auranofin on proviral HIV-1 DNA in individuals under intensified antiretroviral therapy: Results from a randomised clinical trial. Int J Antimicrob Agents. 2019 Nov;54(5):592-600. doi: 10.1016/j.ijantimicag.2019.08.001. Epub 2019 Aug 5.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 9, 2016): 30
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: March 2020
• Actual Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• > 18 years old Documented HIV-1 infection.
• Has voluntarily signed ICF.
• On HAART ≥ 2 years, without changes in the 24 weeks immediately prior to screening.
• HIV viral load <50 copies/mL, and never > 50 copies/mL on 2 consecutive occasions in the last 2 years. CD4 count nadir.
• > 350 cells/ mm3 Current CD4 count > 500 cells/ mm3.
• R5 HIV-1 at Screening as defined by proviral DNA genotropism.

Exclusion Criteria:

A subject will NOT be eligible for study participation if he/she meets ANY of the following criteria:

• Any evidence of an active AIDS-defining condition.
• Any significant acute medical illness in the past 8 weeks.
• Women who are pregnant or breastfeeding.
• Use of any of the following within 90 days prior to entry: systemic cytotoxic chemotherapy; investigational agents; immunomodulators (colony-stimulating factors, growth factors, systemic corticosteroids, HIV vaccines, immune globulin, interleukins, interferons); coumadin, warfarin, or other Coumadin derivative anticoagulants. Use of an agent definitely or possibly associated with effects on QT intervals: amiodarone, arsenic trioxide, astemizole, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, probucol, procainamide, quinidine, sotalol, sparfloxacin, terfenadine, thioridazine.
• Receipt of compounds with HDAC inhibitor-like activity, such as valproic acid or nicotinamide within the last 30 days. Potential participants may enroll after a 30-day washout period.
• Known hypersensitivity to the components of gold salt, nicotinamide or its analogs.
• Hepatitis B (HBsAg +) or Hepatitis C (HCV RNA +) infection.
• Known renal insufficiency defined as calculated creatinine clearance (Cockcroft Gault formula) <60 mL/min.
• Subjects with a laboratory abnormality grade 3 or 4 with the following exceptions: pancreatic amylase, cholesterol, triglyceride, gamma glutamyl transpeptidase, bilirubin.
• Any condition which, in the investigators opinion, could compromise the subject's safety or adherence to the trial protocol.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil

Administrative Information

• NCT Number: NCT02961829
• Other Study ID Numbers: SPARC-7
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Ricardo Sobhie Diaz, MD, PHD, Federal University of São Paulo
• Original Responsible Party: Same as current
• Current Study Sponsor: Federal University of São Paulo
• Original Study Sponsor: Same as current

Collaborators

• Fundação de Amparo à Pesquisa do Estado de São Paulo
• Conselho Nacional de Desenvolvimento Científico e Tecnológico
• ViiV Healthcare

• Investigators: Not Provided
• PRS Account: Federal University of São Paulo
• Verification Date: July 2020