Toll-like Receptor 9 Agonist Treatment in Chronic HIV-1 Infection (TEACH)

Toll-like Receptor 9 Enhancement of Antiviral Immunity in Chronic HIV-1 Infection: a Phase 1b/2a Trial

Combination antiretroviral treatment (cART) effectively suppresses virus replication and partially restores immune functions. However, cART cannot cure HIV infection.

This study aim to investigate whether the antiviral immune response can be enhanced and/or viral transcription reactivated with MGN1703. MGN1703 is an agonist to toll-like receptor (TLR) 9. Activation of TLR9 has been shown to augment innate and adaptive immune effector functions, most notably enhanced NK cell and T cell functions.

Furthermore, TLR9 agonists have been shown in vitro to reactivate viral transcription in latently infected cells, potentially leading to enhanced recognition of infected cells by the immune effector cells.

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: MGN1703; Drug: MGN1703

Detailed Description

In Part A, participants will receive 4 weeks MGN1703 therapy (60 mg s.c. twice weekly). During the 4 weeks, participants will be closely monitored for safety and therapeutic effects of the drug. Targeted enrolment in Part A is 14-16 study subjects.

In Part B, participants will receive 24 weeks of MGN1703 therapy (60 mg s.c. twice weekly). During the 24 weeks, participants will be frequently monitored for safety and therapeutic effects of the drug. Targeted enrolment in Part B is 10-12 study subjects, preferentially recruited from part A.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Aarhus N, Denmark, 8200
    • Department for Infectious Diseases, Aarhus University Hospital
  • Hvidovre, Denmark, 2650
    • Department for Infectious Diseases, Amager and Hvidovre Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Documented HIV-1 infection
• Age >18 years
• CD4+ T-cell count >350/µL at screening
• On cART (for a minimum of 12 months)
• Able to give informed consent.

Exclusion Criteria:

• Pregnancy as determined by a positive urine beta-hCG (if female)
• Males or females who are unwilling or unable to use barrier contraception during sexual intercourse for the entire study period.
• Currently breast-feeding (if female)
• Viral load (HIV RNA) > 50 copies/mL
• Contraindication to receive MGN1703 as per current investigator brochure
• Presence of acute bacterial infection or undiagnosed febrile condition
• Concurrent chronic systemic immune therapy or immunosuppressant medication, including continuous systemic steroid treatment within the last 2 weeks prior to randomization
• Use of antibiotic therapy within the last 2 weeks prior to randomization
• Known HBV or HCV infection
• Any medical, psychiatric, social, or occupational condition or other responsibility that, in the judgment of the Principal Investigator (PI), would interfere with the evaluation of study objectives (such as severe alcohol abuse, severe drug abuse, dementia)
• Unable to follow protocol regimen

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MGN1703; TLR-9 agonist MGN1703 administered to HIV-1 positive patients on cART	Drug: MGN1703; 60 mg s.c. twice weekly for 4 weeks; Other Names: TLR9 agonist; CpG oligodeoxynucleotides; Drug: MGN1703; 60 mg s.c. twice weekly for 24 weeks; Other Names: TLR9 agonist; CpG oligodeoxynucleotides

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: NK cell activation	As measured by CD69 expression	12 weeks
Part B: Quantification of the size of the HIV reservoir	As measured by quantitative viral outgrowth (qVOA) and total HIV DNA	32 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability, as measured by adverse events (AE), adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR) and suspected unexpected serious adverse reactions (SUSAR).	Safety evaluation, as measured by adverse events (AE), adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR) and suspected unexpected serious adverse reactions (SUSAR).	12 weeks
The size of the HIV-1 reservoir	HIV DNA and others measures	12 weeks
Viral transcription	Plasma HIV RNA and cell-associated unspliced HIV RNA	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of MGN1703 on T and NK cell activation in the gut	Changes in the expression of activation markers such as CD69.	12 weeks

Collaborators and Investigators

• Sponsor: University of Aarhus
• Investigators: Study Chair: Lars J Østergaard, MD,PhD,DMSc, Department for Infectious Diseases, Aarhus University Hospital, Denmark

Publications and helpful links

General Publications

• Vibholm LK, Konrad CV, Schleimann MH, Frattari G, Winckelmann A, Klastrup V, Jensen NM, Jensen SS, Schmidt M, Wittig B, Zuwala K, Mack K, Olesen R, Hua S, Lichterfeld M, Ostergaard L, Denton PW, Tolstrup M, Sogaard OS. Effects of 24-week Toll-like receptor 9 agonist treatment in HIV type 1+ individuals. AIDS. 2019 Jul 1;33(8):1315-1325. doi: 10.1097/QAD.0000000000002213.
• Vibholm L, Schleimann MH, Hojen JF, Benfield T, Offersen R, Rasmussen K, Olesen R, Dige A, Agnholt J, Grau J, Buzon M, Wittig B, Lichterfeld M, Petersen AM, Deng X, Abdel-Mohsen M, Pillai SK, Rutsaert S, Trypsteen W, De Spiegelaere W, Vandekerchove L, Ostergaard L, Rasmussen TA, Denton PW, Tolstrup M, Sogaard OS. Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection. Clin Infect Dis. 2017 Jun 15;64(12):1686-1695. doi: 10.1093/cid/cix201.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): June 25, 2017

Study Registration Dates

• First Submitted: April 30, 2015
• First Submitted That Met QC Criteria: May 11, 2015
• First Posted (Estimate): May 14, 2015

Study Record Updates

• Last Update Posted (Actual): June 29, 2017
• Last Update Submitted That Met QC Criteria: June 28, 2017
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; CPG-oligonucleotide
• Other Study ID Numbers: TEA-001