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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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HIV

Intervention / Treatment
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* Drug: MGN1703
* Drug: MGN1703


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |