Early Administration of Romidepsin and 3BNC117 in Treatment-naïve HIV Patients Starting ART

Study Overview
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Brief Summary
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To evaluate the effect of early viral reactivation by latency reversing agents (LRA) and/or administration of potent broadly neutralizing antibodies (bNAb) on the size of the latent HIV-1 reservoir in treatment naïve HIV-1 patients initiating antiretroviral therapy (ART)

Detailed Description
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The study will be conducted among ART naïve HIV-1-infected patients. Subjects will continue ART while receiving LRA romidepsin and/or bNAb 3BNC117.

Official Title
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Early Administration of Latency Reversing Therapy and Broadly Neutralizing Antibodies to Limit the Establishment of the HIV-1 Reservoir During Initiation of Antiretroviral Treatment - a Randomized Controlled Trial

Conditions
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Hiv

Intervention / Treatment
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* Drug: Romidepsin
* Drug: 3BNC117
* Drug: Antiretrovirals


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented HIV-1 infection CD4+ T cell count >200/µL on last visit prior to study entry ART naïve Able to give informed consent Exclusion Criteria: Any significant acute medical illness (not including primary HIV infection) in the past 8 weeks Any evidence of an active AIDS-defining opportunistic infection Active alcohol or substance use that, in the Investigator's opinion, will prevent adequate compliance with study therapy The following laboratory values at screening, but the values can be repeated within the screening period, but test results must be available before baseline (day 0) and checked for eligibility: Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN) Serum total bilirubin ≥3 ULN Estimated glomerular filtration rate (eGFR) ≤60 mL/min (based on serum creatinine or other appropriate validated markers) Platelet count ≤100 x10^9/L Absolute neutrophil count ≤1x10^9/L Serum potassium, magnesium, phosphorus outside ≥1.5 ULN/LLN Total calcium (corrected for serum albumin) or ionized calcium ≥1.5 ULN/LLN Hepatitis B or C infection as indicated by the presence of hepatitis B surface antigen (HBsAg) or hepatitis C virus RNA (HCV-RNA) in blood ECG at screening that shows QTc >450 ms when calculated using the Fridericia formula from either lead V3 or V4 [86] Use of: Warfarin or warfarin-derivatives HDACi An agent definitely or possibly associated with effects on QT intervals within 2 weeks of screening Drugs that induce or inhibit CYP3A4 or P-gp History of: Clinically significant cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for Torsades de pointes (e.g. heart failure) Malignancy or transplantation, including skin cancers or Kaposi sarcoma Diabetes mellitus Receipt of strong immunosuppressive or systemic chemotherapeutic agents within 28 days prior to study entry Known resistance to >2 classes of ART Known hypersensitivity to the components of romidepsin, 3BNC117 or their analogues Women who are pregnant or breastfeeding, or with a positive pregnancy test during screening or Women of Child Bearing Potential (WOCBP) who are unwilling or unable to use an acceptable method of non-estrogen containing contraceptions (according to the Danish Medicines Agency guidelines) to avoid pregnancy for the 3 week study period and 4 weeks after study treatment or until undetectable plasma HIV-1 RNA using standard assays Males or females who are unwilling or unable to use barrier contraception during sexual intercourse for the 3-week study period, and 4 weeks after study treatment or until undetectable plasma HIV-1 RNA using standard assays

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
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: antiretrovirals<br>Standard of care | Drug: Antiretrovirals<br>* Combination antiretroviral therapy<br>* Other names: ART;|
| Active Comparator: antiretrovirals + romidepsin<br>Standard of care + LRA | Drug: Romidepsin<br>* 5mg/m2 romidepsin will be administered IV on days 10, 17, and 24 after initiating ART<br>* Other names: Istodax;Drug: Antiretrovirals<br>* Combination antiretroviral therapy<br>* Other names: ART;|
| Active Comparator: antiretrovirals + 3BNC117<br>Standard of care + bNAb | Drug: 3BNC117<br>* 30 mg/kg 3BNC117 will be administered IV on day 7 and 21 after initiating ART<br>* Other names: Broadly neutralizing antibody;Drug: Antiretrovirals<br>* Combination antiretroviral therapy<br>* Other names: ART;|
| Active Comparator: antiretrovirals + romidepsin + 3BNC117<br>Standard of care + LRA + bNAb | Drug: Romidepsin<br>* 5mg/m2 romidepsin will be administered IV on days 10, 17, and 24 after initiating ART<br>* Other names: Istodax;Drug: 3BNC117<br>* 30 mg/kg 3BNC117 will be administered IV on day 7 and 21 after initiating ART<br>* Other names: Broadly neutralizing antibody;Drug: Antiretrovirals<br>* Combination antiretroviral therapy<br>* Other names: ART;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma HIV RNA kinetics | Time to undetectable (<20 c/mL) | 3 months | 
| Quantification of the size of the proviral HIV reservoir | Copies of total HIV-1 DNA per 10⁶ CD4+ T cells as measured by digital droplet PCR | 1 year | 
| Time to viral rebound during ATI | Days from stopping ART to plasma HIV RNA >5,000 on two consecutive measurements | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emerging events (Safety and tolerability) | Frequence and severity of adverse events (AE), adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR) and suspected unexpected serious adverse reactions (SUSAR). | 1 year | 
| Quantification of the intact proviral DNA | Intact HIV-1 DNA in CD4+ T cells (copies per million cells) as measured by dd-PCR. | 1 year | 
| Quantification of HIV mRNA and/or p24 positive cells | Frequency of mRNA/p24 postive per 1 million CD4+ T cells by FISH-flow | 30 days from study entry | 
| Immune reconstitution | Absolute CD4+ and CD8+ T cell count | 1 year | 
| Analytic treatment interruption (ATI) study | Time to first plasma HIV RNA >5000 c/mL | 64 weeks | 
| Impact of pre-ART virus sensitivity to 3BNC117 on ATI outcomes | 3BNC117 sensitivity determined by PhenoSense and/or HIV env sequencing | Baseline and at viral rebound | 
| T cell mediated HIV specific immunity | T cell immunity as determined by the HIV AIM assay | First of 365 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1, Latency Reversal Agent, Immunotherapy