Early Administration of Romidepsin and 3BNC117 in Treatment-naïve HIV Patients Starting ART
- Registration Number
- NCT03041012
- Lead Sponsor
- Aarhus University Hospital
- Brief Summary
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
The study will be conducted among ART naïve HIV-1-infected patients.
Subjects will continue ART while receiving LRA romidepsin and/or bNAb 3BNC117.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 60
- Documented HIV-1 infection
- CD4+ T cell count >200/µL on last visit prior to study entry
- ART naïve
- Able to give informed consent
-
Any significant acute medical illness (not including primary HIV infection) in the past 8 weeks
-
Any evidence of an active AIDS-defining opportunistic infection
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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
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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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description antiretrovirals Antiretrovirals Standard of care antiretrovirals + romidepsin Antiretrovirals Standard of care + LRA antiretrovirals + romidepsin + 3BNC117 Antiretrovirals Standard of care + LRA + bNAb antiretrovirals + 3BNC117 Antiretrovirals Standard of care + bNAb antiretrovirals + romidepsin + 3BNC117 3BNC117 Standard of care + LRA + bNAb antiretrovirals + 3BNC117 3BNC117 Standard of care + bNAb antiretrovirals + romidepsin Romidepsin Standard of care + LRA antiretrovirals + romidepsin + 3BNC117 Romidepsin Standard of care + LRA + bNAb
- Primary Outcome Measures
Name Time Method Quantification of the size of the proviral HIV reservoir 1 year Copies of total HIV-1 DNA per 10⁶ CD4+ T cells as measured by digital droplet PCR
Plasma HIV RNA kinetics 3 months Time to undetectable (\<20 c/mL)
Time to viral rebound during ATI 12 weeks Days from stopping ART to plasma HIV RNA \>5,000 on two consecutive measurements
- Secondary Outcome Measures
Name Time Method Analytic treatment interruption (ATI) study 64 weeks Time to first plasma HIV RNA \>5000 c/mL
Impact of pre-ART virus sensitivity to 3BNC117 on ATI outcomes Baseline and at viral rebound 3BNC117 sensitivity determined by PhenoSense and/or HIV env sequencing
Quantification of the intact proviral DNA 1 year Intact HIV-1 DNA in CD4+ T cells (copies per million cells) as measured by dd-PCR.
Incidence of treatment emerging events (Safety and tolerability) 1 year 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).
Quantification of HIV mRNA and/or p24 positive cells 30 days from study entry Frequency of mRNA/p24 postive per 1 million CD4+ T cells by FISH-flow
Immune reconstitution 1 year Absolute CD4+ and CD8+ T cell count
T cell mediated HIV specific immunity First of 365 days T cell immunity as determined by the HIV AIM assay
Trial Locations
- Locations (4)
Guy's and St Thomas'
🇬🇧London, United Kingdom
Department of Infectious Diseases
🇩🇰Odense, Denmark
Dept. of Infectious Diseases, Aarhus University Hospital
🇩🇰Aarhus, Denmark
Imperial College Healthcare NHS Trust
🇬🇧London, United Kingdom