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

The study will be conducted among ART naïve HIV-1-infected patients.

Subjects will continue ART while receiving LRA romidepsin and/or bNAb 3BNC117.

• Romidepsin (Drug), also known as Istodax: 5mg/m2 romidepsin will be administered IV on days 10, 17, and 24 after initiating ART
• 3BNC117 (Drug), also known as Broadly neutralizing antibody: 30 mg/kg 3BNC117 will be administered IV on day 7 and 21 after initiating ART
• Antiretrovirals (Drug), also known as ART: Combination antiretroviral therapy

Primary outcomes

• Plasma HIV RNA kinetics [3 months]: Time to undetectable (<20 c/mL)
• 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
• Time to viral rebound during ATI [12 weeks]: Days from stopping ART to plasma HIV RNA >5,000 on two consecutive measurements

Secondary outcomes

• 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 the intact proviral DNA [1 year]: Intact HIV-1 DNA in CD4+ T cells (copies per million cells) as measured by dd-PCR.
• 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
• 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
• T cell mediated HIV specific immunity [First of 365 days]: T cell immunity as determined by the HIV AIM assay

Other outcomes

• Plasma cytokine and immune activation biomarker levels [1 year]: Soluble IL-6, sCD14, sCD163

Sex: All, ages: 18 Years to any

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

• Results publication: Gunst JD, Pahus MH, Rosas-Umbert M, Lu IN, Benfield T, Nielsen H, Johansen IS, Mohey R, Ostergaard L, Klastrup V, Khan M, Schleimann MH, Olesen R, Stovring H, Denton PW, Kinloch NN, Copertino DC, Ward AR, Alberto WDC, Nielsen SD, Puertas MC, Ramos V, Reeves JD, Petropoulos CJ, Martinez-Picado J, Brumme ZL, Jones RB, Fox J, Tolstrup M, Nussenzweig MC, Caskey M, Fidler S, Sogaard OS. Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial. Nat Med. 2022 Nov;28(11):2424-2435. doi: 10.1038/s41591-022-02023-7. Epub 2022 Oct 17. PMID 36253609

• Ole S Søgaard, MD PhD, Principal investigator, Aarhus University Hospital

NIH grants: 2015