Reducing the Residual Reservoir of HIV-1 Infected Cells in Patients Receiving Antiretroviral Therapy (ACTIVATE)

A Phase I-II Pilot Study to Assess the Safety and Efficacy of Combined Administration With Pegylated Interferon-alpha2a and the Histone Deacetylase Inhibitor (HDACi) Panobinostat for Reducing the Residual Reservoir of HIV-1 Infected Cells in cART-Treated HIV-1 Positive Individuals

This study is a prospective, open-label, randomized, three-arm, dose-escalation exploratory pilot clinical trial involving HIV-1 infected participants treated with suppressive combination antiretroviral combination therapy (cART). The study will test whether combined treatment with the histone deacetylase inhibitor panobinostat and the immunomodulatory cytokine Interferon-alpha2a can reduce the residual reservoir of HIV-1 infected cells that persist during treatment with currently available antiretroviral drugs.

Study Overview

• Status: Completed
• Conditions: HIV Infection
• Intervention / Treatment: Drug: Panobinostat; Drug: Pegylated Interferon-alpha2a

Detailed Description

This study is a prospective, triple-arm, randomized, open-label, dose-escalation exploratory clinical trial involving HIV-1 infected participants treated with suppressive combination antiretroviral combination therapy (cART). The primary objective of this study is to evaluate a new strategy for reducing the residual reservoir of HIV-1 infected cells that persists despite treatment with current HIV drugs. The clinical trial is conducted in the Infectious Diseases Clinical Trials Unit (CTU) at the Massachusetts General Hospital.

The study medication includes two agents: panobinostat is an oral tablet that can reverse HIV-1 latency and awaken HIV from a "sleeping" condition during which it is protected from the human immune system. The second drug is pegylated interferon-alpha2a (IFN-alpha2a), an injectable cytokine that activates the immune system. The combined use of both agents may lead to immune-mediated elimination of HIV-1 infected cells in which viral latency has been reversed by panobinostat.

Participants will be randomized to receive a treatment course with panobinostat alone (Arm A, 4 participants total), panobinostat in combination with pegylated IFN-alpha2a (Arm B, 9 participants total), or pegylated IFN-alpha2a alone (Arm C, 4 participants total). Participants receiving panobinostat will undergo one week of treatment (15mg, dosed every second day on Monday, Wednesday, Friday), followed by three weeks off-treatment. Subcutaneous injections with pegylated IFN-alpha2a will be administered at the start of the week-long treatment course (simultaneously with the first dose of panobinostat for Arm B). ART will be continued during the entire treatment duration in all study participants.

Participants will undergo close monitoring for side effects during the entire time of study participation. The total study duration will be 2 months.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital CRS (MGH CRS)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ability and willingness to provide informed consent
• HIV-1 infection prior to entry
• Receiving suppressive ART therapy for a minimum of 24 consecutive months prior to screening with no interruption of therapy (same ART regimen for at least 12 weeks prior to screening)
• Documented suppressed HIV-1 RNA (plasma HIV-1 RNA values <50 copies/ml)
• CD4 T cell count ≥ 400 cells/mm3
• Negative Hepatitis B surface antigen (HBsAg) or Negative HBV DNA PCR
• Negative anti-Hepatitis C virus antibodies (anti-HCV) or negative HCV PCR if anti-HCV antibodies are positive
• Negative TB Test (if positive, completed a recommended treatment course for latent TB)
• Vaccinated for pneumococcal disease within last 5 years
• No clinically significant eye disease
• No evidence of clinical coronary heart disease
• Not pregnant, planning to become pregnant, or breastfeeding
• Willingness to continue to use contraceptives for 90 days after completing treatment
• If male, willingness to use a condom during intercourse while taking panobinostat and total of 80 hours after stopping treatment
• Not pregnant, planning to become pregnant, or breastfeeding
• No evidence of coronary heart disease

Exclusion Criteria:

• HIV-1 RNA > 50 copies/mL within 24 months of screening
• Severe psychiatric disease, chronic liver disease, past or current evidence of immunologically mediated disease
• Severe retinopathy due to diabetes, hypertension, cytomegalovirus or macular degeneration
• Evidence of coronary heart disease
• History of active thyroid disease requiring medication
• Breastfeeding
• Presence of a bacterial, fungal, viral or protozoal infection requiring systemic anti-infective therapy
• Uncontrolled seizure disorders
• History or other evidence of severe illness or other conditions
• History of malignancy of any organ system within the past 5 years
• Female participants who are pregnant or nursing
• History of solid organ transplantation with an existing functional graft
• Use of any immunomodulatory agents within 30 days prior to study enrollment or planned use during the trial
• Active drug or alcohol use or dependence
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the participant in case of participation in the study
• Use of HIV protease inhibitor or other strong or moderately strong CYP3A4 inhibitors
• History of anaphylaxis, allergy or serious adverse reactions to Interferon-alpha2a/Interferon-alpha2b or panobinostat
• Has taken: interleukins, systemic interferons or systemic chemotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Participants in Arm A will receive panobinostat as an oral tablet on days 0, 2, and 4 of the treatment week. The dose of panobinostat will be a 15 mg tablet.	Drug: Panobinostat; Panobinostat will be administered orally.; Other Names: Farydak; LBH589
Experimental: Arm B; Participants in Arm B will receive one subcutaneous injection of pegylated interferon-alpha2a on day 0. The dose of pegylated IFN-alpha2a will be 180 mcg. Simultaneously with interferon-alpha2a, a 15 mg tablet of panobinostat will be administered on day 0. Participants will also receive panobinostat as an oral tablet on days 2 and 4 of the treatment week.	Drug: Panobinostat; Panobinostat will be administered orally.; Other Names: Farydak; LBH589; Drug: Pegylated Interferon-alpha2a; Pegylated Interferon-alpha2a will be administered subcutaneously in one shot.; Other Names: Pegasys
Experimental: Arm C; Participants in Arm C will receive one subcutaneous injection of pegylated interferon-alpha2a on day 0.The dose of pegylated IFN-alpha2a will be 180 mcg.	Drug: Pegylated Interferon-alpha2a; Pegylated Interferon-alpha2a will be administered subcutaneously in one shot.; Other Names: Pegasys

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Grade ≥ 1 Adverse Events (AEs)	Cumulative frequency and severity of Grade ≥ 1 adverse events, Grade ≥ 1 lab abnormalities or serious adverse events	All adverse events measured from day 1 until day 28 after administration of the first dose of panobinostat and/or interferon-alpha2a was recorded.
Change in CD4 T Cell-Associated Proviral HIV-1 DNA From Baseline	Operational measurement of CD4 T cells harboring genome-intact HIV-1 DNA, determined by the IPDA assay.	Measured through week 4 after administration of panobinostat and/or interferon-alpha2a

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Histone H3 Acetylation in CD4 T Cells	CD4 T cells expressing acetylated H3, determined by flow cytometry.	measured after last dose of PBT on day 4
Change From Baseline in Levels of CD4 T Cell-associated HIV-1 RNA	total HIV-1 RNA per ug of RNA in CD4 T cells	measured after last dose of PBT on day 4
Change From Baseline in Frequency of Activated NKp30+ NK Cells.	the proportion of NK cells expressing NKp30	measured after last dose of PBT on day 4

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Novartis; Genentech, Inc.
• Investigators: Principal Investigator: Mathias Lichterfeld, MD, PhD, Massachusetts General Hospital; Principal Investigator: Daniel R Kuritzkes, MD, Massachusetts General Hospital; Principal Investigator: Rajesh T Gandhi, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, Winckelmann A, Palmer S, Dinarello C, Buzon M, Lichterfeld M, Lewin SR, Ostergaard L, Sogaard OS. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV. 2014 Oct;1(1):e13-21. doi: 10.1016/S2352-3018(14)70014-1. Epub 2014 Sep 15.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): August 1, 2022
• Study Completion (Actual): December 1, 2023

Study Registration Dates

• First Submitted: June 11, 2015
• First Submitted That Met QC Criteria: June 11, 2015
• First Posted (Estimated): June 15, 2015

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Histone Deacetylase Inhibitors; Interferons; Interferon-alpha; Peginterferon alfa-2a; Interferon alpha-2; Panobinostat
• Other Study ID Numbers: U01 2015P000858; 12049 (Other Identifier: Division of AIDS (DAIDS-ES))