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

• ClinicalTrials.gov Identifier: NCT02471430
• Recruitment Status: Active, not recruiting
• First Posted: June 15, 2015
• Last Update Posted: March 15, 2023
• Sponsor: Massachusetts General Hospital
• Collaborators: Novartis; Genentech, Inc.
• Information provided by (Responsible Party): Mathias Lichterfeld, Massachusetts General Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HIV Infection	Drug: Panobinostat; Drug: Pegylated Interferon-alpha2a	Phase 1; Phase 2

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, 10 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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 2016
• Actual Primary Completion Date: August 2022
• Estimated Study Completion Date: December 2023

Arms and Interventions

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 Name: 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 Name: Pegasys

Outcome Measures

Primary Outcome Measures :

1. Occurrence of Grade ≥ 1 Adverse Events (AEs) [ Time Frame: Measured through 1 month after administration of panobinostat and/or interferon-alpha2a ]
   Cumulative frequency and severity of Grade ≥ 1 adverse events, Grade ≥ 1 lab abnormalities or serious adverse events
2. Change in CD4 T Cell-Associated Proviral HIV-1 DNA from Baseline [ Time Frame: Measured through 1 week after administration of panobinostat and/or interferon-alpha2a ]
   Operational measurement of HIV-1 reservoir

Secondary Outcome Measures :

1. Change from baseline in levels of infectious viral units per million CD4 T cells [ Time Frame: Measured through 1 week after study drug administration ]
2. Change from baseline in histone H3 acetylation in CD4 T cells [ Time Frame: Measured through 1 week after study drug administration ]
3. Change from baseline in levels of CD4 T cell-associated HIV-1 RNA [ Time Frame: Measured through 1 week after study drug administration ]
4. Change from baseline in levels of plasma HIV-1 RNA [ Time Frame: Measured through 1 week after study drug administration ]
5. Change from baseline in levels of CD4 T cell-associated HIV-1 2-LTR circles and chromosomally integrated proviral HIV-1 DNA [ Time Frame: Measured through 1 week after study drug administration ]
6. Change from baseline in levels of HIV-1 DNA in different CD4 T cell subsets (naïve, T memory stem cells, central-memory, effector-memory, terminally-differentiated) [ Time Frame: Measured through 1 week after study drug administration ]
7. Change from baseline in frequency and function of innate and adaptive immune effector cell responses [ Time Frame: Measured through 1 week after study drug administration ]
8. Change from baseline in levels of cellular and soluble immune activation markers [ Time Frame: Measured through 1 week after study drug administration ]
9. Change from baseline in expression patterns of interferon-stimulated genes (ISG) [ Time Frame: Measured through 1 week after study drug administration ]
10. Comparison of all immunologically and virological parameters in study participants treated with pegylated Interferon-alpha2a and panobinostat according to HLA class I and IL-28b genotypes [ Time Frame: Measured through 1 week after study drug administration ]

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Massachusetts

Massachusetts General Hospital CRS (MGH CRS)

Boston, Massachusetts, United States, 02114

Sponsors and Collaborators

Massachusetts General Hospital

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

More Information

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.

• Responsible Party: Mathias Lichterfeld, Associate Professor of Medicine, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02471430
• Other Study ID Numbers: U01 2015P000858; 12049 ( Other Identifier: Division of AIDS (DAIDS-ES) )
• First Posted: June 15, 2015
• Last Update Posted: March 15, 2023
• Last Verified: March 2023

Additional relevant MeSH terms:

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2a; Panobinostat; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunologic Factors; Physiological Effects of Drugs; Histone Deacetylase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action