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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: Panobinostat
* Drug: Pegylated Interferon-alpha2a


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>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<br>* Panobinostat will be administered orally.<br>* Other names: LBH589;|
| Experimental: Arm B<br>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<br>* Panobinostat will be administered orally.<br>* Other names: LBH589;Drug: Pegylated Interferon-alpha2a<br>* Pegylated Interferon-alpha2a will be administered subcutaneously in one shot.<br>* Other names: Pegasys;|
| Experimental: Arm C<br>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<br>* Pegylated Interferon-alpha2a will be administered subcutaneously in one shot.<br>* Other names: Pegasys;|

What is the study measuring?
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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 | Measured through 1 month after administration of panobinostat and/or interferon-alpha2a | 
| Change in CD4 T Cell-Associated Proviral HIV-1 DNA from Baseline | Operational measurement of HIV-1 reservoir | Measured through 1 week after administration of panobinostat and/or interferon-alpha2a | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in levels of infectious viral units per million CD4 T cells |  | Measured through 1 week after study drug administration | 
| Change from baseline in histone H3 acetylation in CD4 T cells |  | Measured through 1 week after study drug administration | 
| Change from baseline in levels of CD4 T cell-associated HIV-1 RNA |  | Measured through 1 week after study drug administration | 
| Change from baseline in levels of plasma HIV-1 RNA |  | Measured through 1 week after study drug administration | 
| Change from baseline in levels of CD4 T cell-associated HIV-1 2-LTR circles and chromosomally integrated proviral HIV-1 DNA |  | Measured through 1 week after study drug administration | 
| 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) |  | Measured through 1 week after study drug administration | 
| Change from baseline in frequency and function of innate and adaptive immune effector cell responses |  | Measured through 1 week after study drug administration | 
| Change from baseline in levels of cellular and soluble immune activation markers |  | Measured through 1 week after study drug administration | 
| Change from baseline in expression patterns of interferon-stimulated genes (ISG) |  | Measured through 1 week after study drug administration | 
| 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 |  | Measured through 1 week after study drug administration |