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

Phase 1

Completed

Conditions: HIV Infection

Interventions: Drug: Panobinostat
Drug: Pegylated Interferon-alpha2a

Registration Number: NCT02471430

Lead Sponsor: Massachusetts General Hospital

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 17

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B	Pegylated Interferon-alpha2a	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.
Arm A	Panobinostat	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.
Arm B	Panobinostat	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.
Arm C	Pegylated Interferon-alpha2a	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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