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

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.

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.

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