Enhancement by Poly-ICLC During HIV-1 Infection (Poly-ICLC)
This study involves researching new approaches to treating HIV infection. Currently, HIV infection is treated with combinations of drugs called antiretrovirals. These drugs protect cells from infection by interfering with the viruses' ability to make copies of itself by infecting new target cells. Though these drugs are very effective, they cannot cure HIV infection and must be taken each and every day at prescribed doses to maintain their beneficial effect. This research study is investigating a new approach that involves an addition to existing medications.
The study is investigating a medication called Poly-ICLC (Hiltonol®, Oncovir), which is an adjuvant. Adjuvants are medications that are designed to boost your body's immune responses resulting from a vaccine. The investigators want to test whether Poly-ICLC is an adjuvant that is effective in HIV-infected patients. A vaccine is not given in this study, but just investigating the adjuvant, Poly-ICLC, to determine whether it may be safe and useful in future vaccines that could be used to treat HIV, called therapeutic vaccines. One goal of future therapeutic vaccines is to reduce the virus that remains persistently inside of cells in a dormant or resting state despite treatment with HIV medications. This persistent pool is termed the "latent virus pool" or "viral reservoir". One tactic to reduce this viral reservoir is to first stimulate HIV to start replicating in order to force it out of hiding. Once viral replication occurs, the infected cells may then be recognized and killed by cells of the immune system. Therefore, we also want to see what effect Poly-ICLC has on the virus that lives inside of cells. Specifically, the investigators want to look at whether Poly-ICLC increases the level of virus inside your cells while also improving your immune system's responses.
The investigators are doing this research in hope to find new ways to treat HIV infection that may reduce exposure to medications that are called antiretrovirals. Antiretrovirals are medications used to treat HIV infection. They are very effective but have side effects and have to be taken each and every day and cannot cure HIV.
|HIV-1 Infected Adults With Chronic HIV-1 Infection||Drug: Arm A: Poly-ICLC Drug: Arm B: Normal Saline||Phase 1 Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
|Official Title:||Simultaneous Disruption of Latency and Immune Enhancement by Poly-ICLC During HIV-1 Infection|
- To establish if Poly-ICLC is safe and well tolerated in HIV-1-infected subjects on combination anti-retroviral therapy [ Time Frame: Up to 48 weeks ]The primary objective of the trial will be to monitor for safety in each Arm. Patients will be randomized 3:1 to receive the study agent versus placebo. Comparisons among the Arms on the proportions of Poly ICLC-related adverse events will be made using Fisher's exact test.
- To confirm that Poly-ICLC enhances innate immune responses in HIV-infected subjects on anti-retroviral therapy, and that its immunostimulatory properties are transient in nature. [ Time Frame: Up to 48 weeks ]Poly-ICLC enhancement of DC and Natural Killer (NK) cells activation and function will be assessed. Biomarkers of cellular immune activation and exhaustion will be quantified by flow cytometry (HLA-DR, CD38, PD-1, CTLA-4) and transcriptional profiling of PBMC. Systemic immune activation will be determined by measuring levels of circulating cytokines and soluble markers (type I IFN, TNF, IL-6, sCD14, C-reactive protein, D-dimer, IL-12)
- To determine whether Poly-ICLC disrupts viral latency in HIV-1-infected individuals on anti-retroviral therapy. [ Time Frame: Up to 48 weeks ]Viral transcription will be assessed by monitoring cell associated HIV-1 RNA. The viral reservoir will be evaluated by measuring proviral HIV-1 DNA, and plasma viremia
|Study Start Date:||April 2014|
|Estimated Study Completion Date:||April 2017|
|Estimated Primary Completion Date:||April 2017 (Final data collection date for primary outcome measure)|
Experimental: Arm A: Poly-ICLC
Arm A (N=15): Patients will receive an injection of 1.4 mg of Poly-ICLC (Hiltonol®, Oncovir) subcutaneously on day 1 and day 2.
Drug: Arm A: Poly-ICLC
Poly-ICLC (Hiltonol®, Oncovir) Administration - On days 1 and 2, patients randomized to this arm will be injected subcutaneously in the arm with 1.4 mg of Poly-ICLC (Hiltonol®, Oncovir). Each subject will receive a total of 2 SC doses of Poly-ICLC. The volume of each injection is 0.7ml. The investigators who are blinded will not be present at the time of injection by the study nurse.
Other Name: Poly-ICLC (Hiltonol®, Oncovir)
Placebo Comparator: Arm B: Normal Saline
Arm B: (N=5): Patients will receive an injection of normal saline subcutaneously on day 1 and day 2.
Drug: Arm B: Normal Saline
Normal Saline - On days 1 and 2, patients randomized to this arm will be injected subcutaneously in the arm with normal saline obtained from the Rockefeller University Pharmacy. Each subject will receive a total of 2 SC doses of normal saline. The volume of each injection is 0.7ml. The investigators who are blinded will not be present at the time of injection by the study nurse.
Other Name: Placebo
Effective combination antiretroviral therapy (cART) has dramatically altered the morbidity and mortality associated with human immunodeficiency virus (HIV-1) infection. Nevertheless, the current treatment paradigm of lifelong antiviral therapy with near perfect patient adherence to avoid the emergence of drug resistant HIV remains less than ideal and this therapeutic approach has clear limitations.
In addition to long term toxicities associated with currently preferred therapies, combination therapy for HIV-1 infection cannot address the issue of viral persistence. HIV-1 persists in both blood and tissue despite long-term suppression with antiretroviral agents (ARVs). Eradication strategies for HIV-1 are likely to require a multi-faceted approach to reduce the latent reservoir, with key components focusing upon both the disruption of viral latency and the enhancement of cytotoxic T lymphocyte (CTL) function to promote killing of infected cells. In order to successfully achieve these objectives, agents that safely stimulate replication of the latent reservoir AND explore approaches to enhance HIV-specific adaptive immunity to augment CTL function must be investigated. The investigators propose that this may be accomplished with a single therapeutic modality that is devised appropriately. Certain adjuvants may possess immunostimulatory properties that trigger transient activation of viral transcription while simultaneously enhancing HIV-specific CTL function and, thus, may play an important role in such a vaccine.
Here, the investigators propose a proof of concept clinical trial to determine the ability of Poly-ICLC (Hiltonol®, Oncovir), to safely activate the latent viral reservoir and enhance innate immunity when administered to HIV-infected individuals. This randomized, double-blinded, placebo-controlled study will administer two doses of Poly-ICLC to HIV-infected individuals whom are virologically suppressed on combination anti-retroviral therapy (cART). The investigators hypothesize that Poly-ICLC will be safe and well-tolerated and will transiently disrupt viral latency while enhancing innate immune responses. Should this be the case, then Poly-ICLC would be an ideal modality to combine with a therapeutic HIV vaccine to reduce the number of latently infected CD4+ T cells in treated HIV-1 infected individuals.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02071095
|United States, New York|
|The Rockefeller University Hospital|
|New York, New York, United States, 10065|
|Study Director:||Nina Bhardwaj, MD, PhD||Icahn School of Medicine at Mt. Sinai|
|Principal Investigator:||Elizabeth Miller, MD||Icahn School of Medicine at Mount Sinai|
|Principal Investigator:||Martin Markowitz, MD||Aaron Diamond AIDS Research Center|