Enhancement by Poly-ICLC During HIV-1 Infection
| Status: | Completed |
|---|---|
| Conditions: | Infectious Disease, HIV / AIDS |
| Therapuetic Areas: | Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - 55 |
| Updated: | 4/17/2018 |
| Start Date: | April 2014 |
| End Date: | July 26, 2016 |
Simultaneous Disruption of Latency and Immune Enhancement by Poly-ICLC During HIV-1 Infection
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.
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.
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.
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.
Inclusion Criteria:
- HIV-1 infection documented by previous HIV-1 serology or rapid test, or documented
plasma HIV-1 RNA of >2000 copies/ml
- On stable cART regimen in accordance with the DHHS "Guidelines for the Use of
Antiretroviral Agents in HIV-1-Infected Adults and Adolescents" with documented
virologic suppression (VL<50 copies/ml) for ≥ 48 weeks.
- Baseline cell associated HIV-1 RNA is detectable (≥10copies/µg RNA)
- Laboratory values obtained within 30 days prior to study entry.
- VL < 50 copies/ml
- CD4+ T cell count > 500 cells/mm3
- Absolute neutrophil count (ANC) ≥500/mm3
- Hemoglobin ≥9.0 g/dL if female; 10 g/dL if male
- Platelet count ≥75,000/mm3
- AST (SGOT), ALT (SGPT) ≤3.5 × ULN
- Alkaline phosphatase< 2.5 ULN
- Total bilirubin ≤2.5 x ULN
- Lipase ≤2.5 x ULN
- Calculated creatinine clearance ≥70 mL/min as estimated by the Cockcroft-Gault
equation:
- For men(140-age in yrs)x(body wt in kg)÷(serum creatinine in mg/dLx72)=CrCl (mL/min)*
*For women, multiply the result by 0.85 = CrCl (mL/min)
- NOTE: A program to assist in calculations is available on the DMC web site at:
http://www.fstrf.org/ACTG/ccc.html
- For women of reproductive potential, negative serum or urine pregnancy test
- Female candidates of reproductive potential is defined as girls who have reached
menarche or women who have not been post-menopausal for at least 24 consecutive months
(i.e., who have had menses within the preceding 24 months) or have not undergone
surgical sterilization (e.g., hysterectomy, or bilateral oophorectomy, or bilateral
tubal ligation).
- Contraception requirements
- Female candidates of reproductive potential, who are participating in sexual activity
that could lead to pregnancy, must agree that they will use at least two reliable
barrier methods of contraception while receiving the protocol-specified treatments and
for at least 24 weeks after completing stage I of the study.
- Men and women aged 18-55 years.
- Ability and willingness of subject to give written informed consent.
- Adequate venous access for phlebotomy
Exclusion Criteria:
- Previous immune based therapy
- History of vascular disease including h/o coronary artery disease, angina/MI, TIA/CVA,
peripheral vascular disease/claudication
- Strong family history of cardiovascular disease
- Hyperlipidemia requiring medication
- Diabetes
- History of Tobacco use (≥10 pack years)
- HIV-related nephropathy
- History of vascular disease including history of coronary artery disease, angina/MI,
TIA/CVA, peripheral vascular disease/claudication, poorly controlled hypertension
- Pregnancy or currently breast-feeding
- Desire to become pregnant during the course of study
- Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), systemic
cytotoxic chemotherapy, or investigational therapy within 30 days prior to study
entry.
- Known allergy/sensitivity to study drugs or their formulations.
- Active drug or alcohol use or dependence that, in the opinion of the site
investigator, would interfere with adherence to study requirements.
- History of autoimmunity
- Chronic Hepatitis B (HepBSAg+) or C (HCV RNA positive)
- Current imprisonment or involuntary incarceration in a medical facility for
psychiatric or physical (e.g., infectious disease) illness.
- Participation in any other clinical trial within 30 days prior to screening.
- Receipt of routine vaccination(s) within 7 days of study entry, or anticipated receipt
of routine vaccination(s) during the first 4 weeks of the study. If routine
vaccinations are to be administered following the first 4 weeks of the study, they
cannot be administered within 7 days prior to weeks 16 and 48 follow up visits.
- Multi-drug resistant (MDR) HIV-1 precluding standard 3-drug therapy
- Any other clinical conditions or prior therapy that, in the opinion of the
investigator, would make the subject unsuitable for the study or unable to comply with
the requirements.
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