Therapeutic Intensification Plus Immunomodulation to Decrease the HIV-1 Viral Reservoir

Study Overview
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Brief Summary
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The objective of this study is to discover a new approach in which human immunodeficiency virus (HIV) can be eradicated from an infected individual by intensified antiretroviral treatment coupled with immunomodulation. The hypothesis is that eradication is possible only if very potent antiretroviral drugs are delivered in conjunction with an immunomodulatory agent that simultaneously attack the viral reservoirs.

Detailed Description
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The objective of this study is to measure the impact of immunomodulation plus treatment intensification on the HIV reservoir in HIV-infected patients who have viral suppression on combination antiretroviral therapy. Treatment regimens first will be intensified by the addition of raltegravir and maraviroc for 8 week followed by immunomodulation with the NIH HIV-rAd5 vaccine plus DNA prime-boost for 24 weeks. The primary endpoint is measurement of change in peripheral cellular HIV DNA. A decrease of 0.5 log is considered significant. A secondary endpoints include change in HIV DNA in the rectal mucosa, immunologic changes in the peripheral blood and safety.

Official Title
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Multicenter, Randomized, Non-comparative, Controlled Study of Therapeutic Intensification Plus Immunomodulation in HIV-infected Patients With Long-term Viral Suppression

Conditions
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HIV Infection

Intervention / Treatment
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* Biological: DNA + HIV-rAd5 vaccine
* Drug: ART intensification (raltegravir)
* Drug: ART intensification (maraviroc)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection At least 3 years of ART without interruption (less than one month cumulative) ART regimen unchanged in the 3 months prior to screening One HIV plasma viral load (RNA) documented at least 3 years prior to entry, and at least 2 HIV plasma viral load (RNA) documented per year thereafter HIV plasma viral load (RNA) ≤ 500 copies/mL at least 3 years prior to entry, and HIV plasma viral load < 500 copies/mL for >90% of the measures thereafter HIV plasma viral load (RNA) below the limit of detection for all values within the past year (one virologic blip allowed) HIV plasma viral load below the limit of detection within 60 days of entry CD4+ count ≥ 350 cells/mm3 within 60 days of entry Proviral DNA ≥10 and ≤1000 copies/106 PBMCs within 75 days of entry Adeno5 neutralizing antibody titers of 250 or less within 75 days of entry Hemoglobin ≥ 10 g/dL within 60 days of entry Platelets ≥ 100,000 per microliter within 60 days of entry Hepatic transaminases (ALT and AST) ≤ 2.5 x ULN within 60 days of entry Creatinine clearance > 50 mL/min by the Cockcroft-Gault equation within 60 days of entry Exclusion Criteria: Sexually active men and women who will not practice at least one form of barrier birth control (male partner using condoms, female partner using condoms, other barrier contraception, etc) Pregnancy Inability or unwillingness to provide informed consent HBsAg positive HCV antibody positive or HCV RNA detectable Previous use of an integrase inhibitor (ie raltegravir) or a CCR5 inhibitor (ie maraviroc, vicriviroc). Use of raltegravir for non-treatment failure indications such as intensification or toxicity switches is allowed. Immunologic therapeutic intervention (e.g. IL-2) within the past year Participation in another clinical drug or device trial where the last dose of drug was within the past 30 days or an investigational medical device is currently implanted Diagnosis of cancer within the last 5 years (except basal cell cutaneous cancers and cutaneous KS not requiring systemic therapy) Co-morbid condition with an expected survival of less than 12 months History of hypersensitivity to vaccination History of autoimmune disease, such as systemic lupus erythematosis (SLE) or Hashimoto's thyroiditis Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Active Comparator: Maraviroc + raltegravir intensification<br>ART Intensification (addition of raltegravir and maraviroc to suppressive ART for 56 weeks) | Drug: ART intensification (raltegravir)<br>* raltegravir 400 mg PO BID for 56 weeks<br>* Other names: Isentress;Drug: ART intensification (maraviroc)<br>* maraviroc 150, 300, or 600 mg PO BID (depending on PK interactions with other medications) for 56 weeks<br>* Other names: Celsentri;|
| Experimental: Maraviroc + raltegravir intens. plus DNA + HIV-rAd5 vaccine<br>ART Intensification (addition of raltegravir and maraviroc for 56 weeks) PLUS immunomodulation therapy with DNA prime vaccine (Weeks 8,12,16) + HIV-recombinant Ad5-based vaccine (Week 32) | Biological: DNA + HIV-rAd5 vaccine<br>* 4 mg subcutaneous injection at weeks 8 (DNA prime), 12 (DNA prime), 16 (DNA prime), and 32 (HIV-rAd5)<br>Drug: ART intensification (raltegravir)<br>* raltegravir 400 mg PO BID for 56 weeks<br>* Other names: Isentress;Drug: ART intensification (maraviroc)<br>* maraviroc 150, 300, or 600 mg PO BID (depending on PK interactions with other medications) for 56 weeks<br>* Other names: Celsentri;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HIV DNA in PBMCs at Week 56 |  | 56 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HIV DNA in Rectal Tissue at Week 56 |  | Week 56 | 
| Change From Baseline in CD4+ T Cell Count at Week 56 |  | Week 56 | 
| HIV Specific T-cell Response to Env | HIV-specific immunity: Interferon gamma ELISpot response to Env (clades A) at week 36 (one month after rAd5 boosting) | 36 weeks | 
| Serious Adverse Events Attributed to Study Treatments | Grade 3 or 4 serious adverse events related to study treatments (raltegravir, maraviroc, or HIV-recombinant Ad5-based vaccine) | 56 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1 infection, Treatment intensification, Immunomodulation, HIV-rAd5 vaccine