Therapeutic Intensification Plus Immunomodulation to Decrease the HIV-1 Viral Reservoir (EraMune02)

• HIV DNA in gut lymphoid tissue [ Time Frame: 56 weeks ] [ Designated as safety issue: No ]
• HIV plasma viral load (RNA) [ Time Frame: 56 weeks ] [ Designated as safety issue: No ]
• CD4+ T cell count [ Time Frame: 56 weeks ] [ Designated as safety issue: No ]
• HIV-specific immunity [ Time Frame: 56 weeks ] [ Designated as safety issue: No ]
• T cell activation (CD38) [ Time Frame: 56 weeks ] [ Designated as safety issue: No ]
• Adenovirus-specific immunity [ Time Frame: 56 weeks ] [ Designated as safety issue: No ]
• Adverse events attributed to study treatments (raltegravir, maraviroc, or HIV-recombinant Ad5-based vaccine) [ Time Frame: 56 weeks ] [ Designated as safety issue: Yes ]

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.

• HIV Infections
• Treatment Experienced

• Biological: DNA + HIV-rAd5 vaccine
  4 mg subcutaneous injection at weeks 8 (DNA prime), 12 (DNA prime), 16 (DNA prime), and 32 (HIV-rAd5)
• Drug: ART intensification (raltegravir)
  raltegravir 400 mg PO BID for 56 weeks
  Other Name: Isentress
• Drug: ART intensification (maraviroc)
  maraviroc 150, 300, or 600 mg PO BID (depending on PK interactions with other medications) for 56 weeks
  Other Names:

  • Selzentry
  • Celsentri

• Active Comparator: ART intensification only
  Maintenance of suppressive ART with the addition of raltegravir and maraviroc.
  Interventions:

  • Drug: ART intensification (raltegravir)
  • Drug: ART intensification (maraviroc)
• Experimental: ART intensification plus immunomodulation
  Maintenance of suppressive ART with the addition of raltegravir and maraviroc PLUS immunomodulation therapy with HIV-recombinant Ad5-based vaccine (added after 8 weeks of ART intensification)
  Interventions:

  • Biological: DNA + HIV-rAd5 vaccine
  • Drug: ART intensification (raltegravir)
  • Drug: ART intensification (maraviroc)

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

• Objectif Recherche Vaccins SIDA
• National Institute of Allergy and Infectious Diseases (NIAID)
• Pfizer
• Merck