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

• Change From Baseline in HIV DNA in Rectal Tissue at Week 56 [ Time Frame: Week 56 ] [ Designated as safety issue: No ]
• Change From Baseline in CD4+ T Cell Count at Week 56 [ Time Frame: Week 56 ] [ Designated as safety issue: No ]
• HIV Specific T-cell Response to Env [ Time Frame: 36 weeks ] [ Designated as safety issue: No ]
  HIV-specific immunity: Interferon gamma ELISpot response to Env (clades A) at week 36 (one month after rAd5 boosting)
• Serious Adverse Events Attributed to Study Treatments [ Time Frame: 56 weeks ] [ Designated as safety issue: Yes ]
  Grade 3 or 4 serious adverse events related to study treatments (raltegravir, maraviroc, or HIV-recombinant Ad5-based vaccine)

• 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.

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.

• 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: Maraviroc + raltegravir intensification
  ART Intensification (addition of raltegravir and maraviroc to suppressive ART for 56 weeks)
  Interventions:

  • Drug: ART intensification (raltegravir)
  • Drug: ART intensification (maraviroc)
• Experimental: Maraviroc + raltegravir intens. plus DNA + HIV-rAd5 vaccine
  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)
  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 Sharp & Dohme Corp.