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

Phase 2

Completed

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

Brief Summary: 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: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Maraviroc + raltegravir intensification	ART intensification (raltegravir)	ART Intensification (addition of raltegravir and maraviroc to suppressive ART for 56 weeks)
Maraviroc + raltegravir intensification	ART intensification (maraviroc)	ART Intensification (addition of raltegravir and maraviroc to suppressive ART for 56 weeks)
Maraviroc + raltegravir intens. plus DNA + HIV-rAd5 vaccine	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)
Maraviroc + raltegravir intens. plus DNA + HIV-rAd5 vaccine	ART intensification (raltegravir)	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)
Maraviroc + raltegravir intens. plus DNA + HIV-rAd5 vaccine	ART intensification (maraviroc)	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)

Primary Outcome Measures

Name	Time	Method
Change From Baseline in HIV DNA in PBMCs at Week 56	56 weeks

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in CD4+ T Cell Count at Week 56	Week 56
Change From Baseline in HIV DNA in Rectal Tissue at Week 56	Week 56
HIV Specific T-cell Response to Env	36 weeks	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	56 weeks	Grade 3 or 4 serious adverse events related to study treatments (raltegravir, maraviroc, or HIV-recombinant Ad5-based vaccine)

Locations (3): Northwestern University
🇺🇸
Chicago, Illinois, United States
University of California San Francisco
🇺🇸
San Francisco, California, United States
Cornell University
🇺🇸
New York, New York, United States