HIV Persistence and Viral Reservoirs
Condition: HIV; HIV Infections
MeSH terms: HIV Infections
Intervention: Raltegravir, tenofovir/emtricitabine
Intervention description: 16 controllers will be treated with open-label raltegravir/tenofovir/emtricitabine for 24 weeks.
Intervention MeSH terms: Tenofovir; Emtricitabine; Raltegravir Potassium
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: HIV; HIV persistence; HIV reservoirs

Summary:

      Although highly active antiretroviral therapy (HAART) decreases HIV-associated mortality, it
      does not to completely restore health. Patients doing well on otherwise effective HAART
      remain at risk for cancer, cardiovascular/liver disease, osteopenia, and other
      "non-AIDS-defining" events. While complete eradication may never be feasible, a "functional
      cure" in which patients are able to maintain undetectable viral loads indefinitely without
      therapy may be possible. The best evidence for this are the so-called "elite" controllers,
      whom we define as individuals who are HIV-seropositive, with plasma HIV RNA levels below the
      level of conventional detection without treatment. Controllers may be conceptualized as a
      naturally occurring model of a functional cure (or "HIV remission"), and are ideal patients
      in which to study HIV persistence and the possibility of eradication.

      We propose to conduct a pilot study to better characterize the reservoirs that lead to viral
      persistence in a group of well-characterized controllers. We propose two specific aims: 1) to
      characterize the dynamics of viral production in blood and gut-associated lymphoid tissue
      (GALT) in controllers; and 2) to prospectively treat 10 controllers with raltegravir,
      tenofovir/emtricitabine for 24 weeks and study the effects of HAART on viral dynamics and
      host inflammatory responses.

      Our primary hypotheses are: 1) viral replication is ongoing in untreated controllers, 2)
      HAART will reduce viral replication in blood and GALT and decrease immune activation, and 3)
      higher levels of immune activation are associated with greater measures of microbial
      translocation and distribution of virus to more differentiated T cell subsets.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age ≥18 years, and

          2. HIV infection, and

          3. Antiretroviral-naïve, and

          4. CD4+ T cell count >350 cells/mm3, and

          5. "Controllers": antiretroviral untreated with 50-1000 copies/mL viral load for at least
             12 months

        Exclusion criteria:

          1. Persons with known rheumatologic conditions (e.g., systemic lupus erythematosus),
             because of their predilection for biologic false-positive testing on HIV antibody
             tests.

          2. Screening absolute neutrophil count <1,000 cells/mm3, platelet count <70,000
             cells/mm3, hemoglobin < 8 mg/dL, estimated creatinine clearance <40 mL/minute,
             aspartate aminotransferase >100 units/L, alanine aminotransferase >100 units/L.

          3. Screening genotype resistance testing showing resistance to tenofovir or
             emtricitabine.

          4. Known kidney disease.

          5. Known bone disease, including pathologic fractures.

          6. Patients with chronic Hepatitis B infection, because of the risk of liver
             abnormalities after starting and stopping tenofovir/emtricitabine.

          7. Concurrent treatment with lamivudine, adefovir, entecavir, or telbivudine.

          8. Serious illness requiring hospitalization or parental antibiotics within the preceding
             3 months.

          9. Any vaccination 2 weeks prior to baseline (Day 0) visit and throughout the study
             period. NOTE: Because the study will most likely be actively recruiting during the
             influenza season, all subjects will be encouraged to receive their annual influenza
             vaccine at the screening visit (4 weeks prior to baseline [Day 0] visit) if they have
             not already been vaccinated for the 2009-10 season and if it is medically indicated.

         10. Concurrent treatment with immunomodulatory drugs, or exposure to any immunomodulatory
             drug in the preceding 16 weeks (e.g. corticosteroid therapy equal to or exceeding a
             dose of 15 mg/day of prednisone for more than 10 days, IL-2, interferon-alpha,
             methotrexate, cancer chemotherapy). NOTE: Use of inhaled or nasal steroid use is not
             exclusionary.

         11. Concurrent treatment with phenobarbital, phenytoin, or rifampin.

         12. Pregnant or breastfeeding women. Females of childbearing potential must have a
             negative serum pregnancy test at screening and agree to use a double-barrier method of
             contraception throughout the study period.