HIV, HIV Infections
Conditions
Keywords
HIV, HIV persistence, HIV reservoirs
Brief 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.
Interventions
DRUGRaltegravir, tenofovir/emtricitabine
16 controllers will be treated with open-label raltegravir/tenofovir/emtricitabine for 24 weeks.
Sponsors
California HIV/AIDS Research Program
Gilead Sciences
Merck Sharp & Dohme LLC
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Estimated Ultrasensitive Plasma HIV RNA Levels Between Baseline and Week 24 | 24 weeks | The isothermal transcription mediated amplification (TMA) assay (Aptima, Gen-Probe/Hologic) was used to measure ultrasensitive plasma HIV RNA levels at weeks 0, 4, 12, and 24. This is a nucleic acid-amplification test that has been FDA-approved for the early detection of HIV infection in blood donors. It is a highly specific and sensitive assay, with a singlicate 50% detection limit of 3.6-14 copies/mL. The assay was performed in triplicate on 0.5 mL plasma (1.5 mL total plasma), improving the overall 50% detection limit to \< 5 copies/mL. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Controller | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Controller |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 45 years STANDARD_DEVIATION 9.9 |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
Primary
Mean Change in Estimated Ultrasensitive Plasma HIV RNA Levels Between Baseline and Week 24
The isothermal transcription mediated amplification (TMA) assay (Aptima, Gen-Probe/Hologic) was used to measure ultrasensitive plasma HIV RNA levels at weeks 0, 4, 12, and 24. This is a nucleic acid-amplification test that has been FDA-approved for the early detection of HIV infection in blood donors. It is a highly specific and sensitive assay, with a singlicate 50% detection limit of 3.6-14 copies/mL. The assay was performed in triplicate on 0.5 mL plasma (1.5 mL total plasma), improving the overall 50% detection limit to \< 5 copies/mL.
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| HIV Controller | Mean Change in Estimated Ultrasensitive Plasma HIV RNA Levels Between Baseline and Week 24 | 66 fold decrease in signal/cutoff ratio |