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HIV Persistence and Viral Reservoirs

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ClinicalTrials.gov Identifier: NCT01025427
Recruitment Status : Completed
First Posted : December 3, 2009
Results First Posted : July 1, 2020
Last Update Posted : July 1, 2020
California HIV/AIDS Research Program
Gilead Sciences
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
University of California, San Francisco

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.

Condition or disease Intervention/treatment Phase
HIV HIV Infections Drug: Raltegravir, tenofovir/emtricitabine Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treating HIV-infected Elite Controllers as a Model of HIV Remission
Study Start Date : December 2009
Actual Primary Completion Date : November 2012
Actual Study Completion Date : October 2013

Arm Intervention/treatment
Experimental: Elite controller
Sixteen controllers will be treated with open-label raltegravir/tenofovir/emtricitabine for 24 weeks.
Drug: Raltegravir, tenofovir/emtricitabine
16 controllers will be treated with open-label raltegravir/tenofovir/emtricitabine for 24 weeks.

Primary Outcome Measures :
  1. Mean Change in Estimated Ultrasensitive Plasma HIV RNA Levels Between Baseline and Week 24 [ Time Frame: 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.

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01025427

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United States, California
San Francisco General Hospital
San Francisco, California, United States, 94110
Sponsors and Collaborators
University of California, San Francisco
California HIV/AIDS Research Program
Gilead Sciences
Merck Sharp & Dohme LLC
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Principal Investigator: Hiroyu Hatano, MD University of California, San Francisco
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01025427    
Other Study ID Numbers: H52889-35080
First Posted: December 3, 2009    Key Record Dates
Results First Posted: July 1, 2020
Last Update Posted: July 1, 2020
Last Verified: June 2020
Keywords provided by University of California, San Francisco:
HIV persistence
HIV reservoirs
Additional relevant MeSH terms:
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HIV Infections
Blood-Borne Infections
Communicable Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Raltegravir Potassium
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
HIV Integrase Inhibitors
Integrase Inhibitors