HIV Persistence and Viral Reservoirs

Study Description

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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

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	20 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel 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 :	June 2011
Estimated Study Completion Date :	June 2013

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Elite controller; Ten elite controllers will be treated with open-label raltegravir/tenofovir/emtricitabine for 24 weeks.	Drug: Raltegravir, tenofovir/emtricitabine; Ten elite controllers and 10 untreated non-controllers will be treated with open-label raltegravir/tenofovir/emtricitabine for 24 weeks.
Active Comparator: Non-controller; Ten untreated non-controllers will be treated with open-label raltegravir/tenofovir/emtricitabine for 24 weeks.	Drug: Raltegravir, tenofovir/emtricitabine; Ten elite controllers and 10 untreated non-controllers will be treated with open-label raltegravir/tenofovir/emtricitabine for 24 weeks.

Outcome Measures

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Primary Outcome Measures :

1. Change in proportion of controllers with detectable plasma HIV RNA (using an ultrasensitive <1 copy/mL assay) from baseline to Week 4 [ Time Frame: Week 4 ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 70 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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. Meeting one of the following criteria:

1. "Elite controllers": antiretroviral untreated with an undetectable (< 50 copies/mL) viral load for at least 12 months (isolated blips up to 1,000 copies/mL allowed, but must be preceded and followed by undetectable viral load), or 2. "Non-controllers": antiretroviral untreated with a detectable (> 10,000 copies/mL) viral load, with the intent to start antiretroviral drugs.

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.

Contacts and Locations

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Locations

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 Corp.

Investigators

Principal Investigator:	Hiroyu Hatano, MD	University of California, San Francisco

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hatano H, Yukl SA, Ferre AL, Graf EH, Somsouk M, Sinclair E, Abdel-Mohsen M, Liegler T, Harvill K, Hoh R, Palmer S, Bacchetti P, Hunt PW, Martin JN, McCune JM, Tracy RP, Busch MP, O'Doherty U, Shacklett BL, Wong JK, Deeks SG. Prospective antiretroviral treatment of asymptomatic, HIV-1 infected controllers. PLoS Pathog. 2013;9(10):e1003691. doi: 10.1371/journal.ppat.1003691. Epub 2013 Oct 10.

Responsible Party:	University of California, San Francisco
ClinicalTrials.gov Identifier:	NCT01025427 History of Changes
Other Study ID Numbers:	H52889-35080
First Posted:	December 3, 2009
Last Update Posted:	April 3, 2012
Last Verified:	April 2012

Keywords provided by University of California, San Francisco:

HIV; HIV persistence; HIV reservoirs

Additional relevant MeSH terms:

HIV Infections; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Tenofovir; Raltegravir Potassium	Emtricitabine; Antiviral Agents; Anti-Infective Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Retroviral Agents; Anti-HIV Agents; HIV Integrase Inhibitors; Integrase Inhibitors