HIV Persistence and Viral Reservoirs

Treating HIV-infected Elite Controllers as a Model of HIV Remission

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections; HIV
• Intervention / Treatment: Drug: Raltegravir, tenofovir/emtricitabine

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • San Francisco General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	24 weeks

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Merck Sharp & Dohme LLC; Gilead Sciences; California HIV/AIDS Research Program

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: December 1, 2009
• First Submitted That Met QC Criteria: December 2, 2009
• First Posted (Estimate): December 3, 2009

Study Record Updates

• Last Update Posted (Actual): July 1, 2020
• Last Update Submitted That Met QC Criteria: June 29, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: HIV; HIV persistence; HIV reservoirs
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Tenofovir; Emtricitabine; Raltegravir Potassium
• Other Study ID Numbers: H52889-35080