HIV Persistence and Viral Reservoirs

NCT01025427 | Completed Phase 4 Results DMC

• 1 other identifier: H52889-35080
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

HIV; HIV Infections

Keywords

HIV; HIV persistence; HIV reservoirs

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (1)

Elite controller

EXPERIMENTAL

Sixteen controllers will be treated with open-label raltegravir/tenofovir/emtricitabine for 24 weeks.

Drug: Raltegravir, tenofovir/emtricitabine

Interventions

Raltegravir, tenofovir/emtricitabine DRUG

16 controllers will be treated with open-label raltegravir/tenofovir/emtricitabine for 24 weeks.

Elite controller

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years, and
• HIV infection, and
• Antiretroviral-naïve, and
• CD4+ T cell count \>350 cells/mm3, and
• "Controllers": antiretroviral untreated with 50-1000 copies/mL viral load for at least 12 months

You may not qualify if:

• Persons with known rheumatologic conditions (e.g., systemic lupus erythematosus), because of their predilection for biologic false-positive testing on HIV antibody tests.
• 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.
• Screening genotype resistance testing showing resistance to tenofovir or emtricitabine.
• Known kidney disease.
• Known bone disease, including pathologic fractures.
• Patients with chronic Hepatitis B infection, because of the risk of liver abnormalities after starting and stopping tenofovir/emtricitabine.
• Concurrent treatment with lamivudine, adefovir, entecavir, or telbivudine.
• Serious illness requiring hospitalization or parental antibiotics within the preceding 3 months.
• 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.
• Concurrent treatment with phenobarbital, phenytoin, or rifampin.
• 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.

Sponsors & Collaborators

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

Study Sites (1)

San Francisco General Hospital

San Francisco, California, 94110, United States

Location

Related Publications (1)

• 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.

  PMID: 24130489 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Raltegravir Potassium; Tenofovir; Emtricitabine

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Hiroyu Hatano
• Organization: University of California, San Francisco

hhatano@php.ucsf.edu

415-476-4082

Study Officials

• Hiroyu Hatano, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2009
• First Posted: December 3, 2009
• Study Start: December 1, 2009
• Primary Completion: November 1, 2012
• Study Completion: October 1, 2013
• Last Updated: July 1, 2020
• Results First Posted: July 1, 2020

Record last verified: 2020-06

Locations

US (1)