Clinical trial NCT01777997: FTC/RPV/TDF on T-Cell Activation, CD4+ T-Cell Count, Inflammatory Biomarkers and Viral Reservoir
Official title: A Prospective, Single-Arm, Open-Label Study to Evaluate the Effect of Fixed-Dose Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate on T-Cell Activation, Absolute CD4+ T-Cell Count, Inflammatory Biomarkers and Viral Reservoir in Treatment-Naïve HIV-1 Controllers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV-1 Infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2013-01-29
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study was done with people who were infected with HIV, but did not show any signs of having HIV. They were also feeling well without taking HIV medication and had low or undetectable levels of the virus in the blood. The purpose of this study was to see if taking HIV medication (antiretroviral therapy \[ART\]) would reduce immune activation (a signal that the body is fighting an infection) in people who have HIV, but did not show symptoms. Also this study helped determine how safe the drug was and how well people reacted to the drug.

For this study, the following antiretroviral therapy (ART) was be provided in the form of a single tablet that contains three different drugs: emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF). These drugs were combined as one tablet which was approved by the Food and Drug Administration (FDA) as a single pill to treat HIV infection. The HIV medication provided was one of the recommended treatments for HIV, including people with low viral loads (how much HIV you have in your body) who were taking HIV drugs for the first time. The risks seen with this HIV medication were the same that one would encounter when taking these drugs outside of the study.

Detailed description: AIDS Clinical Trials Group (ACTG) A5308 was a single-arm clinical trial to evaluate the effect of initiating fixed-dose combination (FDC) FTC/RPV/TDF on CD8+ T-cell activation and other immunologic and virologic biomarkers among treatment-naïve HIV-1 controllers with any absolute CD4+ T-cell count. At study entry, these participants were followed off ART for a 12-week lead-in period, and then at week 12, participants initiated FDC FTC/RPV/TDF and had 48 weeks of follow-up to evaluate the primary endpoint.

All participants who completed Step 1 (48 weeks of ART) had the option to register to Step 2, for an additional 48 weeks of follow-up, and had the choice of either continuing FDC FTC/RPV/TDF or follow-up with no study treatment.

Participants underwent safety and tolerability evaluations throughout the study, including physical examinations and clinical assessments. Pregnancy tests were performed on women of childbearing potential. Collection of stored blood plasma/peripheral blood mononuclear cell (PBMC) samples occurred at entry and weeks 0, 4, 12, 24, 36, 48, 60, 72 and 96 on ART.

Only participants who were on intervention (ART) for at least 24 weeks had samples sent for testing of immunologic and virologic biomarkers.

Eligibility criteria: Inclusion Criteria:

Step 1

* HIV-1 infection
* ART-naïve defined as ≤7 days of antiretroviral (ARV) treatment at any time prior to entry
* Documentation of HIV-1 RNA \<500 copies/mL verified by at least two measurements prior to the screening RNA specimen
* Screening HIV-1 RNA \<500 copies/mL using an US FDA-approved assay obtained within 60 days prior to study entry by any laboratory that has a CLIA certification or its equivalent
* Laboratory values obtained within 60 days prior to entry by any laboratory that has a CLIA certification or its equivalent:

  * Absolute neutrophil count (ANC) \>=500/mm\^3
  * Hemoglobin \>=8.0 g/dL
  * Platelet count \>=40,000/mm\^3
  * Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT), and alkaline phosphatase \<=5 X Upper Limit of Normal (ULN)
  * Total bilirubin \<=2.5 X ULN
  * Calculated creatinine clearance (CrCl) \>=60 mL/min
* For females of reproductive potential, negative serum or urine pregnancy test within 48 hours prior to study entry by any clinic or laboratory that has a CLIA certification or its equivalent
* Female subjects of reproductive potential, who are participating in sexual activity that could lead to pregnancy, must agree to use at least one reliable form of contraceptive (ie, condoms (male or female) with or without a spermicidal agent; a diaphragm or cervical cap with spermicide; an intrauterine device (IUD); or hormone-based contraceptive) while receiving the protocol-specified treatment and for 6 weeks after stopping the medications
* No evidence of any exclusionary resistance mutations based on results from any genotype assay from any laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent

Step 2

* Completion of Step 1
* Ability and willingness of subject to choose to receive either open-label ART FDC (FTC/RPV/TDF) or no study treatment for an additional 48 weeks
* For females of reproductive potential, negative serum or urine pregnancy test within 48 hours prior to the week 60 visit by any clinic or laboratory that has a CLIA certification or its equivalent

Exclusion Criteria:

Step 1

* Chronic hepatitis B virus (HBV) infection (documented by hepatitis B surface antigen (HBsAg) seropositivity)
* Breastfeeding
* Use of immunomodulators (eg, interleukins, interferons, cyclosporine), topical imiquimod, HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry or plans to start immunomodulators, topical imiquimod, HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy during the study
* Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation
* Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
* Acute or serious illness requiring systemic treatment and/or hospitalization within 30 days prior to entry
* Symptomatic HIV disease and/or AIDS-defining illness.
* Vaccinations within 7 days prior to study entry
* Plans to initiate hepatitis C treatment during the study
* Perinatally-acquired HIV
* Use of any of the following medications within 7 days prior to study entry:

  * St. John's wort (Hypercium perforatum)
  * Anticonvulsants (eg, oxacarbazepine, phenobarbital, phenytoin)
  * Anti-infectives (eg, rifabutin, rifampin, rifapentine)
  * Corticosteroids (eg, dexamethasone (more than 1 dose))
  * Proton pump inhibitors (eg, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)

Step 2

* Plans to start immunomodulators, topical imiquimod, HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy during Step 2 of the study
* Plans to initiate hepatitis C treatment during Step 2 of the study

NOTE: Please refer to the protocol for detailed eligibility criteria.

Primary outcomes:
measure: Change in Levels of CD8+ T-cell Activation (Defined as the Percentage HLA-DR+/CD38+) From Baseline to Weeks 24 and 48 on ART
timeFrame: From baseline (pre-ART and week 0 on ART) to weeks 24 and 48 on ART
Secondary outcomes:
measure: Plasma HIV-1 RNA Level Measured by Single Copy Assay Using Primer in Integrase (iSCA) as the Proportion of Participants Below the Limit of the Assay
timeFrame: At pre-ART and weeks 0, 4, 12, 24, 36 and 48 on ART
measure: Change in CD4+ T-cell Count
timeFrame: From baseline (pre-ART and week 0 on ART) to weeks 12, 24, 36 and 48 on ART
measure: Change in Levels of CD8+ T-cell Activation
timeFrame: From baseline (pre-ART and week 0 on ART) to weeks 4, 12, 24 and 48 on ART
measure: Change in Levels of CD4+ T-cell Activation (Defined as the Percentage HLA-DR+/CD38+)
timeFrame: From baseline (pre-ART and week 0 on ART) to weeks 4, 12, 24 and 48 on ART
measure: Change in Levels of Interleukin (IL)-6
timeFrame: From baseline (pre-ART and week 0 on ART) to weeks 4, 12, 24 and 48 on ART
measure: Change in Levels of D-dimer
timeFrame: From baseline (pre-ART and week 0 on ART) to weeks 4, 24 and 48 on ART
measure: Change in Quality of Life (QoL) Index
timeFrame: From baseline (pre-ART and week 0 on ART) to weeks 4, 24 and 48 on ART
measure: Number of Subjects Who Experience Grade 3 or 4 Signs and Symptoms or Laboratory Abnormalities, Diagnoses (Any Grade), or Other Serious Adverse Events (SAEs)
timeFrame: From initiation of treatment to study completion at week 60 or 108 or premature study discontinuation
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 31788 Alabama CRS
state: Alabama
city: San Francisco
country: United States
facility: 801 University of California, San Francisco HIV/AIDS CRS
state: California
city: Washington
country: United States
facility: Whitman Walker Health CRS (31791)
state: District of Columbia
city: Atlanta
country: United States
facility: The Ponce de Leon Ctr. CRS (5802)
state: Georgia
city: Chicago
country: United States
facility: Northwestern University CRS (2701)
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS (2702)
state: Illinois
city: Baltimore
country: United States
facility: IHV Baltimore Treatment CRS (4651)
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS (101)
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp. ACTG CRS (107)
state: Massachusetts
city: Bronx
country: United States
facility: Bronx-Lebanon Hosp. Ctr. CRS (31469)
state: New York
city: Rochester
country: United States
facility: University of Rochester Adult HIV Therapeutic Strategies Network CRS (31787)
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs (3201)
state: North Carolina
city: Greensboro
country: United States
facility: Moses H. Cone Memorial Hospital CRS (3203)
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati CRS (2401)
state: Ohio
city: Cleveland
country: United States
facility: Metro Health CRS (2503)
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS (6201)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Pitt CRS (1001)
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hosp. ACTG CRS (2951)
state: Rhode Island
city: Houston
country: United States
facility: Houston AIDS Research Team CRS (31473)
state: Texas
Study officials:
affiliation: Brigham and Women's Hospital Therapeutics (BWHT) CRS
name: Jonathan Li, M.D., M.M.S.
role: STUDY_CHAIR
References: