Preservation and Expansion of T-cell Subsets Following HAART De-intensification to Atazanavir/Ritonavir (ATV/r)

Study Overview
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Brief Summary
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This study proposes to evaluate a pre-DHHS guideline of HAART initiation and then de-intensification management strategy in adolescents with mild immunosuppression and compare changes in CD4% from baseline to week 48 and then during de-intensification.

Detailed Description
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This is a randomized, proof of concept study of youth 18- 24 years of age with confirmed HIV after age 9 with CD4+ T cells above 350 cells/mm3 who are randomized 3:1 to begin HAART consisting of TDF/FTC/ATV/r (preferred), AZT/3TC/ATV/r, or other recommended NRTI backbone with ATV/r upon entry or to begin treatment under current DHHS guidelines. Subjects in the experimental group who achieve virologic control by week 24 and maintain good control through 48 weeks will then de-intensify to ATV/r alone and will be followed for two years. Subjects randomized to the standard care arm will begin HAART with TDF/FTC/ATV/r (preferred), AZT/3TC/ATV/r, or other recommended ATV/r based HAART regimen according to current DHHS standard of care.

Official Title
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Preservation and Expansion of T-cell Subsets Following HAART De-intensification to Atazanavir/Ritonavir (ATV/r) in Adolescents With CD4 + T Cells > 350 Cells/mm3 Initiating HAART

Conditions
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HIV Infections

Intervention / Treatment
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* Procedure: Early Initiation of Highly Active Anti-Retroviral Therapy
* Procedure: Standard Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age 18 yrs and 0 days to 24 yrs and 364 days; CD4+ T cells > 350/mm3 and HIV RNA ≥ 1,000 copies/ml as determined by two consecutive measures within 6 months of entry with the second measure being collected at pre-entry; Infected after age 9. HIV-1 infection should be documented by any licensed ELISA test kit and confirmed by Western blot, HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA at any time prior to entry; Note: Subjects who are in acute seroconversion as evidenced by being ELISA negative (antibody negative) and DNA PCR or HIV-1 RNA positive or who are ELISA positive but Western Blot indeterminate are not eligible. Subjects must be naïve to ARV medications except for women who have received HAART for prevention of maternal to child transmission (MTCT) that meet the following criteria: HAART (defined as three medications from two classes) given for no more than six months for prevention of MTCT, Evidence of viral suppression on the HAART regimen defined as a plasma RNA level below the level of detection for the assay used by the site either during the third trimester or around the time of delivery, A minimum of six months since HAART exposure for prevention of MTCT, and Exposure to HAART for a single pregnancy only; Note: Prior treatment with Trizivir for prevention of MCTC is also permitted as long as viral suppression is documented at the time of delivery or in the last trimester, whichever is most recent. HIV genotype without major resistance mutations to ATV/r. The following genotypic mutations exclude subjects from participation in ATN 061: Major ATV mutations I50L; I84V; N88D/S, Major PI mutations including: D30N; V32I; L33I/F/V; M46I/L; I47V/A; G48V; I50V/L; I54V/L/A/M/T/S; L76V; V82A/F/T/S/L; L90M, Any major PI mutation as defined by the most current IAS-USA Drug Resistance Mutations Figures that would adversely affect a subject's future PI choices, Major RT mutations: Q151M and 69 insertion complex; Decisions regarding the selection of an NRTI backbone for subjects with NRTI resistance mutations other than those described above will be made by the site PI in consultation with the protocol chair or his designee. Whenever possible and not otherwise contraindicated, NRTI choices should be congruent with the protocol-specified preferred regimens. The site PI must provide a copy of the genotype analysis along with their proposed regimen for review; Note: Subjects who cannot go onto either FTC/TDF or AZT/3TC must have the regimen approved by the protocol team following pre-entry screening and prior to study entry. Note: All HIV-1 genotype profiles with ANY resistance mutations must be evaluated by a physician specializing in the care of HIV-infected patients prior to final determination of subject eligibility. Polymorphism mutations should NOT be reported since their clinical significance is unknown. All other (major and minor) mutations should be appropriately categorized and reported as indicated by the case report form. In circumstances where there are numerous such mutations or other concerns present, consultation with the protocol team by the evaluating physician via the ATN QNS is highly encouraged. Calculated creatinine clearance ≥60 mL/min as estimated by the Cockcroft-Gault equation: For men, (140 - age in years) x (body weight in kg) ÷ (serum creatinine in mg/dL x 72) = CrCl (mL/min)*;*For women, multiply the result by 0.85 = CrCl (mL/min); For females with child-bearing potential, agreement to use one effective birth control method and willing to postpone pregnancy for the duration of the study (See Section 9.3 - criteria for class C drugs should be followed); and Able to provide written informed consent/assent. Exclusion Criteria Pregnancy; On systemic immunosuppressive therapy or immune modulating therapy (short courses (<14 days) of prednisone for reactive airway disease [RAD] are permitted but not within 30 days prior to study entry); Any history of an AIDS-defining illness (note: a history of a CD4 + T cell count below 200 cells/mm3 is not an exclusion criterion as long as all other inclusion/exclusion criteria are met); Currently breast feeding; Current treatment for active serious systemic bacterial infections; Active hepatitis B infection as defined by Hepatitis B Ag positive; Treatment with immune modulators including IL-2, intravenous gammaglobulin, and therapeutic or other experimental vaccines including HIV-1 vaccine given for primary prevention at any time; History of cardiac conduction abnormalities including one or more of the following: Symptomatic heart block, Third-degree heart block, even if asymptomatic, Pre-excitation syndromes, Heart Rate <40 bpm, Ventricular pause length >3 seconds, QTc > 500 msec, and Cardiomyopathy; Disallowed Medications (see Section 5.3.2); Active drug or alcohol use or dependence that, in the opinion of the site personnel, would interfere with adherence to the study; History of chronic renal insufficiency or Grade 3 or greater serum creatinine; and Any confirmed grade 3 or greater laboratory value at pre-entry (with the exception of grade 3 or greater lipids or platelets).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arm<br>Subjects in the experimental group will begin HAART consisting of TDF/FTC/ATV/r (preferred), AZT/3TC/ATV/r or other recommended NRTI backbone with ATV/r upon entry or to begin treatment under current DHHS guidelines. Subjects in the experimental group who achieve virologic control by week 24 and maintain good control through 48 weeks will then de-intensify to ATV/r alone and will be followed for an additional two years. | Procedure: Early Initiation of Highly Active Anti-Retroviral Therapy<br>* Treatment: TDF/FTC/ATV/r (preferred), AZT/3TC/ATV/r or other recommended NRTI backbone with ATV/r. Duration: Subjects in the experimental group who achieve virologic control by week 24 and maintain good control through 48 weeks will then de-intensify to ATV/r alone and will be followed for an additional two years.<br>|
| Other: Standard Care Arm<br>Subjects randomized to the standard care arm will begin HAART with TDF/FTC/ATV/r (preferred), AZT/3TC/ATV/r, or other recommended ATV/r based HAART regimen according to current DHHS standard of care and will be followed for a total of three years. Under these guidelines and under current clinical standards, subjects on the standard care arm will begin therapy when the CD4+ T cell count drops below 350 cells/mm3 or other clinical criteria necessitating treatment as determined by the site clinician occur. | Procedure: Standard Care<br>* Progression: Subjects on the standard care arm will begin therapy when the CD4+ T cell count drops below 350 cells/mm3 or other clinical criteria necessitating treatment as determined by the site clinician occur. Treatment: HAART with TDF/FTC/ATV/r (preferred), AZT/3TC/ATV/r, or other recommended ATV/r based HAART regimen according to current DHHS standard of care. Duration: three years.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in CD4+ T Cell Percentage Between Week 0 and Week 48 |  | Week 0 and Week 48 | 
| Difference in CD4+ T Cell Percentage Between Week 48 and Week 152 |  | 152 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in CD4+ T Cell Count Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD4+ T Cell Count Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD4+ Naïve T Cell Count Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD4+ Naïve T Cell Count Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD4+ Termed Central Memory (TCM) Count Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD4+ TCM Count Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD4+ Effector Memory (TEM)Ro Count Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD4+ TEMRo Count Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD4+ TEMRa Count Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD4+ TEMRa Count Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8+ Naïve T-Cell Count Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8+ Naïve T-Cell Count Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8+ TCM Count Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8+ TCM Count Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8+ TEMRo Count Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8+ TEMRo Count Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8+ TEMRa Count Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8+ TEMRa Count Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 Naïve CD28 Cell Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 Naïve CD28 Cell Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 Naïve CD38 Cell Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 Naïve CD38 Cell Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 Naïve CD57 Cell Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 Naïve CD57 Cell Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 Naïve T-Cell Percentage Expressing Human Leukocyte Antigen-D Related (HLA-DR) Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 Naïve T-Cell Percentage Expressing HLA-DR Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 TCM CD28 Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 TCM CD28 Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 TCM CD38 Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 TCM CD38 Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 TCM CD57 Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 TCM CD57 Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 TCM HLA-DR Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 TCM HLA-DR Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 TEMRo CD28 Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 TEMRo CD28 Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 TEMRo CD38 Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 TEMRo CD38 Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 TEMRo CD57 Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 TEMRo CD57 Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 TEMRO HLADR Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 TEMRo HLA-DR Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 TEMRa CD28 Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 TEMRa CD28 Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 TEMRa CD38 Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 TEMRa CD38 Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 TEMRa CD57 Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 TEMRa CD57 Percentage Between Week 48 and Week 152 |  | 152 weeks | 
| Difference in CD8 TEMRa HLA-DR Percentage Between Week 0 and Week 48 |  | 48 weeks | 
| Difference in CD8 TEMRa HLA-DR Percentage Between Week 48 and Week 152 |  | 152 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atazanavir/Ritonavir (ATV/r), highly-active antiretroviral therapy (HAART), Treatment Naive