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

This study has been completed.
Sponsor:
Collaborators:
International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Information provided by (Responsible Party):
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:
NCT00491556
First received: June 22, 2007
Last updated: May 15, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention
HIV Infections
Procedure: Early Initiation of Highly Active Anti-Retroviral Therapy
Procedure: Standard Care

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):

Primary Outcome Measures:
  • Ability to maintain or enhance HAART-associated quantitative changes in CD4+ T cell percentages achieved during HAART following therapy de-intensification to ATV/r in adolescents and young adults who began treatment prior to meeting DHHS guidelines. [ Time Frame: 152 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Quantitative and qualitative changes in T cell subsets percentage in those initiating HAART prior to current guidelines followed by de-intensification and in subjects initiating HAART by current DHHS guidelines. [ Time Frame: 152 weeks ] [ Designated as safety issue: No ]
  • Ability to maintain decreases in T cell activation achieved during HAART following therapy de-intensification [ Time Frame: 152 weeks ] [ Designated as safety issue: No ]
  • Ability to maintain virologic control following de-intensification in adolescents treated with HAART prior to meeting DHHS guidelines. [ Time Frame: 152 weeks ] [ Designated as safety issue: No ]
  • Impact of early HAART initiation on thymic output [ Time Frame: 152 weeks ] [ Designated as safety issue: No ]
  • Determine the emergence of drug resistance in subjects who fail therapy de-intensification [ Time Frame: 152 weeks ] [ Designated as safety issue: Yes ]
  • Evaluate the safety of initiating ART prior to significant CD4+ T cell loss with respect to emergence of drug associated toxicity and drug resistance. [ Time Frame: 152 weeks ] [ Designated as safety issue: Yes ]
  • Monitor prevalence of genotypic drug resistance within an ARV naïve or minimally exposed adolescent and young adult population; evaluate the associations of subject demographic and clinical variables with presence of genotypic mutation [ Time Frame: 152 weeks ] [ Designated as safety issue: Yes ]

Enrollment: 102
Study Start Date: October 2007
Study Completion Date: June 2013
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Experimental Arm
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
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.
Standard Care Arm
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
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.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 24 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Age 18 yrs and 0 days to 24 yrs and 364 days;
  2. 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;
  3. 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.
  4. 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.
  5. 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.
  6. 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);
  7. 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
  8. Able to provide written informed consent/assent.

Exclusion Criteria

  1. Pregnancy;
  2. 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);
  3. 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);
  4. Currently breast feeding;
  5. Current treatment for active serious systemic bacterial infections;
  6. Active hepatitis B infection as defined by Hepatitis B Ag positive;
  7. 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;
  8. 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;
  9. Disallowed Medications (see Section 5.3.2);
  10. Active drug or alcohol use or dependence that, in the opinion of the site personnel, would interfere with adherence to the study;
  11. History of chronic renal insufficiency or Grade 3 or greater serum creatinine; and
  12. Any confirmed grade 3 or greater laboratory value at pre-entry (with the exception of grade 3 or greater lipids or platelets).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00491556

  Show 23 Study Locations
Sponsors and Collaborators
International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Investigators
Study Chair: Bret J Rudy, M.D. Children's Hospital of Philadelphia
Study Chair: John Sleasman, M.D. University of South Florida, Dept of Pediatrics
  More Information

Additional Information:
No publications provided

Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier: NCT00491556     History of Changes
Other Study ID Numbers: ATN 061
Study First Received: June 22, 2007
Last Updated: May 15, 2014
Health Authority: United States: Federal Government

Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):
Atazanavir/Ritonavir (ATV/r)
highly-active antiretroviral therapy (HAART)
Treatment Naive

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Ritonavir
Atazanavir
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 14, 2014