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

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00491556
• Other study ID #: ATN 061
• Status: Completed
• Phase: N/A
• First received: June 22, 2007
• Last updated: May 15, 2014
• Start date: October 2007
• Est. completion date: June 2013

Study information

• Verified date: May 2014
• Source: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 102
• Est. completion date: June 2013
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 24 Years

Eligibility

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).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infections

Intervention

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
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.

Locations

Country	Name	City	State
Puerto Rico	University of Puerto Rico	San Juan
United States	Children's Hospital of Denver - IMPAACT Site	Aurora	Colorado
United States	Johns Hopkins University - IMPAACT Site	Baltimore	Maryland
United States	University of Maryland	Baltimore	Maryland
United States	Montefiore Medical Center	Bronx	New York
United States	Childrens Memorial Hospital	Chicago	Illinois
United States	Stoger Hospital of Cook County	Chicago	Illinois
United States	Children's Hospital of Michigan - IMPAACT Site	Detroit	Michigan
United States	Duke Pediatric Infectious Diseases - IMPAACT Site	Durham	North Carolina
United States	Children's Diagnostic and Treatment Center	Fort Lauderdale	Florida
United States	Children's Hopsital of Los Angeles	Los Angeles	California
United States	University of Southern California - IMPAACT Site	Los Angeles	California
United States	St. Jude Children's Research Hospital (Memphis) - IMPAACT Site	Memphis	Tennessee
United States	St. Jude Childrens Research Hospital	Memphis	Tennessee
United States	University of Miami	Miami	Florida
United States	Tulane Medical Center	New Orleans	Louisiana
United States	Mount Sinai Medical Center	New York	New York
United States	UMDNJ - IMPAACT Site	Newark	New Jersey
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of California at San Francisco	San Francisco	California
United States	University of Southern Florida College of Medicine	Tampa	Florida
United States	Children's National Medical Center	Washington	District of Columbia
United States	Howard University - IMPAACT Site	Washington	District of Columbia

Sponsors (4)

Lead Sponsor	Collaborator
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)	International Maternal Pediatric Adolescent AIDS Clinical Trials Group, National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.		152 weeks	No
Secondary	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.		152 weeks	No
Secondary	Ability to maintain decreases in T cell activation achieved during HAART following therapy de-intensification		152 weeks	No
Secondary	Ability to maintain virologic control following de-intensification in adolescents treated with HAART prior to meeting DHHS guidelines.		152 weeks	No
Secondary	Impact of early HAART initiation on thymic output		152 weeks	No
Secondary	Determine the emergence of drug resistance in subjects who fail therapy de-intensification		152 weeks	Yes
Secondary	Evaluate the safety of initiating ART prior to significant CD4+ T cell loss with respect to emergence of drug associated toxicity and drug resistance.		152 weeks	Yes
Secondary	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		152 weeks	Yes

External Links

•   Description of Adolescent Trials Networks (ATN) and contact information