Preservation and Expansion of T-cell Subsets Following HAART De-intensification to Atazanavir/Ritonavir (ATV/r)
Information source: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: HIV Infections
Intervention: Early Initiation of Highly Active Anti-Retroviral Therapy (Procedure); Standard Care (Procedure)
Phase: N/A
Status: Completed
Sponsored by: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Official(s) and/or principal investigator(s): Bret J Rudy, M.D., Study Chair, Affiliation: Children's Hospital of Philadelphia John Sleasman, M.D., Study Chair, Affiliation: University of South Florida, Dept of Pediatrics
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.
Clinical Details
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
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: 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.
Secondary outcome: 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.Ability to maintain decreases in T cell activation achieved during HAART following therapy de-intensification Ability to maintain virologic control following de-intensification in adolescents treated with HAART prior to meeting DHHS guidelines. Impact of early HAART initiation on thymic output Determine the emergence of drug resistance in subjects who fail therapy de-intensification Evaluate the safety of initiating ART prior to significant CD4+ T cell loss with respect to emergence of drug associated toxicity and drug resistance. 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
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
Minimum age: 18 Years.
Maximum age: 24 Years.
Gender(s): Both.
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).
Locations and Contacts
University of Puerto Rico, San Juan 00927, Puerto Rico
Children's Hopsital of Los Angeles, Los Angeles, California 90027, United States
University of Southern California - IMPAACT Site, Los Angeles, California 90033, United States
University of California at San Francisco, San Francisco, California 94118, United States
Children's Hospital of Denver - IMPAACT Site, Aurora, Colorado 80045, United States
Children's National Medical Center, Washington, District of Columbia 20010, United States
Howard University - IMPAACT Site, Washington, District of Columbia 20060, United States
Children's Diagnostic and Treatment Center, Fort Lauderdale, Florida 33316, United States
University of Miami, Miami, Florida 33101, United States
University of Southern Florida College of Medicine, Tampa, Florida 33606, United States
Childrens Memorial Hospital, Chicago, Illinois 60614, United States
Stoger Hospital of Cook County, Chicago, Illinois 60612, United States
Tulane Medical Center, New Orleans, Louisiana 70112, United States
Johns Hopkins University - IMPAACT Site, Baltimore, Maryland 21287, United States
University of Maryland, Baltimore, Maryland 21201, United States
Children's Hospital of Michigan - IMPAACT Site, Detroit, Michigan 48201, United States
UMDNJ - IMPAACT Site, Newark, New Jersey 07103, United States
Montefiore Medical Center, Bronx, New York 10467, United States
Mount Sinai Medical Center, New York, New York 10128, United States
Duke Pediatric Infectious Diseases - IMPAACT Site, Durham, North Carolina 27710, United States
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States
St. Jude Children's Research Hospital (Memphis) - IMPAACT Site, Memphis, Tennessee 38105, United States
St. Jude Childrens Research Hospital, Memphis, Tennessee 38105, United States
Additional Information
Description of Adolescent Trials Networks (ATN) and contact information
Starting date: October 2007
Last updated: May 15, 2014
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