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Optimizing Antiretroviral Therapy in HIV-Infected Children and Adolescents

This study has been terminated.
(no measurable response was detected at the 50% increase threshold.)
Sponsor:
Information provided by (Responsible Party):
Children's Research Institute
ClinicalTrials.gov Identifier:
NCT00207948
First received: September 13, 2005
Last updated: October 28, 2014
Last verified: October 2014
  Purpose

This was a feasibility study aimed at elevating protease inhibitors (PI) dosage as a part of active antiretroviral therapy (HAART). After the pharmacokinetics for the currently prescribed PI were determined,patients with a vIQ<1 were eligible for a 50% dose increase for an 8 week time frame after which their vIQ would be reassessed to determine if increasing their PI dosage thereby increasing the bioavaiability would reduce their viral load.


Condition Intervention Phase
HIV Infections
Drug: Dose adjustment of Kaletra
Phase 4

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Optimizing Antiretroviral Therapy in HIV-Infected Children and Adolescents

Resource links provided by NLM:


Further study details as provided by Children's Research Institute:

Primary Outcome Measures:
  • evaluation of vIQ [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    vIQ would be reassessed to determine if increasing their PI dosage thereby increasing the bioavaiability would reduce their viral load.


Enrollment: 4
Study Start Date: November 2004
Study Completion Date: July 2009
Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Therapeutic Dose Adjustment
To adjust the doses of medications to meet target therapeutic concentrations
Drug: Dose adjustment of Kaletra
Adjust the dose by up to +50% of reccomended dosa off the drug to meet target therapeutic concentrations
Other Names:
  • Lopinavir
  • Ritonavir

Detailed Description:

Although, the use of protease inhibitors (PI) containing highly active antiretroviral therapy (HAART) has led to a remarkable improvement in the prognosis and outcome of HIV infection, only 45% to 70% of treatment-naïve patients who commence HAART achieve complete virological suppression. The emergence of HIV resistance to antiretroviral drugs is one of the main obstacles to the successful long-term suppression of HIV replication. Poor adherence and unfavorable pharmacokinetics (PK) caused by altered absorption, genetic variations in metabolism and drug-drug interactions frequently lead to antiretroviral drug concentrations below the inhibitory concentration for 50% of the viral quasispecies (IC50) and loss of viral suppression.

Enzymes of the cytochrome (CYP) P450 (CYP2C19, CYP3A4, CYP3A5) family located in the liver and small intestine are responsible for the metabolism of PIs. The absence of expression of certain enzymes from this family was recently correlated with a genetic polymorphism, which may have a major role in variation of cytochrome P450-mediated drug metabolism. Results of these studies suggest significant differences in the distribution of the polymorphism associated alleles between ethnic groups, in particular between Caucasians and African Americans. Detection of cytochrome P450 variant alleles and more detailed data on their allelic frequency in various ethnic groups is critical to assess their impact on PK of antiretroviral agents, in particular PIs.

This research proposal is aimed at the development of a novel multidisciplinary approach to optimize HAART in HIV infected children. It is increasingly clear that inter-individual variation in drug metabolism and responsiveness has a strong genetic component. The metabolic pathways leading to drug clearance, bio-availability, and cellular responses are complex, and only beginning to be understood. Key to our understanding of inter-individual responses is identification of the genetic polymorphisms that contribute to this variability, the relative contribution of different genes/SNPs, and the possible interactions between the corresponding protein products or pathways. We propose to develop a dosing regimen of PIs in HIV-infected children that takes into account genetic variability in drug metabolism and transport, and resistance of the dominant viral strain (as determined by virtual phenotype).

In order to do so, the protocol address the following Specific Aims:

  • Specific Aim 1 (completed previously): Determine the prevalence of genetic variations in CYP2C19, CYP3A4, CYP3A5, and MDR-1 genes in a cohort of children and adolescents with HIV infection.
  • Specific Aim 2 (completed previously): Evaluate the relationship of this genetic variability to the pharmacokinetic parameters (Cmin, Cmax, AUC) and toxicity (graded by the Division of AIDS [DAIDS] classification) of protease inhibitors in pediatric patients with HIV infection.
  • Specific Aim 3 (THIS STUDY): Evaluate the impact of dose adjustment of protease inhibitors based on pharmacogenetic profile and virtual inhibitory quotient (VIQ) on clinical outcome (measured by HIV-RNA viral load and CD4+ cell count changes) and toxicity (graded by the DAIDS classification) in pediatric patients with HIV infection.
  Eligibility

Ages Eligible for Study:   4 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

The total number of recruited subjects in a previous the study was 78 with 50 subjects on LPV/RTV based ART. Based on PK analysis 4 patients fit inclusion criteria for a dose adjustment feasibility pilot (this study)

Criteria

Inclusion criteria:

  • Evidence of HIV infection confirmed by positive culture or PCR on at least two occasions, or a positive ELISA and a confirmatory Western Blot. At least one of these tests must be done in an ACTG certified laboratory which is approved to perform the assay for protocol testing
  • Age 4-21 years
  • Current use of HAART regimen (NRTI or/and NNRTI based) containing a PI
  • HIV-RNA levels above 1,000 copies/mL (Stage II)
  • vIQ<1 for Kaletra
  • Signed informed consent and, if indicated, signed informed assent or waiver of assent.

Exclusion criteria:

  • Grade 3-4 DAIDS defined toxicity
  • Use of cimetidine (used as the internal standard for the HPLC-MS/MS assay)
  • Any active opportunistic infection
  • Any of the following laboratory findings at entry: absolute neutrophil count <750 cells/mm3; platelet count <75,000 cells/mm3; AST >3 times upper limit of age adjusted normal values; ALT >3 times upper limit of age adjusted normal values; serum creatinine >1.2mg/dL.
  • Patients on dual PI regimen (except when second PI is given for boosting) at the time of enrollment
  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: NCT00207948

Locations
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
Sponsors and Collaborators
Children's Research Institute
Investigators
Principal Investigator: Natella Y Rakhmanina, MD Children's National Medical Center, Children's Research Institute
  More Information

Publications:
Responsible Party: Children's Research Institute
ClinicalTrials.gov Identifier: NCT00207948     History of Changes
Other Study ID Numbers: 1K12RR017613-03
Study First Received: September 13, 2005
Last Updated: October 28, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Children's Research Institute:
Human Immunodeficiency Virus
Protease Inhibitors
Pharmacogenetics
Genes, MDR1, Cytochrome P-450 enzymes
Pharmacokinetics
Pediatrics
Treatment Experienced

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
RNA Virus Infections
Retroviridae Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases

ClinicalTrials.gov processed this record on November 20, 2014