Ignite Creation Date:
2024-05-05 @ 11:59 AM
Last Modification Date:
2024-10-26 @ 9:18 AM
Study NCT ID:
NCT00207948
Status:
TERMINATED
Last Update Posted:
2015-08-05
First Post:
2005-09-13
Brief Title:
Optimizing Antiretroviral Therapy in HIV-Infected Children and Adolescents
Sponsor:
Childrens National Research Institute
Organization:
Childrens National Research Institute
Study Overview
Official Title:
Optimizing Antiretroviral Therapy in HIV-Infected Children and Adolescents
Status:
TERMINATED
Status Verified Date:
2015-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
no measurable response was detected at the 50 increase threshold
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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 determinedpatients with a vIQ1 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
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 genesSNPs 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
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 genesSNPs 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None