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Sponsored by: |
Children's Research Institute |
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Information provided by: | Children's Research Institute |
ClinicalTrials.gov Identifier: | NCT00207948 |
The proposal is aimed at the development of a dosing regimen of existing protease inhibitors (PIs) in human immunodeficiency virus (HIV)-infected children that takes into account genetic variability in drug metabolism and transport, and resistance of the dominant viral strain. The long-term goal of the research investigation is to improve dosing of protease inhibitors (PIs) in HIV-infected children, leading to improved outcome and decreased adverse drug reactions.
Condition | Intervention | Phase |
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HIV Infections |
Drug: Nelfinavir Drug: Lopinavir/ritonavir Drug: Ritonavir Drug: Amprenavir Drug: Indinavir Drug: Saquinavir Drug: Fosamprenavir Drug: Atazanavir Drug: Tipranavir |
Phase IV |
Study Type: | Interventional |
Study Design: | Randomized, Open Label, Active Control, Parallel Assignment, Pharmacokinetics Study |
Official Title: | Optimizing Antiretroviral Therapy in HIV-Infected Children and Adolescents |
Estimated Enrollment: | 150 |
Study Start Date: | November 2004 |
Estimated Study Completion Date: | July 2009 |
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:
Ages Eligible for Study: | 4 Years to 21 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion criteria:
Exclusion criteria:
Contact: Natella Y Rakhmanina, MD | (202) 884-2083 | nrakhmanina@cnmc.org |
Contact: Keetra Williams, RN | (202) 884-4705 | kwilliams@cnmc.org |
United States, District of Columbia | |
Children's National Medical Center | Recruiting |
Washington, District of Columbia, United States, 20010 | |
Contact: Natella Y Rakhmanina, MD 202-884-2083 nrakhmanina@cnmc.org | |
Contact: Keetra Williams, RN (202) 884-4705 kwilliams@cnmc.org | |
Principal Investigator: Natella Y Rakhmanina, MD | |
Sub-Investigator: Hans L Spiegel, MD, PhD | |
Sub-Investigator: John N Van Den Anker, MD, PhD | |
Sub-Investigator: Eric Hoffman, PhD | |
Sub-Investigator: Lawrence D'Angelo, MD | |
Sub-Investigator: Steven Soldin, PhD |
Principal Investigator: | Natella Y Rakhmanina, MD | Children's National Medical Center, Children's Research Institute |
Study ID Numbers: | 1K12RR017613-03 |
Study First Received: | September 13, 2005 |
Last Updated: | March 6, 2008 |
ClinicalTrials.gov Identifier: | NCT00207948 |
Health Authority: | United States: Institutional Review Board |
Human Immunodeficiency Virus Protease Inhibitors Pharmacogenetics Genes, MDR1, Cytochrome P-450 enzymes |
Pharmacokinetics Pediatrics Treatment Experienced |
Sexually Transmitted Diseases, Viral Indinavir Saquinavir Acquired Immunodeficiency Syndrome Atazanavir Immunologic Deficiency Syndromes Tipranavir Virus Diseases |
Amprenavir Fosamprenavir Lopinavir HIV Infections Ritonavir Sexually Transmitted Diseases Nelfinavir Retroviridae Infections |
Anti-Infective Agents RNA Virus Infections HIV Protease Inhibitors Slow Virus Diseases Anti-HIV Agents Immune System Diseases Molecular Mechanisms of Pharmacological Action Enzyme Inhibitors Infection |
Antiviral Agents Pharmacologic Actions Antibiotics, Antitubercular Protease Inhibitors Anti-Bacterial Agents Anti-Retroviral Agents Therapeutic Uses Lentivirus Infections Antitubercular Agents |