- ICH GCP
- Registre américain des essais cliniques
- Essai clinique NCT00207948
Optimizing Antiretroviral Therapy in HIV-Infected Children and Adolescents
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
Description détaillée
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.
Type d'étude
Inscription (Réel)
Contacts et emplacements
Lieux d'étude
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District of Columbia
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Washington, District of Columbia, États-Unis, 20010
- Children's National Medical Center
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Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
Accepte les volontaires sains
Sexes éligibles pour l'étude
Méthode d'échantillonnage
Population étudiée
La description
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
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
Cohortes et interventions
Groupe / Cohorte |
Intervention / Traitement |
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Therapeutic Dose Adjustment
To adjust the doses of medications to meet target therapeutic concentrations
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Adjust the dose by up to +50% of reccomended dosa off the drug to meet target therapeutic concentrations
Autres noms:
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
---|---|---|
evaluation of vIQ
Délai: 8 weeks
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vIQ would be reassessed to determine if increasing their PI dosage thereby increasing the bioavaiability would reduce their viral load.
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8 weeks
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Collaborateurs et enquêteurs
Parrainer
Les enquêteurs
- Chercheur principal: Natella Y Rakhmanina, MD, Children's National Medical Center, Children's Research Institute
Publications et liens utiles
Publications générales
- Rakhmanina N, van den Anker J, Baghdassarian A, Soldin S, Williams K, Neely MN. Population pharmacokinetics of lopinavir predict suboptimal therapeutic concentrations in treatment-experienced human immunodeficiency virus-infected children. Antimicrob Agents Chemother. 2009 Jun;53(6):2532-8. doi: 10.1128/AAC.01374-08. Epub 2009 Mar 2.
- Neely MN, Rakhmanina NY. Comment on: Pharmacokinetics and 48 week efficacy of low-dose lopinavir/ritonavir in HIV-infected children. J Antimicrob Chemother. 2010 Apr;65(4):808-9; author reply 809-10. doi: 10.1093/jac/dkp489. Epub 2010 Jan 19. No abstract available.
- Rakhmanina NY, Neely MN, Van Schaik RH, Gordish-Dressman HA, Williams KD, Soldin SJ, van den Anker JN. CYP3A5, ABCB1, and SLCO1B1 polymorphisms and pharmacokinetics and virologic outcome of lopinavir/ritonavir in HIV-infected children. Ther Drug Monit. 2011 Aug;33(4):417-24. doi: 10.1097/FTD.0b013e318225384f.
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude
Achèvement primaire (Réel)
Achèvement de l'étude (Réel)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Estimation)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Estimation)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Mots clés
Termes MeSH pertinents supplémentaires
- Infections par virus à ARN
- Maladies virales
- Infections
- Infections transmissibles par le sang
- Maladies transmissibles
- Maladies sexuellement transmissibles, virales
- Maladies sexuellement transmissibles
- Infections à lentivirus
- Infections à rétroviridae
- Syndromes d'immunodéficience
- Maladies du système immunitaire
- Infections à VIH
- Mécanismes moléculaires de l'action pharmacologique
- Agents anti-infectieux
- Agents antiviraux
- Inhibiteurs d'enzymes
- Agents anti-VIH
- Agents antirétroviraux
- Inhibiteurs de protéase
- Inhibiteurs du cytochrome P-450 CYP3A
- Inhibiteurs des enzymes du cytochrome P-450
- Inhibiteurs de la protéase du VIH
- Inhibiteurs de la protéase virale
- Ritonavir
- Lopinavir
Autres numéros d'identification d'étude
- 1K12RR017613-03 (Subvention/contrat des NIH des États-Unis)
Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .
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