Optimizing Antiretroviral Therapy in HIV-Infected Children and Adolescents

HIV Infections Clinical Trial

Official title:

Optimizing Antiretroviral Therapy in HIV-Infected Children and Adolescents

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00207948
• Other study ID #: 1K12RR017613-03
• Status: Terminated
• Phase: Phase 4
• First received: September 13, 2005
• Last updated: August 3, 2015
• Start date: November 2004
• Est. completion date: July 2009

Study information

• Verified date: August 2015
• Source: Children's Research Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial 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 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 4
• Est. completion date: July 2009
• Est. primary completion date: May 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 4 Years to 21 Years

Eligibility

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

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Dose adjustment of Kaletra
Adjust the dose by up to +50% of reccomended dosa off the drug to meet target therapeutic concentrations

Locations

Country	Name	City	State
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Children's Research Institute

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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 Agen — View Citation

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. 20 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	evaluation of vIQ	vIQ would be reassessed to determine if increasing their PI dosage thereby increasing the bioavaiability would reduce their viral load.	8 weeks	No