Optimizing Antiretroviral Therapy in HIV-Infected Children and Adolescents

This study has been completed.
Information provided by:
Children's Research Institute
ClinicalTrials.gov Identifier:
First received: September 13, 2005
Last updated: May 14, 2009
Last verified: March 2008

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
HIV Infections
Drug: Nelfinavir
Drug: Lopinavir/ritonavir
Drug: Ritonavir
Drug: Amprenavir
Drug: Indinavir
Drug: Saquinavir
Drug: Fosamprenavir
Drug: Atazanavir
Drug: Tipranavir
Drug: Dose adjustment
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
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:
  • The parameters of pharmacokinetic (PK) analysis (Cmin, Cmax, AUC) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Toxicities (complete blood count [CBC], liver function tests [LFTs], albumin, creatinine, blood urea nitrogen, amylase, lipase, cholesterol, triglycerides, glucose) - at 6 weeks [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Enrollment: 78
Study Start Date: November 2004
Study Completion Date: May 2009
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Therapeutic Dose Adjustment
To adjust the doses of medications to meet target therapeutic concentrations
Drug: Nelfinavir
Adjust the dose of Nelfinavir to meet target therapeutic concentraions
Other Name: Viracept
Drug: Lopinavir/ritonavir
Adjust the dose of Lopinavir/ritonavir to meet target therapeutic concentrations
Other Name: Kaletra
Drug: Ritonavir
Adjust the dose of Ritonavir to meet target therapeutic concentrations
Other Name: Norvir
Drug: Amprenavir
Adjust the dose of Amprenavir to meet target therapeutic concentrations
Other Name: Agenerase
Drug: Indinavir
Adjust the dose of Indinavir to meet target therapeutic concentrations
Other Name: Crixivan
Drug: Saquinavir
Adjust the dose of Saquinavir to meet target therapaeutic concentrations
Other Name: Invirase-HGC
Drug: Fosamprenavir
Adjust the dose of Fosamprenavir to meet target therapeutic concentraions
Other Name: Lexiva
Drug: Atazanavir
Adjust the doe of Atazanavir to meet target therapeutic concentrations
Other Name: Reyataz
Drug: Tipranavir
Adjust the dose of Tipranavir to meet target therapeutic concentrations
Other Name: Aptivus
Drug: Dose adjustment
Adjust the dose off the drug to meet target therapeutic concentration
Other Names:
  • Amprenavir
  • Fosamprenavir
  • Kaletra
  • Ritonavir
  • Saquinavir
  • Nelfinavir
  • Tiprnavir
  • Atazanavir
  • Indinavir

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: 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: 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: 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.

Ages Eligible for Study:   4 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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)
  • 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
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00207948

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

No publications provided

ClinicalTrials.gov Identifier: NCT00207948     History of Changes
Other Study ID Numbers: 1K12RR017613-03
Study First Received: September 13, 2005
Last Updated: May 14, 2009
Health Authority: United States: Institutional Review Board

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

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 19, 2014