HIV InfectionsNCT00207948
Optimizing Antiretroviral Therapy in HIV-Infected Children and Adolescents
An observational study of HIV Infections, run by Children's National Research Institute at 1 site in United States.
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… Read more about this study
- Who is it for?
- Ages 4 to 21 years
- Conditions the study is for
- HIV Infections
- What is being tested?
- Dose adjustment of Kaletra
- How many people
- 4 participants
- Where
- 1 siteUnited States
- Study dates
- Nov 2004to Jul 2009
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 4 to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Study population: The total number of recruited subjects in a previous the study was 78 with 50 subjects on LPV/RTV based ART. Based on PK analysis 4 patients fit inclusion criteria for a dose adjustment feasibility pilot (this study)
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's National Medical Center
Washington D.C., District of Columbia, 20010
About this study
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.
Read the 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 (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.
- Conditions
- HIV Infections
- Being tested
- Dose adjustment of Kaletra
- Keywords
- Human Immunodeficiency Virus, Protease Inhibitors, Pharmacogenetics, Genes, MDR1, Cytochrome P-450 enzymes, Pharmacokinetics, Pediatrics, Treatment Experienced
- Medical subject headings
- HIV Infections, Acquired Immunodeficiency Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dose adjustment of KaletraDrug
Also called Lopinavir, Ritonavir
Adjust the dose by up to +50% of reccomended dosa off the drug to meet target therapeutic concentrations
| Study group | Role | What they receive |
|---|---|---|
| Therapeutic Dose Adjustment | To adjust the doses of medications to meet target therapeutic concentrations Receives: Drug: Dose adjustment of Kaletra |
What is being measured
The primary outcome is the main question the study is designed to answer.
evaluation of vIQ
vIQ would be reassessed to determine if increasing their PI dosage thereby increasing the bioavaiability would reduce their viral load.
Measured: 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Sep 2005 (estimated)
- Study startNov 2004
- Primary completionMay 2009
- Study completionJul 2009
Why it stopped: no measurable response was detected at the 50% increase threshold.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- More trials run by Children's National Research InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's National Research Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Natella Rakhmanina, Children's National Research Institute
- Investigators
- Natella Y Rakhmanina, MD, Principal investigator, Children's National Medical Center, Children's Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00207948
- Sponsor's protocol ID
- 1K12RR017613-03
- Status last verified
- Aug 2015
- First submitted
- 13 Sep 2005
- Last updated
- 5 Aug 2015
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 19258274Neely 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.
PubMed 20086000Rakhmanina 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.
PubMed 21743379
Study at a glance
From the registry record, last updated by the sponsor on 5 Aug 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimizing Antiretroviral Therapy in HIV-Infected Children and Adolescents
- ClinicalTrials.gov ID
- NCT00207948
- Acronym / sponsor ID
- 1K12RR017613-03
- Conditions
- HIV Infections
- Keywords
- Human Immunodeficiency Virus, Protease Inhibitors, Pharmacogenetics, Genes, MDR1, Cytochrome P-450 enzymes, Pharmacokinetics, Pediatrics, Treatment Experienced
- Study type
- Observational
- Recruitment status
- TerminatedReason stopped: no measurable response was detected at the 50% increase threshold.
- Enrolment
- 4 participants (actual)
- Lead sponsor
- Children's National Research InstituteUniversity, hospital or other
- Study start
- Nov 2004
- Primary completion
- May 2009 (actual)
- Study completion
- Jul 2009 (actual)
- First posted
- 21 Sep 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 (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 design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Therapeutic Dose Adjustment | – | Drug: Dose adjustment of KaletraTo adjust the doses of medications to meet target therapeutic concentrations |
Who may qualify
- Ages
- 4 to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
- Study population
- The total number of recruited subjects in a previous the study was 78 with 50 subjects on LPV/RTV based ART. Based on PK analysis 4 patients fit inclusion criteria for a dose adjustment feasibility pilot (this study)
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Dose adjustment of KaletraAlso: Lopinavir, RitonavirAdjust the dose by up to +50% of reccomended dosa off the drug to meet target therapeutic concentrations | Drug | Therapeutic Dose Adjustment |
Primary outcome
evaluation of vIQ
Time frame: 8 weeks
vIQ would be reassessed to determine if increasing their PI dosage thereby increasing the bioavaiability would reduce their viral load.
Results and safety
The study was stopped early (reason given: no measurable response was detected at the 50% increase threshold.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Aug 2015.
- Results publication: PubMed 19258274Rakhmanina 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.
- Results publication: PubMed 20086000Neely 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.
- Results publication: PubMed 21743379Rakhmanina 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Natella Y Rakhmanina, MD principal investigator
Children's National Medical Center, Children's Research Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of HIV Infections, run by Children's National Research Institute at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 5 Aug 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: no measurable response was detected at the 50% increase threshold.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
evaluation of vIQ (time frame: 8 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00207948, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Aug 2015.