Adjusting Antiretroviral Therapy Dosage Using Therapeutic Drug Monitoring (TDM)
Recruitment status was Recruiting
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Purpose
Background
Low concentrations of protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs) are associated with an increased risk of virological failure. Likewise, excessive antiretroviral drug concentrations increase the risk of toxicity. Therapeutic drug monitoring (TDM) may identify and correct excessively high or low PI and/or NNRTI concentrations, and thus minimize toxicity and risk of treatment failure. Treatment guidelines only recommend using TDM to help optimize ARV therapy in selected patients, and there are no clear recommendations to guide the clinician who decides to adjust drug doses. Prospective studies have demonstrated the relationship between EFV plasma concentration and neuropsychiatric symptoms. Moreover, EFV is metabolized mainly by cytochrome P450 2B6 and its concentration was reported to be associated with the CYP2B6 516GrT genetic polymorphism.
For drugs such as EFV or LPV/r, lower doses than the ones validated for standard clinical use have demonstrated efficacy in dose-ranging studies.
The investigators will use a standardised algorithm to reduce doses in patients with plasma EFV or LPV/r concentration above percentile 75. This algorithm is based on a Bayesian approach from the pharmacology unit in Lausanne. The investigators hypothesize that a dosage individualisation is feasible and safe.
2.2 Study Aims
The investigators aim at testing a simplified algorithm for dose reduction in patients with documented virological efficacy, treated by a stable LPV/r or EFV based regimen with elevated plasma concentration of these drugs.
Study Design
Prospective open label study in which all eligible patients screened with a plasma drug concentration of either EFV or LPV/r above percentile 75 will be included. After confirmation of the results at baseline, patients will be offered to decrease drug dosage by a third or a half according to a standardised algorithm. All patients will undergo HIVRNA, biochemistry and validated questionnaires after 3 and 6 months to assess the safety and the benefit of this strategy.
| Condition | Intervention | Phase |
|---|---|---|
|
Human Immunodeficiency Virus HIV Infections |
Drug: Reducing dose of Lopinavir Drug: Reducing dose of efavirenz |
Phase 4 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Adjusting Antiretroviral Therapy Dosage Using Therapeutic Drug Monitoring |
- Number of patients who reach a plasma concentration within targets (P25-P75) after at least one cycle (and maximum two cycles) of dose reduction according to the provided algorithm at 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Number of patients who reach a plasma concentration within targets (P25-P75) after at least one cycle of dose reduction -percentage of spared drugs through TDM-guided dosage adaptation over a 6 months period. Compliance: electronic pills count [ Time Frame: 6 months ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 12 |
| Study Start Date: | March 2008 |
| Estimated Study Completion Date: | April 2009 |
| Estimated Primary Completion Date: | April 2009 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: LPV
Patients with blood levels measured 2 times at 2 weeks intervals in the upper quartile (>percentile 75) of concentrations reported under standard therapy (i.e. EFV 600 mg q.d. or LPV/r 400 or 533 mg bid) will have their dose reduced by approximately one third, with the aim to bring their concentration in the 25-75% percentile range.
|
Drug: Reducing dose of Lopinavir
Patients with blood levels measured 2 times at 2 weeks intervals in the upper quartile (>percentile 75) of concentrations reported under standard therapy (i.e. EFV 600 mg q.d. or LPV/r 400 or 533 mg bid) will have their dose reduced by approximately one third, with the aim to bring their concentration in the 25-75% percentile range.
|
|
Experimental: EFV
Patients with blood levels measured 2 times at 2 weeks intervals in the upper quartile (>percentile 75) of concentrations reported under standard therapy (i.e. EFV 600 mg q.d. or LPV/r 400 or 533 mg bid) will have their dose reduced by approximately one third, with the aim to bring their concentration in the 25-75% percentile range.
|
Drug: Reducing dose of efavirenz
Patients with blood levels measured 2 times at 2 weeks intervals in the upper quartile (>percentile 75) of concentrations reported under standard therapy (i.e. EFV 600 mg q.d. or LPV/r 400 or 533 mg bid) will have their dose reduced by approximately one third, with the aim to bring their concentration in the 25-75% percentile range.
|
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Stable regimen including either EFV or LPV/r
- HIVRNA below 40 copies since at least 3 months
- Antiretroviral drug concentration (EFV, LPV/r) plasma concentration at screening above P75
- Signed consent for the SHCS genetics core project
Exclusion Criteria:
- Concomitant medication:Amiodarone, bepidril, flecainide, propafenone, quinidine,Astemizole, terfenadine,Dihydroergotamine, ergotamine,Midazolam, triazolam,Cisapride,Pimozide,Rifabutin
- Renal or hepatic impairment
- Pregnancy or wish to become pregnant within the next 6 months
- Both EFV and LPV/r as part of the antiretroviral drug regimen
Contacts and Locations| Contact: Alexnadra AC Calmy | 022 372 98 08 ext +41 | Alexandra.Calmy@hcuge.ch |
| Switzerland | |
| University Hopistal of Geneva | Recruiting |
| Geneva, Switzerland, 1211 | |
| Contact: Alexandra AC Calmy, MD 022 372 98 08 ext +41 Alexandra.Calmy@hcuge.ch | |
| Principal Investigator: Bernard BH Hirschel, MD | |
| Principal Investigator: Alexandra AC Calmy, MD | |
| Principal Investigator: | Alexandra AC Calmy | University Hospital, Geneva |
More Information
Additional Information:
No publications provided
| Responsible Party: | Alexandra Calmy / Doctor, University Hospital, Geneva |
| ClinicalTrials.gov Identifier: | NCT00836212 History of Changes |
| Other Study ID Numbers: | SHCS 571 |
| Study First Received: | February 3, 2009 |
| Last Updated: | July 21, 2009 |
| Health Authority: | Switzerland: Swissmedic |
Keywords provided by University Hospital, Geneva:
|
HIV Adjusting Antiretroviral Therapy Dosage using Therapeutic Drug Monitoring Swiss HIV Cohort Study |
HIV Geneva lopinavir efavirenz Treatment Experienced |
Additional relevant MeSH terms:
|
Acquired Immunodeficiency Syndrome HIV Infections Immunologic Deficiency Syndromes Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Slow Virus Diseases Immune System Diseases Efavirenz Lopinavir |
Reverse Transcriptase Inhibitors Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Therapeutic Uses Anti-HIV Agents HIV Protease Inhibitors Protease Inhibitors |
ClinicalTrials.gov processed this record on May 19, 2013