Adjusting Antiretroviral Therapy Dosage Using Therapeutic Drug Monitoring (TDM)

• ClinicalTrials.gov Identifier: NCT00836212
• Recruitment Status: Unknown
• First Posted: February 4, 2009
• Last Update Posted: July 23, 2009
• Sponsor: University Hospital, Geneva
• Collaborator: Swiss HIV Cohort Study
• Information provided by: University Hospital, Geneva

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Human Immunodeficiency Virus; HIV Infections	Drug: Reducing dose of Lopinavir; Drug: Reducing dose of efavirenz	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Adjusting Antiretroviral Therapy Dosage Using Therapeutic Drug Monitoring
• Study Start Date: March 2008
• Estimated Primary Completion Date: April 2009
• Estimated Study Completion Date: April 2009

Arms and Interventions

Arm	Intervention/treatment
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.

Outcome Measures

Primary Outcome Measures :

1. 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 ]

Secondary Outcome Measures :

1. 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 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts

Contact: Alexnadra AC Calmy; 022 372 98 08 ext +41; Alexandra.Calmy@hcuge.ch

Locations

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

Sponsors and Collaborators

University Hospital, Geneva

Swiss HIV Cohort Study

Investigators

• Principal Investigator: Alexandra AC Calmy; University Hospital, Geneva

More Information

Additional Information:

Profil of Alexandra Calmy 

Profil of Professor Bernard Hirschel 

Swiss HIV Cohort Study 

• Responsible Party: Alexandra Calmy / Doctor, University Hospital, Geneva
• ClinicalTrials.gov Identifier: NCT00836212
• Other Study ID Numbers: SHCS 571
• First Posted: February 4, 2009
• Last Update Posted: July 23, 2009
• Last Verified: July 2009

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:

HIV Infections; Acquired Immunodeficiency Syndrome; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; Efavirenz; Lopinavir; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors