Adjusting Antiretroviral Therapy Dosage Using Therapeutic Drug Monitoring (TDM)

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.

Study Overview

• Status: Unknown
• Conditions: HIV Infections; Human Immunodeficiency Virus
• Intervention / Treatment: Drug: Reducing dose of Lopinavir; Drug: Reducing dose of efavirenz

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 4

Contacts and Locations

Study Locations

• Switzerland
  • Geneva, Switzerland, 1211
    • Recruiting
    • University Hopistal of Geneva
    • Contact: Alexandra AC Calmy, MD; Phone Number: +41 022 372 98 08; Email: Alexandra.Calmy@hcuge.ch
    • Principal Investigator: Bernard BH Hirschel, MD
    • Principal Investigator: Alexandra AC Calmy, MD

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
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	6 months

Collaborators and Investigators

• Sponsor: University Hospital, Geneva
• Collaborators: Swiss HIV Cohort Study
• Investigators: Principal Investigator: Alexandra AC Calmy, University Hospital, Geneva

Publications and helpful links

Helpful Links

• Swiss HIV Cohort Study
• Profil of Alexandra Calmy
• Profil of Professor Bernard Hirschel

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (Anticipated): April 1, 2009
• Study Completion (Anticipated): April 1, 2009

Study Registration Dates

• First Submitted: February 3, 2009
• First Submitted That Met QC Criteria: February 3, 2009
• First Posted (Estimate): February 4, 2009

Study Record Updates

• Last Update Posted (Estimate): July 23, 2009
• Last Update Submitted That Met QC Criteria: July 21, 2009
• Last Verified: July 1, 2009

More Information

Terms related to this study

• Keywords: HIV; Treatment Experienced; efavirenz; lopinavir; Adjusting Antiretroviral Therapy; Dosage using Therapeutic Drug Monitoring; Swiss HIV Cohort Study; HIV Geneva
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Lopinavir; Efavirenz
• Other Study ID Numbers: SHCS 571