EFV Pharmacokinetics & Pharmacogenomics in Older HIV-infected Patients

This study is currently recruiting participants.
Verified December 2013 by University of Nebraska
Sponsor:
Information provided by (Responsible Party):
Uriel Sandkovsky, MD, University of Nebraska
ClinicalTrials.gov Identifier:
NCT01886404
First received: June 10, 2013
Last updated: December 24, 2013
Last verified: December 2013
  Purpose

The primary purpose of this study is to investigate the steady-state pharmacokinetics of efavirenz in older HIV-infected patients as compared to historical controls; to investigate the relationship of drug exposure to neuropsychiatric side effects and neuropsychological performance; and to explore the role of host polymorphisms in drug metabolism in the older patient.


Condition Intervention
HIV Infection
Drug: Efavirenz

Study Type: Observational [Patient Registry]
Study Design: Time Perspective: Cross-Sectional
Target Follow-Up Duration: 12 Months
Official Title: Efavirenz Pharmacokinetics and Pharmacogenomics in Older HIV-infected Patients

Resource links provided by NLM:


Further study details as provided by University of Nebraska:

Primary Outcome Measures:
  • Pharmacokinetics of EFV in older HIV-infected patients [ Time Frame: one year ] [ Designated as safety issue: No ]
    plasma concentrations of efavirenz in older HIV-infected patients measured by Liquid Chromatography Mass Spectrometry (LC-MS-MS).


Secondary Outcome Measures:
  • EFV relation to neuropsychiatric side effects and neuropsychological performance [ Time Frame: one year ] [ Designated as safety issue: No ]
    Incidence and severity of Neuropsychological (NP) side effects measured by NP testing and composite NPZ score.


Other Outcome Measures:
  • Role of Host polymorphisms in Efavirenz metabolism [ Time Frame: one year ] [ Designated as safety issue: No ]
    presence or absence of cytochrome 2B6, 3A4, 2D6, 2A6 and androstane receptor polymorphisms


Estimated Enrollment: 50
Study Start Date: July 2013
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Efavirenz Group
Participants will be taking efavirenz as part of their antiretroviral regimen.
Drug: Efavirenz

HIV-infected subjects currently receiving efavirenz (EFV) containing antiretroviral therapy (ART) will be asked to provide plasma samples. In addition to blood samples for determination of EFV concentrations, we will collect whole blood samples for functional Single Nucleotide Polymorphism (SNP) discovery within known candidate genes of interest in drug metabolism and transport.

Subjects will be at steady state for efavirenz when blood samples are collected. EFV is usually taken during the evening hours. The study consists of 2 blood draws at 12 and 18 hours post EFV dose. At the first blood draw, venous blood will be obtained by venous puncture for plasma concentrations of EFV and pharmacogenetics. At 18 hours post EFV dose , a second blood draw by venous puncture will be obtained for EFV plasma concentrations.

Demographics and clinical parameters will be collected at the time of the first visit, Neuropsychological tests and questionnaires completed as well.

Other Names:
  • EFV
  • Sustiva

Detailed Description:

The Centers for Disease Control estimates that up to 15% of newly diagnosed cases of HIV infection are among people 50 years of age or older. By 2015, more than one-half of all HIV-infected individuals in the United States will be aged >50 years, not only from new cases but the greatly increased lifespan due to antiretroviral treatment (High 2012). Assessments of antiretroviral pharmacokinetics in older HIV-infected patients are very few, and there are no specific dosing guidelines for older patients in contrast to the general geriatric population (Hanlon 2009). Studies in older populations demonstrate decrements in liver metabolism and renal clearance, which may require dosage adjustments for drugs eliminated by the kidney. Additionally, decreased bioavailability due to changes in drug transporters alter pharmacokinetics of many drugs in older populations (Crawford 2010, Hilmer 2007). In a relevant study of older HIV-infected patients, trough lopinavir concentrations from 44 subjects showed that higher levels were associated with older age (Crawford 2010). The authors concluded that decreased lopinavir clearance was likely the reason for higher trough lopinavir concentrations in older patients. In a study of 51 patients receiving darunavir, a univariate analysis determined that every 10 years of age lowered clearance (CL/F) of darunavir by 19% (Dickinson 2011). Importantly, efavirenz has not been carefully evaluated in older patients, even though this is one of the most commonly prescribed agents, and is recommended in combination with other drugs as a preferred regimen by the Department of Health and Human Services (DHHS) and World Health Organization WHO (WHO 2010, DHHS 2012).

Central nervous system side effects associated with efavirenz are common, and for this reason it is recommended that the drug be taken at bedtime (Sustiva package insert). Neuropsychological performance and symptoms associated with efavirenz were carefully evaluated in AIDS Clinical Trials Group (ACTG) study 5097s (Clifford 2009). We plan to use similar assessments for the proposed study, to allow for comparison with historical controls. The assessments include questionnaires for assessment of sleep, depression, and anxiety. We will also administer a short battery of neuropsychological testing that has been shown to be sensitive to HIV-related neurocognitive impairment.

Pharmacogenetics may also play an important role in antiretroviral pharmacokinetics in the older population. Several polymorphisms have been shown to be associated with adverse effects to nucleoside reverse transcriptase inhibitors (NRTI) (Tozzi 2010). The very strong association between the abacavir hypersensitivity reaction and Human Leukocyte Antigen (HLA) type B*5701 is an excellent example that has changed clinical practice (Mallal 2002). Nonnucleoside reverse transcriptase inhibitor (NNRTI) hepatotoxicity also appears to be associated with a Multi Drug Resistance 1 (MDR1)gene polymorphism as the 3435 CT genotype confers reduced risk (Haas 2006). Efavirenz is primarily hepatically metabolized. Clearance of efavirenz occurs predominantly via Cytochrome 2B6 (CYP2B6) to an 8-hydroxy-efavirenz (8-OH-Efavirenz); additionally there is a subsequent pathway via cytochrome CYP2A6 to a7-OH-Efavirenz metabolite (Avery 2012, di Iulio 2009, Markwalder 2001).CYP2B6 polymorphisms have been observed inpatients with increased frequency of efavirenz-related side effects, and are associated with drug discontinuation (Haas 2004, Ribaudo 2006). In addition to CYP2B6, early treatment discontinuation of efavirenz was also recently associated with a polymorphism in the constitutive androstane receptor (Wyen 2011). Within this study we will correlate efavirenz plasma metabolite concentrations with pharmacogenetic data on CYP2B6 and CYP2A6 status in order to define the role of these metabolizing enzymes in efavirenz concentrations in older HIV-infected individuals. Our goal will be to assess whether CYP2B6 and CYP2A6 status exacerbate efavirenz-related side effects in this aging population.

  Eligibility

Ages Eligible for Study:   50 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

HIV Infected Older than 50 years Of Age and Taking Efavirenz as Part of The Antiretroviral regimen

Criteria

Inclusion criteria:

  1. HIV infection.
  2. 50 years of age or older.
  3. Ability to provide written informed consent.
  4. Ability to complete the questionnaires in English, as the questionnaires have not been validated in other languages.
  5. On stable efavirenz containing antiretroviral therapy for the past 12 weeks and not anticipated to require a change in therapy during the following 6 weeks.

Exclusion Criteria:

  1. Completion of treatment for any intercurrent acute infection less than four weeks before study entry. Maintenance or prophylactic therapy is permitted for opportunistic infections.
  2. Any active, severe psychiatric illness that, in the opinion of the investigator, could confound performance of the study procedures and/or analysis of the test results.
  3. Active drug or alcohol abuse that, in the investigator's opinion, could compromise compliance with study procedures or confound the analysis of the test results.
  4. Major neurologic disease such as multiple sclerosis or stroke, active brain infection (except for HIV-1), brain neoplasm, or space-occupying brain lesion.
  5. Current delirium or intoxication.
  6. Pregnancy.
  7. Breastfeeding.
  8. Any other condition that, in the opinion of the investigator, is a contraindication to participation.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01886404

Contacts
Contact: Angela Felton-Coleman, MSN, RN 402-559-4408 angela.feltoncoleman@unmc.edu
Contact: Frances J Van Meter, APRN 402-559-8163 fvanmete@unmc.edu

Locations
United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198-8106
Contact: Angela Felton-Coleman, MSN, RN    402-559-4408    angela.feltoncoleman@unmc.edu   
Contact: Frances J Van Meter, APRN    402-559-8163    fvanmete@unmc.edu   
Sub-Investigator: Susan Swindells, MBBS         
Sub-Investigator: Courtney V Fletcher, PharmD         
Sub-Investigator: Anthony T Podany, PharmD         
Principal Investigator: Uriel S Sandkovsky, MD         
Sponsors and Collaborators
University of Nebraska
Investigators
Principal Investigator: Uriel S Sandkovsky, MD University of Nebraska
  More Information

Publications:

Responsible Party: Uriel Sandkovsky, MD, Assistant Professor, University of Nebraska
ClinicalTrials.gov Identifier: NCT01886404     History of Changes
Other Study ID Numbers: 209-13-FB
Study First Received: June 10, 2013
Last Updated: December 24, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Nebraska:
HIV
efavirenz
Sustiva
pharmacokinetics
Pharmacogenomics

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
Efavirenz
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

ClinicalTrials.gov processed this record on April 17, 2014