EFV Pharmacokinetics & Pharmacogenomics in Older HIV-infected Patients (EFV)
University of Nebraska
Information provided by (Responsible Party)
Uriel Sandkovsky, MD, University of Nebraska
First received: June 10, 2013
Last updated: August 16, 2017
Last Verified: August 2017
History of Changes
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.
Drug : Efavirenz
|Study Type:||Observational [Patient Registry]|
|Official Title:||Efavirenz Pharmacokinetics and Pharmacogenomics in Older HIV-infected Patients|
Further study details as provided by Uriel Sandkovsky, MD, University of Nebraska:
Primary Outcome Measures
Pharmacokinetics of EFV in older HIV-infected patients
[ Time Frame: one year ]
plasma concentrations of efavirenz in older HIV-infected patients measured by Liquid Chromatography Mass Spectrometry (LC-MS-MS).
- EFV relation to neuropsychiatric side effects and neuropsychological performance
[ Time Frame: one year ]
Incidence and severity of Neuropsychological (NP) side effects measured by NP testing and composite NPZ score.
- Role of Host polymorphisms in Efavirenz metabolism [ Time Frame: one year ]
presence or absence of cytochrome 2B6, 3A4, 2D6, 2A6 and androstane receptor polymorphisms
|Study Start Date:||December 2013|
|Study Completion Date:||August 2014|
|Primary Completion Date:||May 2014 (Final data collection date for primary outcome measure)|
Participants will be taking efavirenz as part of their antiretroviral regimen.
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.
|Ages Eligible for Study:||50 Years and older|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
|Sampling Method:||Non-Probability Sample|
Study PopulationHIV Infected Older than 50 years Of Age and Taking Efavirenz as Part of The Antiretroviral regimen
- HIV infection.
- 50 years of age or older.
- Ability to provide written informed consent.
- Ability to complete the questionnaires in English, as the questionnaires have not been validated in other languages.
- 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.
- Completion of treatment for any intercurrent acute infection less than four weeks before study entry. Maintenance or prophylactic therapy is permitted for opportunistic infections.
- 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.
- 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.
- Major neurologic disease such as multiple sclerosis or stroke, active brain infection (except for HIV-1), brain neoplasm, or space-occupying brain lesion.
- Current delirium or intoxication.
- Any other condition that, in the opinion of the investigator, is a contraindication to
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01886404
Locations Show More
|United States, Nebraska|
|University of Nebraska Medical Center|
|Omaha, Nebraska, United States, 68198-8106|
Sponsors and CollaboratorsUniversity of Nebraska
|Principal Investigator:||Uriel S Sandkovsky, MD||University of Nebraska|
|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:||August 16, 2017|
Keywords provided by Uriel Sandkovsky, MD, University of Nebraska:HIV
Additional relevant MeSH terms:
ClinicalTrials.gov processed this data on December 18, 2017
This information is provided by ClinicalTrials.gov.