EFV Pharmacokinetics & Pharmacogenomics in Older HIV-infected Patients

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.

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.