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.