Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder

Abstract

HIV-associated neurocognitive disorder (HAND) is the result of neural damage caused by HIV replication and immune activation. Potent antiretroviral therapy has reduced the prevalence of severe HAND but not mild to moderate HAND. Brief symptom questionnaires, screening tests, and neuropsychological tests can be used with relative ease in the clinic to identify cognitive and neurologic deficits and to track patient status. Increasing data on pharmacokinetics of antiretrovirals in cerebrospinal fluid (CSF) have permitted formulation of central nervous system (CNS) penetration-effectiveness (CPE) rankings for single drugs and combinations. Available data indicate that regimens with higher CPE scores are associated with lower HIV RNA levels in CSF and improvement in neurocognitive functioning. This article summarizes a presentation by Scott Letendre, MD, at the IAS-USA live continuing medical education course held in San Francisco in May 2011.

Figure 1.

Results of selected studies of antiretroviral pharmacokinetics in cerebrospinal fluid (CSF). Top left: Efavirenz plasma concentration and CSF concentration over time from dose. Adapted from Best et al. Top right: Ratio of nevirapine CSF concentration to minimum 50% inhibitory concentration (IC₅₀ min) and maximum 50% inhibitory concentration (IC₅₀ max). Adapted from van Praag et al and Antinori et al. Middle: Plasma concentration and CSF concentraton over time from dose for lopinavir (left, adapted from Capparelli et al21) and atazanavir/ritonavir (right, adapted from Best et al18). Bottom left: Raltegravir CSF concentration over time from dose. Size of data point indicates ratio of CSF concentration to serum albumin. LLQ indicates lower limit of quantitation; IC₉₅, 95% inhibitory concentration. Adapted from Yilmaz et al. Bottom right: Maraviroc plasma concentration and CSF concentration over time from dose. EC₉₀ indicates 90% effective concentration. Adapted from Yilmaz et al.

Figure 2.

Left: Association of antiretroviral regimen CNS (central nervous system) Penetration-Effectiveness (CPE) score with proportion of patients with detectable HIV RNA in cerebrospinal fluid (CSF). Adapted from Letendre et al. Right: Proportion of patients with CSF viral load between 2 copies/mL and 50 copies/mL, according to antiretroviral regimen CPE score of ≤ 7 or > 7 (the median value). OR indicates odds ratio. Adapted from Letendre et al.

Figure 3.

Conceptual therapeutic window for effectiveness of antiretroviral therapy in the central nervous system (CNS).