Persistent HIV in the central nervous system during treatment is associated with worse antiretroviral therapy penetration and cognitive impairment.

Type: Poster
Title: Persistent HIV in the central nervous system during treatment is associated with worse antiretroviral therapy penetration and cognitive impairment.
Authors: Munoz-Moreno J, Letendre S, McClernon D, Ellis RJ, LeBlanc S, Rosario D, Clifford D, Collier A, Gelman B, Marra C, McArthur J, McCutchan A, Morgello S, Simpson D, Franklin D, Heaton RK, Grant I, and the CHARTER Group
Date: 10-2009
Abstract:Background: Cognitive impairment can occur or persist during antiretroviral therapy (ART). Explanations include comorbidities, neurotoxic ART, persistent neuroinflammation, or persistent HIV replication in central nervous system (CNS). This analysis assessed whether low levels of HIV in cerebrospinal fluid (CSF) were associated with inter-individual differences in ART regimens and neuropsychological (NP) performance. Methods: 329 participants (pts) were selected from the CHARTER cohort because they were taking ART, and had HIV RNA levels below 50 c/mL with an ultrasensitive assay (Roche Amplicor) in CSF and blood. Paired CSF and blood plasma (PL) specimens that were obtained within 1 hour of each other were assayed with a more sensitive assay, a modified version of the NucliSens EasyQ (bioMerieux) assay capable of qualitatively detecting HIV at 2 c/mL. To determine the stability of low-level HIV in CSF, a follow-up specimen from 61 pts was assayed (median duration between visits, 7.0 months). Penetration of ART into the CNS was estimated by CNS Penetration-Effectiveness (CPE) ranks. NP performance was summarized by the Global Deficit Score (GDS), a validated method which integrates relevant information about 7 NP performance domains. Results: Pts were mostly non-white (55%), middle- aged (mean 45 yr) men (76%) with AIDS (75%) who were HCV seronegative (68%). Median duration of the current ART regimen was 15 months. Median CD4 count was 467/mL. By the more sensitive assay, 136 (41%) had detectable HIV in CSF and 216 (66%) had detectable HIV in plasma. Detectable HIV in CSF was associated with worse CPE scores (mean 1.49 vs. 1.70, d0.29, p0.009) and detectable HIV in PL (71% pts with HIV detected in CSF vs. 62% undetected, p0.077). Other demographic or disease characteristics were not found in association. Of this group of pts, 39 (28%) had detectable HIV in CSF but not in PL, had worse global deficit scores (GDS) (0.63 vs. 0.37, p0.012), and were particularly likely to have at least moderate global impairment (GDS greater than 0.93, 28% vs. 8%, p0.005). Multivariate analyses identified that worse global deficit scores were associated with detectable HIV in CSF but not in PL (B0.13, p 0.007), HCV seropositivity, shorter durations of ART, and ethnicity other than white (model R2 0.29, pB0.0001). In the subgroup with a follow-up CSF specimen assayed, CSF values became undetectable in 18 (30%) pts although remained detectable in the other 43 (70%). Transition from detectable to undetectable was associated with higher CD4 counts at the second visit (46% of undetectable pts had CD4500 vs. 12% in detectable, p0.09), and HCV seropositivity (57% vs. 24%, p0.04), but not CPE scores or improved global NP performance. Conclusions: Despite having achieved virologic suppression in CSF and plasma by the Roche ultrasensitive assay, we found that ART-treated individuals frequently (41%) had low, detectable levels of HIV in CSF, and this was associated with less penetrant ART. At least a quarter of these individuals (28%) had persistent HIV in CSF, but not in PL, and this was linked to the presence of worse neurocognitive functioning. People living with HIV may have cognitive impairment as a result of ART that is incompletely effective in the CNS