No abstract

The association of previous advanced immunosuppression with prevalent and sustained impairment suggests that there is a non-reversible component of neural injury that tracks with a history of disease progression. The association of sustained impairment with worse current immune status (low CD4 cell count) suggests that restoring immunocompetence increases the likelihood of neurocognitive recovery. Finally, the lack of association between incident neurocognitive impairment and virological and immunological indicators implies that neural injury continues in some patients regardless of the success of antiretroviral therapy on these laboratory measures.

Combination antiretroviral therapy (CART) has proven to effectively suppress systemic HIV burden, however, poor penetration into the central nervous system (CNS) provides incomplete protection. Although the severity of HIV-associated neurocognitive disorders (HAND) has been reduced, neurological disease is expected to exert an increasing burden as HIV-infected patients live longer. Strategies to enhance penetration of antiretroviral compounds into the CNS could help to control HIV replication in this reservoir but also carries an increased risk of neurotoxicity. Efforts to target antiretroviral compounds to the CNS will have to balance these risks against the potential gain. Unfortunately, little information is available on the actions of antiretroviral compounds in the CNS, particularly at concentrations that provide effective virus suppression. The current studies evaluated the direct effects of 15 anti-retroviral compounds on neurons to begin to provide basic neurotoxicity data that will serve as a foundation for the development of dosing and drug selection guidelines. Using sensitive indices of neural damage, we found a wide range of toxicities, with median toxic concentrations ranging from 2 to 10,000 ng/ml. Some toxic concentrations overlapped concentrations currently seen in the CSF but the level of toxicity was generally modest at clinically relevant concentrations. Highest neurotoxicities were associated with abacavir, efavarenz, etravirine, nevaripine, and atazanavir, while the lowest were with darunavir, emtracitabine, tenofovir, and maraviroc. No additive effects were seen with combinations used clinically. These data provide initial evidence useful for the development of treatment strategies that might reduce the risk of antiretroviral neurotoxicity.

Objective Determine if antiretroviral (ARV) regimens with good central nervous system (CNS) penetration control HIV in cerebrospinal fluid (CSF) and improve cognition. Design Multi-site longitudinal observational study. Setting Research clinics. Subjects 101 individuals with advanced HIV beginning or changing a new potent ARV regimen. Data for 79 subjects were analyzed. Participants underwent structured history and neurological examination, venipuncture, lumbar puncture, neuropsychological tests at entry, 24 and 52 weeks. Intervention ARV regimens were categorized as CNS penetration effectiveness (CPE) rank ≥ 2 or < 2. Generalized estimating equations were used to examine associations over the course of the study. Main Outcome Measures Concentration of HIV RNA in CSF and blood, neuropsychological test scores. Results Odds of suppression of CSF HIV RNA were higher when CPE rank ≥ 2 compared to < 2. Odds of suppression of plasma HIV RNA were not associated with CPE rank. Among subjects with impaired neuropsychological performance at entry, those prescribed regimens with a CPE rank ≥ 2 or more ARVs had lower NPZ4 over the course of the study. Conclusions ARV regimens with good CNS penetration, as assessed by CPE rank, are more effective in controlling CSF (and presumably CNS) viral replication than regimens with poorer penetration. In this study, ARVs with good CNS penetration were associated with poorer neurocognitive performance. A larger, controlled trial is required before any conclusions regarding the influence of specific ARVs on neurocognitive performance should be made.

The IHDS may be a useful screening test to identify individuals at risk for HIV dementia in both the industrialized world and the developing world. Full neuropsychological testing should then be performed to confirm a diagnosis of HIV dementia.

Although HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of ≥ 24 hours. The optimal schedule for VOR administration is still to be defined.

HIV produces a chronic viral infection of the central nervous system that elicits chronic glial activation and overexpression of glial cytokines that are also implicated in Alzheimer disease (AD) pathogenesis. A genetic risk factor for AD is the E4 isoform for apolipoprotein E (APOE). Here we compare the frequency of neurologic symptoms for subjects with and without the E4 isoform (E4(+)and E4(-), respectively) in an HIV cohort. Compared with E4(-) subjects, twice as many E4(+) subjects were demented (30% compared with 15%) or had peripheral neuropathy (70% compared with 39%) at least once, and they had threefold more symptomatic examinations (13% compared with 3% and 42% compared with 14%, respectively)(P < 0.0001). Thus, neurologic symptoms for HIV-infection and AD are linked through an etiologic risk factor. Long-term survivors of HIV infection with E4 may be at high risk for AD; conversely, gene-viral interactions may speed AD pathogenesis.

Objective: To determine factors associated with baseline neurocognitive performance in HIVinfected participants enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) neurology substudy. Methods:Participants from Australia, North America, Brazil, and Thailand were administered a 5-test neurocognitive battery. Z scores and the neurocognitive performance outcome measure, the quantitative neurocognitive performance z score (QNPZ-5), were calculated using US norms. Neurocognitive impairment was defined as z scores ϽϪ2 in two or more cognitive domains. Associations of test scores, the QNPZ-5, and impairment with baseline factors including demographics and risk factors for HIV-associated dementia (HAD) and cardiovascular disease (CVD) were determined in multiple regression. Results:The 292 participants had a median CD4 cell count of 536 cells/mm 3 , 88% had an HIV viral load Յ400 copies/mL, and 92% were taking antiretrovirals. Demographics, HIV, and clinical factors differed between locations. The mean QNPZ-5 score was Ϫ0.72; 14% of participants had neurocognitive impairment. For most tests, scores and z scores differed significantly between locations, with and without adjustment for age, sex, education, and race. Prior CVD was associated with neurocognitive impairment. Prior CVD, hypercholesterolemia, and hypertension were associated with poorer neurocognitive performance but conventional HAD risk factors and the CNS penetration effectiveness rank of antiretroviral regimens were not. Conclusions:In this HIV-positive population with high CD4 cell counts, neurocognitive impairment was associated with prior CVD. Lower neurocognitive performance was associated with prior CVD, hypertension, and hypercholesterolemia, but not conventional HAD risk factors. The contribution of CVD and cardiovascular risk factors to the neurocognition of HIV-positive populations warrants further investigation. Neurology In advanced untreated HIV disease, HIV-associated dementia (HAD) develops in approximately 15% of patients 1 and combination antiretroviral therapy (ART) has effectively reduced the incidence of HAD.2 The Strategies for Management of Antiretroviral Therapy (SMART) study randomized participants to intermittent, CD4-guided ART or continuous ART.3 In a neurology substudy, a neurocognitive test battery was administered. We hypothesized that neurocognitive