CHARTER Group: HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study

University of California, San Diego, USA.
Neurology (Impact Factor: 8.29). 12/2010; 75(23):2087-96. DOI: 10.1212/WNL.0b013e318200d727
Source: PubMed


This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART).
A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment).
Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups).
The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.

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    • "The CNS is a critical site that must be studied when considering the use of LRA, as it has several unique characteristics that could greatly affect the outcome in the use of LRA. These include, but are not limited to, the potential to develop HIV-associated neurocognitive disorders (HAND) (Gonzalez-Scarano and Martin-Garcia 2005; Heaton et al. 2010); altered immune surveillance which may compromise the Bkill^ once virus is reactivated (Carson et al. 2006); restricted cART penetration into the CNS with some regimens which may lead to incomplete blocking of all new rounds of infection (Letendre et al. 2008); restricted LRA penetration into the CNS which may limit the ability to Bshock^ cells (Churchill et al. 2015); phylogenetically distinct HIV-1 within the CNS which may respond differently to LRA (Ait-Khaled et al. 1995; Gray et al. 2013a); and finally, unique long lived infected cells in the CNS including macrophages, microglia, and astrocytes (Kramer-Hammerle et al. 2005). "
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    ABSTRACT: Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells; however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid.
    Full-text · Article · Jan 2016 · Journal of NeuroVirology
    • "We administered a neuropsychological battery to assess five domains of neuropsychological functions that are known to be most vulnerable to HIV infection (i.e., learning , memory, speed of information processing, working memory, and motor functions) (Grant et al. 2005; Durvasula et al. 2001; Martin et al. 2001; Heaton et al. 2010). Learning and memory were assessed with the "
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    ABSTRACT: Since the introduction of combination antiretroviral therapy (cART), the incidence of severe HIV-associated neurocognitive impairment has declined significantly, whereas the prevalence of the milder forms has increased. Studies suggest that better distribution of cART drugs into the CNS may be important in reducing viral replication in the CNS and in reducing HIV-related brain injury. Correlates of neuropsychological (NP) performance were determined in 417 participants of the Ontario HIV Treatment Cohort Study (OCS). All participants were on three cART drugs for at least 90 days prior to assessment. Multiple logistic and linear regression methods were used. Most participants were Caucasian men with mean age of 47 years. About two thirds had a nadir CD4+ T-cell count below 200 cells/μL and 92 % had an undetectable plasma HIV viral load. The median CNS penetration effectiveness (CPE) score was 7. Sixty percent of participants had neuropsychological impairment. Higher CPE values significantly correlated with lower prevalence of impairment in bivariate and multivariate analyses. In this cross-sectional analysis of HIV+ adults who had a low prevalence of comorbidities and were taking three-drug cART regimens, greater estimated distribution of cART drugs into the CNS was associated with better NP performance.
    No preview · Article · Nov 2015 · Journal of NeuroVirology
    • "HIV-1 can cause neurocognitive impairment in infected individuals , even among those taking effective antiretroviral therapy (ART) (Heaton et al. 2010). The underlying mechanisms by which HIV-associated neurocognitive disorder (HAND) develops are not fully understood, but HAND has been associated with infecting HIV-1 subtype, nadir and current CD4 + T cell count, diversity in HIV-1 proteins Env and Tat, and blood and cerebrospinal fluid (CSF) HIV RNA levels (Ellis et al. 2011; Kaul et al. 2001; Munoz-Moreno et al. 2008). "
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    ABSTRACT: Factors associated with HIV-associated neurocognitive disorders (HAND) include CD4(+) nadir and count, HIV RNA level, and HIV-1 subtype. Here, we investigated demographical and clinical markers with respect to HAND in a homogenous Chinese population. Individuals with HAND (global deficit score ≥0.5) had lower nadir (p < 0.01) and CD4(+) counts (p = 0.03). HAND was also associated with AIDS (p < 0.01), but subtype was not (p = 0.198). Furthermore, worse impairment correlated with higher viral diversity (r = 0.16, p < 0.01), lower nadir (r = -0.17, p < 0.01), and CD4(+) counts (r = -0.11, p = 0.01). These remained significant even when correcting for subtype. Our findings suggest that subtype does not have a major impact on HAND.
    No preview · Article · Aug 2015 · Journal of NeuroVirology
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