The prevalence and incidence of neurocognitive impairment in the HAART era

Harvard University, Cambridge, Massachusetts, United States
AIDS (Impact Factor: 5.55). 09/2007; 21(14):1915-21. DOI: 10.1097/QAD.0b013e32828e4e27
Source: PubMed


HAART suppresses HIV viral replication and restores immune function. The effects of HAART on neurological disease are less well understood. The aim of this study was to assess the prevalence and incidence of neurocognitive impairment in individuals who initiated HAART as part of an AIDS clinical trial.
A prospective cohort study of HIV-positive patients enrolled in randomized antiretroviral trials, the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) study.
We examined the association between baseline and demographic characteristics and neurocognitive impairment among 1160 subjects enrolled in the ALLRT study.
A history of immunosuppression (nadir CD4 cell count < 200 cells/microl) was associated with an increase in prevalent neurocognitive impairment. There were no significant virological and immunological predictors of incident neurocognitive impairment. Current immune status (low CD4 cell count) was associated with sustained prevalent impairment.
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.

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    • "Since the introduction of combination antiretroviral therapy (cART), the incidence of severe neurocognitive impairment has declined significantly, whereas the prevalence of the milder forms has increased (Heaton et al. 2010; Vivithanaporn et al. 2010; Zipursky et al. 2013). Up to 50 % of people living with HIV experience milder forms of HIV-associated neurocognitive disorder (HAND) (Antinori et al. 2007; Robertson et al. 2007; Letendre et al. 2009; Vivithanaporn et al. 2010), which can significantly impact quality of life (Trepanier et al. 2005) and daily functioning, interfering with work place performance (Heaton et al. 1994; Heaton et al. 1996), ability to carry out tasks independently (Heaton et al. 2004; Woods et al. 2008; Morgan et al. 2009), and ability to manage medication (Hinkin et al. 2002; Heaton et al. 2004). Neurocognitive impairment has been associated with greater mortality risk (Mayeux et al. 1993; Albert et al. 1995; Ellis et al. 1997; Marder et al. 1998; Vivithanaporn et al. 2010) and worse adherence to cART; the latter is "
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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.
    Journal of NeuroVirology 11/2015; DOI:10.1007/s13365-015-0404-5 · 2.60 Impact Factor
    • "While the number of HIV-infected patients who present with HIV-associated dementia has declined dramatically since the introduction of highly active antiretroviral therapy (HAART), approximately 50% of patients will still continue to present with primarily mild-to-moderate degrees of neurocognitive impairment (Harezlak et al., 2011; Heaton et al., 2010; Heaton et al., 2011; Robertson et al., 2007). Characteristically, the types of cognitive problems observed in HIV+ adults reflect that of frontal-subcortical dysfunction (Grant & Heaton, 1990; Hestad et al., 1993; Paul, Cohen, & Stern, 2003; Reger, Welsh, Razani, Martin, & Boone, 2002) involving frontal-subcortical networks (Ances et al., 2006; Ernst, Chang, Jovicich, Ames, & Arnold, 2002; Lentz et al., 2009; Melrose, Tinaz, Castelo, Courtney, & Stern, 2008; Paul, Cohen, Navia, & Tashima, 2002). "
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    ABSTRACT: Background: Deficits in lexical retrieval, present in approximately 40% of HIV+ patients, are thought to reflect disruptions to frontal-striatal functions and may worsen with immunosuppression. Coupling frontal-striatal tasks such as lexical retrieval with functional neuroimaging may help delineate the pathophysiologic mechanisms underlying HIV-associated neurological dysfunction. Objective: We examined whether HIV infection confers brain functional changes during lexical access and retrieval. It was expected that HIV+ individuals would demonstrate greater brain activity in frontal-subcortical regions despite only minimal differences between groups on neuropsychological testing. Within the HIV+ sample, we examined associations between indices of immunosuppression (recent and nadir CD4+ count) and task-related signal change in frontostriatal structures. Method16 HIV+ participants and 12 HIV- controls underwent fMRI while engaged in phonemic/letter and semantic fluency tasks. Participants also completed standardized measures of verbal fluency RESULTS: HIV status groups performed similarly on phonemic and semantic fluency tasks prior to being scanned. fMRI results demonstrated activation differences during the phonemic fluency task as a function of HIV status, with HIV+ individuals demonstrating significantly greater activation in BG structures than HIV- individuals. There were no significant differences in frontal brain activation between HIV status groups during the phonemic fluency task, nor were there significant brain activation differences during the semantic fluency task. Within the HIV+ group, current CD4+ count, though not nadir, was positively correlated with increased activity in the inferior frontal gyrus and basal ganglia. Conclusion: During phonemic fluency performance, HIV+ patients recruit subcortical structures to a greater degree than HIV- controls despite similar task performances suggesting that fMRI may be sensitive to neurocompromise before overt cognitive declines can be detected. Among HIV+ individuals, reduced activity in the frontal-subcortical structures was associated with lower CD4+ count.
    Neurobiology of Disease 10/2015; DOI:10.1016/j.nbd.2015.10.017 · 5.08 Impact Factor
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    • "With the advent of combined antiretroviral therapy (CART), the incidence of HAD has dramatically decreased (Dore et al. 2003). However , the incidence of milder forms of cognitive impairment appears to remain high (Robertson et al. 2007; Simioni et al. 2010; Tozzi et al. 2005). The exact reasons behind the continuing prevalence of milder forms of HAND are not clear. "
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    ABSTRACT: In the era of combined antiretroviral therapy (CART), many of the complications due to HIV-1 infection have diminished. One exception is HIV-associated neurocognitive disorder (HAND). HAND is a spectrum of disorders in cognitive function that ranges from asymptomatic disease to severe dementia (HAD). The milder form of HAND has actually remained the same or slightly increased in prevalence in the CART era. Even in individuals who have maintained undetectable HIV RNA loads, viral proteins such as Nef and Tat can continue to be expressed. In this report, we show that Nef protein and nef messenger RNA (mRNA) are packaged into exosomes that remain in circulation in patients with HAD. Plasma-derived Nef exosomes from patients with HAD have the ability to interact with the neuroblastoma cell line SH-SY5Y and deliver nef mRNA. The mRNA can induce expression of Nef in target cells and subsequently increase expression and secretion of beta-amyloid (Aβ) and Aβ peptides. Increase secretion of amyloid peptide could contribute to cognitive impairment seen in HAND.
    Journal of NeuroVirology 09/2015; DOI:10.1007/s13365-015-0383-6 · 2.60 Impact Factor
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