HIVassociated neurocognitive disorders before and

Authors: Robert K Heaton Donald R Franklin Ronald J Ellis J Allen McCutchan Scott L Letendre Shannon LeBlanc Stephanie H Corkran Nichole A Duarte David B Clifford Steven P Woods Ann C Collier Christina M Marra Susan Morgello Monica Rivera Mindt Michael J Taylor Thomas D Marcotte J Hampton Atkinson Tanya Wolfson Benjamin B Gelman Justin C McArthur David M Simpson Ian Abramson Anthony Gamst Christine FennemaNotestine Terry L Jernigan Joseph Wong Igor Grant for the CHARTER and HNRC Groups

Publish Date: 2010/12/21

Volume: 17, Issue: 1, Pages: 3-16

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Abstract

Combination antiretroviral therapy CART has greatly reduced medical morbidity and mortality with HIV infection but high rates of HIVassociated neurocognitive disorders HAND continue to be reported Because large HIVinfected HIV+ and uninfected HIV− groups have not been studied with similar methods in the preCART and CART eras it is unclear whether CART has changed the prevalence nature and clinical correlates of HAND We used comparable methods of subject screening and assessments to classify neurocognitive impairment NCI in large groups of HIV + and HIV − participants from the preCART era 1988–1995 N = 857 and CART era 2000–2007 N = 937 Impairment rate increased with successive disease stages CDC stages A B and C in both eras 25 42 and 52 in preCART era and 36 40 and 45 in CART era In the medically asymptomatic stage CDCA NCI was significantly more common in the CART era Low nadir CD4 predicted NCI in both eras whereas degree of current immunosuppression estimated duration of infection and viral suppression in CSF on treatment were related to impairment only preCART Pattern of NCI also differed preCART had more impairment in motor skills cognitive speed and verbal fluency whereas CART era involved more memory learning and executive function impairment High rates of mild NCI persist at all stages of HIV infection despite improved viral suppression and immune reconstitution with CART The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND Clinical trials targeting HAND prevention should specifically examine timing of ART initiationSince the beginning of the HIV/AIDS epidemic HIVassociated neurocognitive disorders HAND have been commonly observed in infected populations American Academy of Neurology AIDS Task Force 1991 Antinori et al 2007 These conditions ranging from subtle neuropsychological impairments to profoundly disabling HIVassociated dementia are more frequently seen in advanced stages of HIV disease AIDS but can occur even in individuals having medically asymptomatic HIV infection CDC 1993 Stage A Grant et al 1987 Heaton et al 1995 White et al 1995 Moreover HAND confers an increased risk for early mortality independent of medical predictors Ellis et al 1997a Mayeux et al 1993 and often interferes significantly with cognitively demanding activities of daily living eg employment medication management driving Heaton et al 2004b Hinkin et al 2004 Marcotte et al 1999 2004The availability of combination antiretroviral therapy CART since 1996 has successfully controlled HIV viremia and improved immune function in many treated HIVinfected HIV+ patients leading to dramatic improvements in medical morbidity and life expectancy Clear improvement in neurological outcomes in the era of CART also has been achieved with a significant drop in the rate of frank HIVassociated dementia Dore et al 2003 Robertson et al 2007 Sacktor et al 2002 PreCART prevalence estimates were approximately 16 in AIDS cases McArthur et al 1993 whereas more recent estimates are less than 5 Heaton et al 2010 Further benefits of CART on the broader spectrum of HAND have been suggested by studies of neurocognitive change in HIV + groups initiating CART regimens A recent review of 15 such studies indicated that 11 found some improvement in neurocognitive test performance after an average of 6 months on CART although most studies had relatively small sample sizes and did not control for practice effects on repeated testing Joska et al 2010Unfortunately however beneficial effects of CART on neurologic manifestations of HIV infection especially HAND have been less than complete McArthur and Brew 2010 Neurocognitive responses to CART have been varied across individuals and studies of HAND in treated patients have documented high persisting rates of mildtomoderate neurocognitive impairment NCI For example Robertson et al 2007 assembled data on 1160 HIV + patients involved in 14 different clinical trials involving CART All participants completed a brief neurocognitive battery at least 20 weeks after randomization to treatment 921 participants completed a followup exam 48 weeks later Prevalence of NCI was 39 at baseline Although 44 of those with NCI at baseline appeared to show CARTrelated improvement at followup performed within the “normal” range but with no apparent correction for practice effect 21 of participants who were NC normal at baseline experienced incident impairment at followup As a result the total rate of NCI at followup was not very different from that at baseline 34 vs 39 In another study of persisting NCI on CART Tozzi et al 2007 followed 94 treated patients for a mean of 5 years multiple assessments All had NCI at baseline and 63 showed persisting impairment however this could be an underestimate because again it is unclear whether or not they controlled for practice effects on the neurocognitive tests A third recent study reported HAND in 69 of 200 HIV + patients who had maintained good virologic response undetectable HIV RNA in plasma on CART over a median of 48 months Simioni et al 2010Causes of continuing high rates of HAND in the CART era are uncertain but multiple nonexclusive possibilities have been suggested irreversible brain injury prior to initiating CART incomplete viral suppression in the central nervous system CNS due to poor CNS penetration of some commonly used antiretroviral drugs and/or presence of drugresistant viral strains the possibility that even very low levels of viral replication in the CNS could result in neural injury or dysfunction due to prolonged exposure to inflammatory responses and neurotoxic viral proteins possible neurotoxicity of antiretroviral therapy ART drugs and exposure to other conditions that may affect cognition in longterm survivors such as increased rates of metabolic abnormalities and associated vascular pathology or increased Bamyloid deposition in the brainIn sum although the most severe form of HAND HIVassociated dementia appears to be much less common in the era of CART questions remain about any longterm benefit of CART with respect to milder forms of HAND These abnormalities remain highly prevalent and it is unclear whether their nature pathophysiological mechanisms and clinical predictors have changed Optimal comparison of HAND across time requires consistent definitions and testing substantial representative cohorts and sufficient knowledge of context including nonHIV comorbid conditions to achieve informative analysisThis study compares baseline neuropsychological NP and neuromedical findings of two large cohorts of HIV + and HIV − participants who were recruited and assessed as part of a longrange program of research coordinated by the UCSD HIV Neurobehavioral Research Center HNRC Through collaborations with multiple institutions listed in the acknowledgements we performed comparable neuromedical and neurocognitive examinations on 857 participants from the preCART era and 936 from the CART era Participants were recruited through advertisements and outreach to various communities and health care providers It should be noted that these were not referral populations ie not weighted to persons suspected or known to have neurologic disease An almost identical NP test battery covering seven ability domains was used to classify HAND according to recently published international guidelines Antinori et al 2007 In order to provide comparable exclusions and minimize the effects of comorbid conditions on NP results potential participants in both cohorts were carefully screened and excluded if they had any history of significant nonHIVrelated risks for cognitive impairment Rates of HAND were compared across eras in subgroups that were stratified by HIV serostatus and clinical stage of infection HIV − controls vs CDC 1993 stages A B and C Although the 2008 CDC classification system has deemphasized the distinction between historic asymptomatic and mildly symptomatic HIV disease we included all three stages in the current analyses to provide links with earlier studies of HAND and because most of our participants had been classified before the new guidelines were published Centers for Disease Control 2008 Immunological and virological predictors of HAND also were assessed and compared across eras Finally to explore possible qualitative differences in neurobehavioral outcomes we compared severity and patterns of impairment across the seven ability domains for HIV + participants from the two eras

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