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Brain Atrophy in HIV+ > 60 is Progressive Despite Viral Suppression / ART Neurotoxicity /LIMC / Aging/ Mental & Substance Abuse Disorders
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Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Over Age 60
"In summary, we find that long-term virally suppressed HIV-infected individuals have brain atrophy rates that exceed that expected from healthy controls. These results inform a potential gap in neuroprotection despite adherence to cART with long-term maximal viral suppression in plasma.......By virtue of the older age of our study participants compared to other studies, they may be particularly vulnerable to faster changes in brain atrophy as age-associated brain atrophy rates do not appear to have linear slopes in healthy aging"....."The mean age of study participants was 63 years.....There is controversy as to whether plasma viral suppression is sufficient to halt detrimental brain changes with some arguing that volumetric reductions described in HIV are due to past injury. This study was designed to test whether plasma viral suppression is sufficient to halt progressive atrophy in older HIV-infected participants.....All had documented plasma viral suppression for each visit during longitudinal follow-up. Additionally, among the HIV-infected participants, 57% self reported persistent viral suppression for between 5-10 years, while 39% self-reported suppression for >10 years, although 17% reported either small "blips," or a planned drug holiday prior to enrollment, where their plasma HIV RNA was elevated for a short time but then returned to undetectable.......In longitudinal ROI models adjusted for age and sex, we uncovered progressive atrophy in the HIV-infected group exceeding rates seen among healthy controls (Table 2, bottom panel) with faster annualized rates of progressive atrophy in the cerebellum (0.42% vs 0.02%, p=0.016), caudate (0.74% vs 0.03%, p=0.012), frontal lobe (0.48% vs 0.01%, p=0.034), total cortical gray matter (0.65% vs 0.16%, p=0.027), brainstem (0.31% vs 0.01%, p=0.026), and pallidum (0.73% vs 0.39%, p=0.046) (Figure 1)......We add to a growing number of studies identifying detrimental neuropathogenic pathways, typically associated with persistent inflammation."
Excerpted from:
Global HIV neurology
a comprehensive review - pdf attached
AIDS Feb 2019
Given increased global access to cART, neurological conditions are becoming more frequent in an aging HIV-infected (HIV+) population with longstanding HIV including cognitive sequelae, cerebrovascular disease, and peripheral neuropathy. There is also an ongoing impact of neurotoxicity because of continued use of older generation antiretroviral drugs in resource-limited regions. Here we review the most common neurological complications of HIV with an emphasis on their impact in low and middle-income countries (LMICs), as well as the current knowledge gaps in the field including the impact of the central nervous system (CNS) as a reservoir for HIV and its effects on eradication efforts [6].
Mental and substance use disorders
Mental and substance use disorders are common among HIV+ individuals [208]. When HIV+ individuals suffer from multiple stigma-laden medical conditions, the effect is more than additive [209]. Adherence to cART is negatively associated with depressive symptoms and drug use [210,211].
There is some evidence that depression may be associated with the same underlying HIV-mediated inflammatory process that causes HIV-associated neurocognitive disorders (HAND) [27,212]. Elevated plasma pro-inflammatory cytokine levels contribute to the development of depression and depressive-like behaviors in HIV+ patients [213]. A study of HIV+ patients in an Irish clinic reported 51.1% (N = 604) screened positive for cognitive impairment; of those positive, 9.1% screened for depression and 24.5% screened positive for anxiety [214]. Moreover, depression prevalence among HIV+ individuals screened positive for depression has been found to increase with age [215].
Aging in the HIV-positive population
The widespread availability of cART in resource-rich settings has led to the transition of HIV from an acute, deadly illness to a chronic disease. In LMIC regions, HIV remains a cause of significant morbidity and mortality in younger populations because of ongoing sociocultural challenges, stigma, and minimal access to newer, less toxic antiretrovirals; however, global trends demonstrate an aging population of HIV+ individuals who receive adequate antiretrovirals in resource-limited regions [226]. For example, HIV+ Ugandans in their forties who are receiving antiretrovirals can expect to live into their sixties [227]. Approximately one in eight HIV+ adults and one in ten HIV+ patients receiving antiretrovirals in sub-Saharan Africa are more than 50 years old [228]. Despite global decreases in HIV-associated mortality, infection remains a leading cause of disability-adjusted life years (DALYs) [229]. Neurological disease remains common among treated HIV+ patients because of early viral entry into the CNS and ongoing inflammation and immune activation that persist in chronic infection. Progressive brain atrophy despite persistent viral suppression in HIV+ adults over age 60 is also of concern [230]. Co-existing conditions and risk factors, including hypertension, hyperlipidemia, substance abuse, and antiretroviral treatment effects, contribute to the effects of primary HIV infection on the nervous system. In addition, neurological conditions often associated with older age, including stroke and dementia, are occurring at younger ages in people with chronic HIV infection, a phenomenon referred to as 'accelerated aging.' This may be because of chronic systemic inflammation, which occurs despite virological suppression, long-term antiretroviral toxicity, lifestyle factors, or a combination thereof [231,232]. Therefore, it is important for providers to be aware of this and screen for neurologic diseases of older age in younger adults with chronic HIV infection.
Systemically, HIV is associated with frailty, a geriatric syndrome characterized by unintentional weight loss, diminished gait speed and grip strength, exhaustion, and low-energy expenditure [233,234]. In Western HIV+ cohorts, frailty has been associated with increased mortality and morbidity, including hospitalizations, and occurs at younger ages than in HIV-uninfected populations [235-241]. Furthermore, frailty at the time of cART initiation was predictive of lower AIDS-free survival, increased mortality rates, and was inversely related to CD4+ cell counts. Frailty is likely a major contributor to neurological deterioration in aging HIV+ patients. Studies have shown an increased risk of cognitive impairment among HIV− older adults with frailty, and HIV+ adults with cognitive impairment have significantly increased odds of frailty [242]. However, little is known about the burden of frailty in LMIC, particularly in sub-Saharan Africa, and gaps in knowledge regarding the health of older people in this region is increasingly being recognized as a public health concern [243,244].
HAND refers to a spectrum of neurocognitive impairment that includes asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). HAND is diagnosed using neuropsychological testing and functional status assessments, and HAND stages are differentiated based on the severity of deficits on these tests [245]. Although HAND stabilizes and sometimes improves with initiation of cART, it rarely resolves completely, even in the setting of optimal systemic virological suppression, and incident HAND can occur in patients on cART. Thus, although less severe HAND stages predominate today, the overall prevalence of HAND remains relatively unchanged compared with the pre-cART era, affecting up to 50% of HIV-infected persons and remaining one of the most common neurological complications of HIV [246-248]. Recognition of HAND is important as individuals with HAND have higher rates of cART nonadherence and steeper declines in adherence over time compared with individuals without HAND [249-251].
The reported prevalence of HAND in LMICs varies widely, ranging from 6 to 64% in children and adults [230,252-258], likely reflecting vast differences in methodology (e.g. use of screening tests versus full neuropsychological test batteries for diagnosis) and patient populations (e.g. cART-naive versus cART-treated patients). In a study of adult HIV+ Malawians on cART, 15% reported symptomatic neurocognitive impairment (12% MND, 3% HAD) whereas 55% met criteria for ANI [259]. In a meta-analysis on the epidemiology of neurodegenerative disease in sub-Saharan Africa, 47 of 144 (33%) studies reported HAND as a major contributor to neurodegenerative disease [260]. Accurate epidemiologic data about HAND in sub-Saharan Africa is important, however, as rates may differ from Western population because of differences in risk factors including differing genetics and rates of comorbidities known to increase HAND risk such as hypertension and diabetes. The biology of HIV itself also differs in this region with different circulating HIV subtypes compared with Western populations, though there are conflicting results regarding the effect of HIV subtypes on HAND (Supplemental Table 8, http://links.lww.com/QAD/B246). Some studies suggest subtype D is most neurovirulent, followed by subtypes B, C, and A, respectively, but other studies suggest HAND prevalence is not affected by subtype [261]. Methodological limitations may account for at least some of these differences, but further investigation is needed to definitively answer these questions.
The impact of HAND will likely continue to grow as the global HIV+ population ages as there is mounting evidence that HIV exacerbates age-associated cognitive decline [262-265] and older age is associated with increased risk of HAND [250,251,266-269]. Older HIV+ individuals also demonstrate greater than expected brain atrophy on neuroimaging studies, which is associated with impaired performance in multiple cognitive domains compared with older HIV− individuals [270]. Longitudinal studies demonstrate synergistic effects of HIV and aging on cognitive function [271-275]. Cognitive decline is likely multifactorial because of direct damage from the virus and indirect damage through secondary risk factors, including vascular disease, chronic drug use, and toxic long-term effects of antiretrovirals. Importantly, premature age-associated neurocognitive decline correlated with structural and functional brain changes on neuroimaging and histopathology, including signs of Alzheimer's disease pathology. This is observed in some HIV+ patients at younger ages than would otherwise be expected and may be related to accelerated aging as discussed above [276-278].
Currently, no HAND-specific therapies exist, but small trials of paroxetine and maraviroc showed some benefit in improving neurocognitive function in HIV+ cART-treated adults. Trials of intranasal insulin are ongoing after in-vitro evidence suggested insulin may have neuroprotective effects in HIV infection [279-283]. Development of validated biomarkers and improved clinical neurocognitive tests that can holistically and accurately assess the risk of developing HAND are also needed to facilitate future trials of novel HAND therapies. Table 6 includes a review of key biomarkers associated with HIV-associated cognitive impairment [284-294].
Neurotoxic effects of HIV treatment
Antiretroviral drugs may lead to a wide spectrum of adverse effects along the neuroaxis, sometimes leading to adherence problems, regimen changes, or withdrawal from therapy [34,41,136,186-192]. The lack of access to newer, less neurotoxic antiretrovirals is particularly concerning in resource-limited settings. Table 4 highlights some of the major adverse neurological effects associated with antiretroviral drugs; antiretroviral side effects tend to vary by drug class [41,91,136,187,189-194].
The nucleoside analogs, didanosine (ddI), stavudine (d4T), and zalcitabine (ddC) are most frequently associated with peripheral neuropathy, and as a result have largely been phased out in resource-rich settings [187]. However, in many resource-limited settings, these drugs remain in use. Zidovudine and abacavir both remain cornerstones of therapy in many resource-limited settings, and have minimal association with peripheral neuropathy, though both have been reported to cause myopathy and psychiatric symptoms [41,187]. The nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz has the highest rate of CNS side effects, affecting more than 50% of patients in some studies [186]. Side effects include insomnia, confusion, nightmares, and psychiatric symptoms including anxiety and depression. In contrast, nevirapine appears to have few CNS side effects. The newer NNRTI, etravirine, has also been associated with peripheral neuropathy, though at lower rates than the older nucleoside analogs. Rilpivirine appears to have relatively few CNS side effects, though depression, headache, and insomnia have been reported. Protease inhibitors have largely been thought to have minimal CNS side effects, although in-vitro data suggests that there is at least a theoretical risk of neurotoxicity [187]. In addition, protease inhibitor-induced hyperlipidemia increases risk for cerebrovascular disease.
The integrase inhibitors (raltegravir, dolutegravir, elutegravir) have only recently become available in many resource-limited settings, and are primarily used in those settings as third-line or salvage therapy. Although the profile of CNS side effects is similar to those reported for efavirenz (sleep disturbance, confusion, and psychiatric changes), the incidence is much lower and in practice discontinuation because of side effects is rare with these drugs [195-197].
Given growing evidence that the CNS is a viral reservoir, another important aspect of antiretroviral therapy is its ability to cross the BBB and penetrate brain parenchyma. The CNS is an immune-privileged compartment and few antiretrovirals demonstrate effective penetration. Newer therapeutic agents with good CNS penetration and minimal neurotoxicity are appealing but are often unavailable in resource-limited settings where older-generation antiretrovirals remain the mainstay of treatment because of cost [174,194].

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