An alternative approach to activating Nrf2 pathway is supplementation with the antioxi‐ dant vitamin C (ascorbate), which is capable of directly scavenging reactive oxygen and ni‐ trogen species. This method has been shown to be effective in counteracting the deleterious effects of gp120, as well as nelfinavir *in vitro*, and has been shown to have beneficial out‐ comes in patients, when supplemented to ART regimens [100, 195, 204]. Along these same lines, supplementation with a variety of other antioxidants and micronutrients including minocycline, glutathione replenishing peptide alpha-lipoic acid, selenium, vitamin A, Vita‐ min E, and a multivitamin regimen including vitamins A, C, E selenium and coenzyme Q10 have demonstrated partial protection from the deleterious oxidative effects of HIV/SIV and ART *in vivo*, with particular emphasis on restoration of the total blood glutathione levels [127, 195, 212-214]. Finally, the NMDA-receptor blocker memantine, and monoamide oxi‐ dase type B inhibitor selegiline, approved for treatment in Alzheimer and Parkinson Diseas‐ es, respectively, have also been proposed as potential therapeutics for HAND [1, 214]. Memantine might exert therapeutic effects through reduction of residual virus-mediated glutamate excitotoxicity, and selegiline has been reported to be capable of reducing oxygenbased free radicals [215, 216]. The use of these compounds and their efficacy in reducing oxi‐ dative damage in HAND are still in early stages. Initial studies were confounded by the fact that much damage was already present in late stage HAD patients and a protective effect at this stage was not evident [217]. Further work with these compounds will require identify‐ ing patients with ANI or MND to enroll in longitudinal studies to determine whether these compounds will have long-term benefit.

Hepatitis B and C (HBV and HCV) are also commonly found in HIV-infected individuals due to the shared risk factors of contracting the virus. While these viruses are not thought to target the primary cells of the CNS, a recent study has reported the presence of HCV anti‐ gens in astrocytes and the cells of the macrophage/microglial lineage in the human brain. Additionally, there is limited evidence suggesting that HCV core protein might be detrimen‐ tal to neurons *in vitro* and *in vivo*. Further, several studies have suggested that HCV and HIV can potentiate each other's replication. Currently, there is no conclusive data regarding a possible correlation between HCV presence in the CNS and the neurocognitive deficits in HAND patients. However, the potential implications of HCV infection in the CNS are at least three-fold. First, HCV co-infection can hinder the efforts to suppress HIV replication in the CNS. Second, weakened immune system function secondary to HCV will negatively im‐ pact subsequent alleviation of neurocognitive functions. Finally, compromised functioning of CNS support cells, mainly astrocytes, secondary to concomitant HCV infection will aug‐ ment the neuroinflammatory environment with a negative impact on neuronal health. These implications may underlie the evidence that suggests that viral suppression and CD4+ cell recovery is not as successful in the presence of HCV, and might partially explain the spora‐ dic data suggesting that worse neurocognitive impairment is observed in HIV-HCV co-in‐

Persistence of HIV-Associated Neurocognitive Disorders in the Era of Antiretroviral Therapy

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179

Illicit drug use, as well as alcohol abuse, put HIV-positive patients at a greater risk for HAND [6, 218-224]. The prevalence of HIV infection is 11-17% among illicit drug users, and methamphetamine (METH) is among the most frequently abused drug with well-known toxic effects on the BBB and in the CNS [220]. HIV-infected patients using METH exhibit more neurocognitive deficits, compared to those not using METH. These findings are likely due to the effects of METH on several fronts in the CNS. First, extensive studies have con‐ clusively shown that METH alters the BBB permeability through direct damage to the BMECs, which in turn can augment HIV access to the CNS. Additionally, METH can exert neurotoxic effects in the CNS through oxidative stress and mitochondrial dysfunction [184], and precipitate further synaptic and neuronal damage. METH may also interfere with the expected benefits of ART in several ways. Most importantly, studies have shown that al‐ tered patient behavior due to METH use can interfere with drug adherence. Secondly, al‐ tered BBB function in a patient using METH can potentially alter antiretroviral access to the

CNS, hindering efforts to establish an efficient regimen with limited side effects.

The widespread use of ART has drastically decreased the incidence of AIDS-related compli‐ cations and improved the long-term prognosis of HIV-positive individuals. Currently, 30% of the HIV-positive population in the United States is over the age of 50,and by 2015 it is estimated that more than 50% will be over the age of 50 [225, 226]. Despite this remarkable development, the life expectancy for ART-treated HIV-positive individuals remains 10-30 years less than that of uninfected individuals [227]. Given the rapid global expansion of this

fected patients [184].

**6. Aging and HAND**

Going forward, it is imperative that the oxidative stress imposed by HIV and ART are tar‐ geted by adjunctive therapies. As research progresses with the quest for eliminating viral reservoirs and designing more effective, less toxic antiretroviral compounds, it is important to keep in mind that oxidative stress is and will continue to be a persistent burden, especial‐ ly in a patient population with a significantly enhanced life expectancy.

### **5. The impact of co-morbidities on HAND**

HIV, once an acute and catastrophic infection, has now become a chronic and manageable disease, with advances made in diagnosis and treatment. These changes are reflected in the increases in life expectancy from 5 years to up to the projected 50 years from the time of di‐ agnosis. However, with the increased lifespan, co-morbidities, such as chronic co-infections, substance abuse, and aging have become major contributors to HAND persistence, and need to be addressed for successful evaluation and treatment of HAND.

The compromised immune system in an HIV-infected individual increases the risk of op‐ portunistic infections in the CNS, much like that observed in the peripheral tissue. Most commonly observed infections, CNS toxoplasmosis, cryptococcosis, CNS tuberculosis, and cytomegalovirus encephalitis can be treated successfully by a combination of antimicrobi‐ als, antiviral and antiretroviral drugs. However, there are several other viral agents that can either directly target or indirectly compromise CNS, and cannot be readily managed by antiretroviral drugs or chemotherapeutics. One important virus with serious complica‐ tions in HAND patients is JC virus, the causative agent of progressive multifocal leukoen‐ cephelopathy (PML). While approximately 60-80% of adults globally are seropositive for JC virus, it leads to the development of PML mostly in individuals who are immuno-com‐ promised, either due to an underlying cancer or immunosuppressive treatment, or who are HIV-positive. The current incidence of PML in HIV patients is 3%. Studies have shown that JC virus can traffic across the BBB within the B cells, can enter the CNS as a free virus, or can infect brain vascular endothelial cells. Once in the CNS, JC virus causes the lytic infection of oligodendrocytes, and results in multifocal demyelination in multiple regions of the white matter. Thus, PML may exacerbate white matter loss that may al‐ ready be occurring in HAND patients. Further, the most efficient, however limited, treat‐ ment for PML, which is immune restoration with aggressive antiretroviral therapy, can potentiate immune reconstitution inflammatory syndrome (IRIS). IRIS, a T-cell mediated encephalitis, can precipitate further injury and worsening of neurological symptoms. While fatality due to PML in HIV-infected individuals can be as high as 50%, the number of cases with non-lethal PML is increasing and PML may be contributing to the persis‐ tence of HIV-associated neurological complications.

Hepatitis B and C (HBV and HCV) are also commonly found in HIV-infected individuals due to the shared risk factors of contracting the virus. While these viruses are not thought to target the primary cells of the CNS, a recent study has reported the presence of HCV anti‐ gens in astrocytes and the cells of the macrophage/microglial lineage in the human brain. Additionally, there is limited evidence suggesting that HCV core protein might be detrimen‐ tal to neurons *in vitro* and *in vivo*. Further, several studies have suggested that HCV and HIV can potentiate each other's replication. Currently, there is no conclusive data regarding a possible correlation between HCV presence in the CNS and the neurocognitive deficits in HAND patients. However, the potential implications of HCV infection in the CNS are at least three-fold. First, HCV co-infection can hinder the efforts to suppress HIV replication in the CNS. Second, weakened immune system function secondary to HCV will negatively im‐ pact subsequent alleviation of neurocognitive functions. Finally, compromised functioning of CNS support cells, mainly astrocytes, secondary to concomitant HCV infection will aug‐ ment the neuroinflammatory environment with a negative impact on neuronal health. These implications may underlie the evidence that suggests that viral suppression and CD4+ cell recovery is not as successful in the presence of HCV, and might partially explain the spora‐ dic data suggesting that worse neurocognitive impairment is observed in HIV-HCV co-in‐ fected patients [184].

Illicit drug use, as well as alcohol abuse, put HIV-positive patients at a greater risk for HAND [6, 218-224]. The prevalence of HIV infection is 11-17% among illicit drug users, and methamphetamine (METH) is among the most frequently abused drug with well-known toxic effects on the BBB and in the CNS [220]. HIV-infected patients using METH exhibit more neurocognitive deficits, compared to those not using METH. These findings are likely due to the effects of METH on several fronts in the CNS. First, extensive studies have con‐ clusively shown that METH alters the BBB permeability through direct damage to the BMECs, which in turn can augment HIV access to the CNS. Additionally, METH can exert neurotoxic effects in the CNS through oxidative stress and mitochondrial dysfunction [184], and precipitate further synaptic and neuronal damage. METH may also interfere with the expected benefits of ART in several ways. Most importantly, studies have shown that al‐ tered patient behavior due to METH use can interfere with drug adherence. Secondly, al‐ tered BBB function in a patient using METH can potentially alter antiretroviral access to the CNS, hindering efforts to establish an efficient regimen with limited side effects.

### **6. Aging and HAND**

that much damage was already present in late stage HAD patients and a protective effect at this stage was not evident [217]. Further work with these compounds will require identify‐ ing patients with ANI or MND to enroll in longitudinal studies to determine whether these

Going forward, it is imperative that the oxidative stress imposed by HIV and ART are tar‐ geted by adjunctive therapies. As research progresses with the quest for eliminating viral reservoirs and designing more effective, less toxic antiretroviral compounds, it is important to keep in mind that oxidative stress is and will continue to be a persistent burden, especial‐

HIV, once an acute and catastrophic infection, has now become a chronic and manageable disease, with advances made in diagnosis and treatment. These changes are reflected in the increases in life expectancy from 5 years to up to the projected 50 years from the time of di‐ agnosis. However, with the increased lifespan, co-morbidities, such as chronic co-infections, substance abuse, and aging have become major contributors to HAND persistence, and need

The compromised immune system in an HIV-infected individual increases the risk of op‐ portunistic infections in the CNS, much like that observed in the peripheral tissue. Most commonly observed infections, CNS toxoplasmosis, cryptococcosis, CNS tuberculosis, and cytomegalovirus encephalitis can be treated successfully by a combination of antimicrobi‐ als, antiviral and antiretroviral drugs. However, there are several other viral agents that can either directly target or indirectly compromise CNS, and cannot be readily managed by antiretroviral drugs or chemotherapeutics. One important virus with serious complica‐ tions in HAND patients is JC virus, the causative agent of progressive multifocal leukoen‐ cephelopathy (PML). While approximately 60-80% of adults globally are seropositive for JC virus, it leads to the development of PML mostly in individuals who are immuno-com‐ promised, either due to an underlying cancer or immunosuppressive treatment, or who are HIV-positive. The current incidence of PML in HIV patients is 3%. Studies have shown that JC virus can traffic across the BBB within the B cells, can enter the CNS as a free virus, or can infect brain vascular endothelial cells. Once in the CNS, JC virus causes the lytic infection of oligodendrocytes, and results in multifocal demyelination in multiple regions of the white matter. Thus, PML may exacerbate white matter loss that may al‐ ready be occurring in HAND patients. Further, the most efficient, however limited, treat‐ ment for PML, which is immune restoration with aggressive antiretroviral therapy, can potentiate immune reconstitution inflammatory syndrome (IRIS). IRIS, a T-cell mediated encephalitis, can precipitate further injury and worsening of neurological symptoms. While fatality due to PML in HIV-infected individuals can be as high as 50%, the number of cases with non-lethal PML is increasing and PML may be contributing to the persis‐

ly in a patient population with a significantly enhanced life expectancy.

to be addressed for successful evaluation and treatment of HAND.

**5. The impact of co-morbidities on HAND**

tence of HIV-associated neurological complications.

compounds will have long-term benefit.

178 Current Perspectives in HIV Infection

The widespread use of ART has drastically decreased the incidence of AIDS-related compli‐ cations and improved the long-term prognosis of HIV-positive individuals. Currently, 30% of the HIV-positive population in the United States is over the age of 50,and by 2015 it is estimated that more than 50% will be over the age of 50 [225, 226]. Despite this remarkable development, the life expectancy for ART-treated HIV-positive individuals remains 10-30 years less than that of uninfected individuals [227]. Given the rapid global expansion of this population, it has become increasingly important to understand the risk factors that lie at the intersection of HIV, ART, and aging.

HIV-positive patients [243]. In addition, older HIV-positive individuals are at increased risk for frailty, bone loss and non-AIDS related cancers [244, 245]. It remains unclear if HIV itself places older individuals at higher risk for heart disease compared to older, HIV-negative in‐ dividuals, though specific classes of antiretrovirals, especially protease inhibitors, have been

Persistence of HIV-Associated Neurocognitive Disorders in the Era of Antiretroviral Therapy

http://dx.doi.org/10.5772/52683

181

The CNS is particularly susceptible to the synergistic neurodegenerative effects of HIV and aging. Several studies have demonstrated that, compared to younger (age 20 to 39 years) co‐ horts, older HIV-positive individuals (age > 50 years) display decreased neurocognitive functioning in several areas including memory, psychomotor speed, and executive functions [225, 248, 249]. The persistence of HAND in individuals with an undetectable viral load and CD4 cell counts greater than 200/µL is not well understood and may be a result of aging-

Several recent neuroimaging studies have begun to address the structural, physiological, and functional changes in the CNS in the context of HIV and aging. Six MRI investigations that assessed the structural changes in the brains of older HIV-positive individuals between 1998 and 2012 found evidence of premature or accelerated aging characterized by significant brain atrophy in the basal ganglia, cerebellum, and frontal and temporal brain regions, when compared to seronegative controls [231]. However, several diffusion tensor imaging (DTI) studies found only normal, age-dependent changes in mean diffusion and fractional anisotropy, which reflects the directionality of water diffusion in the brain, and is greater along organized white matter tracts but decreased in pathologically damaged, disorganized

Other studies have employed proton magnetic resonance spectroscopy (MRS) to assess the changes in brain metabolite levels that are indicative of neuronal damage and death or glial activation. Ernst and Chang demonstrated a five-fold acceleration of aging effects in a rela‐ tively young (mean age 36 years) ART-naïve, HIV-positive cohort, as compared to HIV-neg‐ ative controls, as reflected by increased levels of glial activation markers, myoinositol (MI) and choline compounds (CHO), and a decrease in the neuronal marker, N-acetylaspartate (NAA) [253]. A recent multicenter MRS study of slightly older (ages 30-70], ART-treated HIV-positive individuals demonstrated elevated MI and CHO in all brain regions of pa‐ tients with asymptomatic or mild neurocognitive impairment, but decreased levels of MI in those with dementia, which the authors interpreted as premature microglial senescence [231, 254]. In addition, this study found an age-dependent decrease in NAA in frontal white matter, but only in patients with HAD [254]. Thus, while ART-naïve HIV-positive patients show evidence of increased, age-dependent glial activation and neuronal damage leading to accelerated aging, ART-treated individuals show only signs of premature aging [231].

As mentioned previously, the clinical and pathological hallmarks of post-ART HAND differ from those in the pre-ART era. While HAD presented as a subcortical dementia afflicting the basal ganglia and white matter, some post-ART studies suggest the focus of neuroinflamma‐ tion has shifted primarily to the hippocampus, even in effectively treated patients [255-257]. Furthermore, there is emerging evidence that pathologic similarities exist between HAND and some common neurodegenerative disorders such as Alzheimer Disease, which is char‐

associated processes rendering the cells of the CNS more vulnerable.

linked to atherosclerosis [237, 246, 247].

tracts [231, 250-252].

Older HIV-positive patients, including those treated with ART, are at increased risk for systemic diseases including atherosclerosis, liver and kidney failure, cancer, and osteopo‐ rosis [227, 228]. The aging brain may also be more vulnerable to the effects of HIV as old‐ er adults display an increased susceptibility to HAND, and emerging evidence suggests an increased prevalence of neurodegenerative diseases, including Alzheimer and Parkin‐ son, in this patient population [229, 230]. It remains unclear if the increased prevalence of HAND is a result of HIV and related comorbidities, including hypertension, insulin resist‐ ance, and lipodystrophy, or other confounding factors such as immunosenescence and ART toxicities, all of which are likely to impact CNS disease progression in older HIVpositive individuals [231, 232].

Antiretroviral therapy effectively limits HIV disease progression, maintains patients in a state of partial immune competence, and arrests subjects in a pre-symptomatic state [233]. However, despite the ability of ART to reduce plasma HIV RNA to undetectable levels, HIV-positive individuals remain at higher risk for opportunistic illnesses and premature death [234, 235]. Thus, ART may reduce, but does not appear to eliminate, premature and/or accelerated aging in HIV-infected individuals. This may be attributed to many factors in‐ cluding drug toxicity and slower immune recovery following ART initiation in older pa‐ tients, compared to younger adults [236]. Furthermore, advanced age has been linked to decreased production of T cells, B cells, and cytokines as well as to chronic immune activa‐ tion, the latter of which may be linked to the breakdown of gut-associated lymphoid tissue (GALT) and to the elevated levels of systemic lipopolysaccharide (LPS) [237, 238].

Older patients also display a dampened recovery of CD4 cells following treatment with ART, which may increase their risk for systemic diseases ranging from heart disease to can‐ cer [238]. Thus, it is not surprising that advanced age at seroconversion and/or onset of ART treatment is considered a major risk factor for severe HIV disease [239, 240]. Goetz, *et al.* performed a retrospective study on HIV-positive patients receiving ART treatment at the Veteran's Administration Greater Los Angeles Medical center between 1996 and 1999, and found that for every 10 years of additional age at the onset of ART treatment, the rate of CD4 cell replenishment decreased by 35 cells per microliter of blood [241]. Yet, despite the obvious benefits of beginning ART treatment in asymptomatic HIV-positive individuals, there remain significant concerns for initiating drug therapy sooner than necessary and how this may negatively impact drug toxicity, long-term patient outcome, and the evolution of drug resistant strains of HIV [240, 242]. Based on the updated recommendations for treat‐ ment initiation, as mentioned previously, all HIV-infected individuals will be put on ART regimen upon diagnosis, and the impact of this approach on older patients will be revealing.

Lower CD4 count, in addition to advanced age, also places older patients at a nearly fourfold higher risk for liver-related mortality compared to younger patients [243]. This risk is exacerbated by other factors commonly afflicting ART-treated, HIV-positive individuals in‐ cluding diabetes, alcohol abuse, as well as antiretroviral and cholesterol drug toxicity [243]. Among all non-AIDS-related complications, liver disease is the primary cause of death in HIV-positive patients [243]. In addition, older HIV-positive individuals are at increased risk for frailty, bone loss and non-AIDS related cancers [244, 245]. It remains unclear if HIV itself places older individuals at higher risk for heart disease compared to older, HIV-negative in‐ dividuals, though specific classes of antiretrovirals, especially protease inhibitors, have been linked to atherosclerosis [237, 246, 247].

population, it has become increasingly important to understand the risk factors that lie at

Older HIV-positive patients, including those treated with ART, are at increased risk for systemic diseases including atherosclerosis, liver and kidney failure, cancer, and osteopo‐ rosis [227, 228]. The aging brain may also be more vulnerable to the effects of HIV as old‐ er adults display an increased susceptibility to HAND, and emerging evidence suggests an increased prevalence of neurodegenerative diseases, including Alzheimer and Parkin‐ son, in this patient population [229, 230]. It remains unclear if the increased prevalence of HAND is a result of HIV and related comorbidities, including hypertension, insulin resist‐ ance, and lipodystrophy, or other confounding factors such as immunosenescence and ART toxicities, all of which are likely to impact CNS disease progression in older HIV-

Antiretroviral therapy effectively limits HIV disease progression, maintains patients in a state of partial immune competence, and arrests subjects in a pre-symptomatic state [233]. However, despite the ability of ART to reduce plasma HIV RNA to undetectable levels, HIV-positive individuals remain at higher risk for opportunistic illnesses and premature death [234, 235]. Thus, ART may reduce, but does not appear to eliminate, premature and/or accelerated aging in HIV-infected individuals. This may be attributed to many factors in‐ cluding drug toxicity and slower immune recovery following ART initiation in older pa‐ tients, compared to younger adults [236]. Furthermore, advanced age has been linked to decreased production of T cells, B cells, and cytokines as well as to chronic immune activa‐ tion, the latter of which may be linked to the breakdown of gut-associated lymphoid tissue

(GALT) and to the elevated levels of systemic lipopolysaccharide (LPS) [237, 238].

Older patients also display a dampened recovery of CD4 cells following treatment with ART, which may increase their risk for systemic diseases ranging from heart disease to can‐ cer [238]. Thus, it is not surprising that advanced age at seroconversion and/or onset of ART treatment is considered a major risk factor for severe HIV disease [239, 240]. Goetz, *et al.* performed a retrospective study on HIV-positive patients receiving ART treatment at the Veteran's Administration Greater Los Angeles Medical center between 1996 and 1999, and found that for every 10 years of additional age at the onset of ART treatment, the rate of CD4 cell replenishment decreased by 35 cells per microliter of blood [241]. Yet, despite the obvious benefits of beginning ART treatment in asymptomatic HIV-positive individuals, there remain significant concerns for initiating drug therapy sooner than necessary and how this may negatively impact drug toxicity, long-term patient outcome, and the evolution of drug resistant strains of HIV [240, 242]. Based on the updated recommendations for treat‐ ment initiation, as mentioned previously, all HIV-infected individuals will be put on ART regimen upon diagnosis, and the impact of this approach on older patients will be revealing. Lower CD4 count, in addition to advanced age, also places older patients at a nearly fourfold higher risk for liver-related mortality compared to younger patients [243]. This risk is exacerbated by other factors commonly afflicting ART-treated, HIV-positive individuals in‐ cluding diabetes, alcohol abuse, as well as antiretroviral and cholesterol drug toxicity [243]. Among all non-AIDS-related complications, liver disease is the primary cause of death in

the intersection of HIV, ART, and aging.

180 Current Perspectives in HIV Infection

positive individuals [231, 232].

The CNS is particularly susceptible to the synergistic neurodegenerative effects of HIV and aging. Several studies have demonstrated that, compared to younger (age 20 to 39 years) co‐ horts, older HIV-positive individuals (age > 50 years) display decreased neurocognitive functioning in several areas including memory, psychomotor speed, and executive functions [225, 248, 249]. The persistence of HAND in individuals with an undetectable viral load and CD4 cell counts greater than 200/µL is not well understood and may be a result of agingassociated processes rendering the cells of the CNS more vulnerable.

Several recent neuroimaging studies have begun to address the structural, physiological, and functional changes in the CNS in the context of HIV and aging. Six MRI investigations that assessed the structural changes in the brains of older HIV-positive individuals between 1998 and 2012 found evidence of premature or accelerated aging characterized by significant brain atrophy in the basal ganglia, cerebellum, and frontal and temporal brain regions, when compared to seronegative controls [231]. However, several diffusion tensor imaging (DTI) studies found only normal, age-dependent changes in mean diffusion and fractional anisotropy, which reflects the directionality of water diffusion in the brain, and is greater along organized white matter tracts but decreased in pathologically damaged, disorganized tracts [231, 250-252].

Other studies have employed proton magnetic resonance spectroscopy (MRS) to assess the changes in brain metabolite levels that are indicative of neuronal damage and death or glial activation. Ernst and Chang demonstrated a five-fold acceleration of aging effects in a rela‐ tively young (mean age 36 years) ART-naïve, HIV-positive cohort, as compared to HIV-neg‐ ative controls, as reflected by increased levels of glial activation markers, myoinositol (MI) and choline compounds (CHO), and a decrease in the neuronal marker, N-acetylaspartate (NAA) [253]. A recent multicenter MRS study of slightly older (ages 30-70], ART-treated HIV-positive individuals demonstrated elevated MI and CHO in all brain regions of pa‐ tients with asymptomatic or mild neurocognitive impairment, but decreased levels of MI in those with dementia, which the authors interpreted as premature microglial senescence [231, 254]. In addition, this study found an age-dependent decrease in NAA in frontal white matter, but only in patients with HAD [254]. Thus, while ART-naïve HIV-positive patients show evidence of increased, age-dependent glial activation and neuronal damage leading to accelerated aging, ART-treated individuals show only signs of premature aging [231].

As mentioned previously, the clinical and pathological hallmarks of post-ART HAND differ from those in the pre-ART era. While HAD presented as a subcortical dementia afflicting the basal ganglia and white matter, some post-ART studies suggest the focus of neuroinflamma‐ tion has shifted primarily to the hippocampus, even in effectively treated patients [255-257]. Furthermore, there is emerging evidence that pathologic similarities exist between HAND and some common neurodegenerative disorders such as Alzheimer Disease, which is char‐ acterized by the presence of extracellular beta amyloid (Aβ) plaque deposits, and intracellu‐ lar neurofibrillary tangles composed of hyperphosphorylated Tau [228, 233, 258, 259]. *In vitro* work involving the viral protein Tat has demonstrated the ability of this viral protein to inhibit the activity of the Aβ-degrading enzyme, Neprilysin, and the ability to bind to the receptor for advanced glycation end products, all of which may promote Aβ accumulation in the CNS. Indeed, some individuals with HAND display CSF levels of Aβ42 comparable to those observed in AD patients [228, 260, 261]. However, a recent report utilizing the amy‐ loid-binding, carbon 11-labeled Pittsburgh compound B (11C-PiB) and PET imaging found that irrespective of neurocognitive impairment, HIV-positive individuals showed no in‐ crease in 11C-PiB levels, highlighting a potential key difference between Aβ metabolism in HAND vs. AD despite some overlapping pathological features [258].

penetrant ART regimens and worse neurocognitive and motor performance, despite decreased CSF HIV RNA in a small HIV-positive cohort [181]. In addition, Robertson et al. reported an improvement in neuropsychological outcome in a cohort of patients with interrupted drug treatment [277]. Studies using SCID mice, which display neuropatho‐ logical hallmarks similar to those associated with HIV, showed reduced viral load and astrogliosis following administration of ART, but no improvement in cognitive dysfunc‐ tion [278]. Altogether, these studies reinforce an emerging hypothesis that antiretroviral drugs may be contributing to the rising prevalence of HAND in the aging HIV-positive

Persistence of HIV-Associated Neurocognitive Disorders in the Era of Antiretroviral Therapy

http://dx.doi.org/10.5772/52683

183

However, many clinical studies have demonstrated beneficial effects on neurocognitive functioning by ART regimens with high CPE scores [279, 280]. A cross-sectional study of 2636 adults from the AIDS Clinical Trials Group Longitudinal Linked Randomized Tri‐ als (ALLRT cohort), on effective ART for at least 6 weeks showed better neurocognitive performance in individuals receiving ART medications with higher CPE scores [281]. In some cases, participants required more than 3 antiretrovirals to treat HIV in the CNS. Letendre et al. demonstrated improvements in cognition over a 15-week period in pa‐ tients beginning ART with higher CPE ART regimens [282]. Another recent investigation utilized MRS imaging to investigate the effect of different CPE ART regimens with dif‐ ferent CPE scores on changes in brain NAA metabolite levels. Over 48 weeks, HIV-posi‐ tive, ART-naïve individuals receiving the regimens with highest CPE scores displayed the highest increases in NAA levels, and showed the greatest improvement in a battery of neuropsychological tests [283]. These studies suggest that ART medications with high‐ er CNS penetrance may have a neuroprotective effect in successfully treated HIV-posi‐ tive adults. However, given the well-characterized toxicities of ART medications in the periphery, and the potential impact of related co-morbidities on CNS pathology, it may be necessary to consider adjunctive therapies to minimize the synergistic effects of ART

The advent of ART has profoundly changed the landscape of disease; however, neurocogni‐ tive impairments continue to be debilitating to patients with the expected life expectancy closer to that of the uninfected population. A better understanding and appreciation of the confounding factors has become more acute as the recent focus in the race to cure AIDS has shifted towards the eradication of latent viral reservoirs, including those in the CNS. It is im‐ perative to anticipate and control the immune responses due to viral reactivation, the poten‐ tial neurotoxicities of viral proteins in the brain parenchyma when latent viral progeny is activated, and the oxidative damage that may be precipitated by viral particles and the acti‐ vated immune cells. These factors will be even more crucial to control in the aging brain

population.

and aging in HIV-positive individuals.

with limited cognitive reserves.

**7. Summary**

Among the studies underlining the similarities between HAND and AD, Esiri *et al.* were the first to report a predisposition to plaque formation in the brains of pre-ART HIV-positive individuals [262]. Such pathological changes have been observed in HIV-positive patients despite successful virologic control with ART, suggesting that antiretrovirals either cannot achieve therapeutic concentrations within the brain parenchyma, allowing for ongoing viral replication and neuroinflammation, or may have toxic effects that could facilitate neurode‐ generation [263, 264]. To address the latter concern, several reports investigated differences in either phospho-tau or beta amyloid levels in ART-naïve vs. ART-treated individuals. Two groups independently reported elevated Aβ deposition in the hippocampus of ART-treated individuals compared to pre-ART patients, yet Anthony *et al*. reported only increased hy‐ perphosphorylated tau, but no Aβ deposition in the hippocampus and entorhinal cortex of HIV-positive individuals [257, 259, 265]. To date, no group has reported concomitant phos‐ pho-tau and Aβ plaque depositions in the same brain samples from HIV-positive cohorts. Differences in patient age and ART-regimens, as well as the antibodies used to detect Aβ may account for the varied outcomes of these reports.

Importantly, the aforementioned studies highlight the potentially under-appreciated con‐ cern of antiretroviral-associated toxicity and its effect on neuropsychological outcomes in long-term ART-treated patients. As described earlier, ART drugs have been linked to wide-ranging, peripheral metabolic and neural disturbances that could themselves influ‐ ence the progression of HAND and foretell potential mechanisms of toxicity in the CNS [246, 266-276]. While CNS effects of ART are poorly understood, Schweinsburg et al. dem‐ onstrated an association between NRTIs and decreased levels of frontal white matter NAA, which they attributed to NRTI-mediated mitochondrial dysfunction and depletion of cellular respiration [268]. Confounding the issue of direct CNS toxicity of antiretroviral medications is the variability in BBB permeability amongst different drug classes as deter‐ mined by various physicochemical properties such as plasma protein binding, lipophilici‐ ty, and molecular size.

Although it is a widely held that ART regimens with higher CNS penetrance generally confer greater neuropsychological outcomes in HIV-positive individuals, numerous clini‐ cal studies have suggested these regimens may negatively impact cognition. In a pro‐ spective study, Marra et al. found a significant association between highly CNS- penetrant ART regimens and worse neurocognitive and motor performance, despite decreased CSF HIV RNA in a small HIV-positive cohort [181]. In addition, Robertson et al. reported an improvement in neuropsychological outcome in a cohort of patients with interrupted drug treatment [277]. Studies using SCID mice, which display neuropatho‐ logical hallmarks similar to those associated with HIV, showed reduced viral load and astrogliosis following administration of ART, but no improvement in cognitive dysfunc‐ tion [278]. Altogether, these studies reinforce an emerging hypothesis that antiretroviral drugs may be contributing to the rising prevalence of HAND in the aging HIV-positive population.

However, many clinical studies have demonstrated beneficial effects on neurocognitive functioning by ART regimens with high CPE scores [279, 280]. A cross-sectional study of 2636 adults from the AIDS Clinical Trials Group Longitudinal Linked Randomized Tri‐ als (ALLRT cohort), on effective ART for at least 6 weeks showed better neurocognitive performance in individuals receiving ART medications with higher CPE scores [281]. In some cases, participants required more than 3 antiretrovirals to treat HIV in the CNS. Letendre et al. demonstrated improvements in cognition over a 15-week period in pa‐ tients beginning ART with higher CPE ART regimens [282]. Another recent investigation utilized MRS imaging to investigate the effect of different CPE ART regimens with dif‐ ferent CPE scores on changes in brain NAA metabolite levels. Over 48 weeks, HIV-posi‐ tive, ART-naïve individuals receiving the regimens with highest CPE scores displayed the highest increases in NAA levels, and showed the greatest improvement in a battery of neuropsychological tests [283]. These studies suggest that ART medications with high‐ er CNS penetrance may have a neuroprotective effect in successfully treated HIV-posi‐ tive adults. However, given the well-characterized toxicities of ART medications in the periphery, and the potential impact of related co-morbidities on CNS pathology, it may be necessary to consider adjunctive therapies to minimize the synergistic effects of ART and aging in HIV-positive individuals.

### **7. Summary**

acterized by the presence of extracellular beta amyloid (Aβ) plaque deposits, and intracellu‐ lar neurofibrillary tangles composed of hyperphosphorylated Tau [228, 233, 258, 259]. *In vitro* work involving the viral protein Tat has demonstrated the ability of this viral protein to inhibit the activity of the Aβ-degrading enzyme, Neprilysin, and the ability to bind to the receptor for advanced glycation end products, all of which may promote Aβ accumulation in the CNS. Indeed, some individuals with HAND display CSF levels of Aβ42 comparable to those observed in AD patients [228, 260, 261]. However, a recent report utilizing the amy‐ loid-binding, carbon 11-labeled Pittsburgh compound B (11C-PiB) and PET imaging found that irrespective of neurocognitive impairment, HIV-positive individuals showed no in‐ crease in 11C-PiB levels, highlighting a potential key difference between Aβ metabolism in

Among the studies underlining the similarities between HAND and AD, Esiri *et al.* were the first to report a predisposition to plaque formation in the brains of pre-ART HIV-positive individuals [262]. Such pathological changes have been observed in HIV-positive patients despite successful virologic control with ART, suggesting that antiretrovirals either cannot achieve therapeutic concentrations within the brain parenchyma, allowing for ongoing viral replication and neuroinflammation, or may have toxic effects that could facilitate neurode‐ generation [263, 264]. To address the latter concern, several reports investigated differences in either phospho-tau or beta amyloid levels in ART-naïve vs. ART-treated individuals. Two groups independently reported elevated Aβ deposition in the hippocampus of ART-treated individuals compared to pre-ART patients, yet Anthony *et al*. reported only increased hy‐ perphosphorylated tau, but no Aβ deposition in the hippocampus and entorhinal cortex of HIV-positive individuals [257, 259, 265]. To date, no group has reported concomitant phos‐ pho-tau and Aβ plaque depositions in the same brain samples from HIV-positive cohorts. Differences in patient age and ART-regimens, as well as the antibodies used to detect Aβ

Importantly, the aforementioned studies highlight the potentially under-appreciated con‐ cern of antiretroviral-associated toxicity and its effect on neuropsychological outcomes in long-term ART-treated patients. As described earlier, ART drugs have been linked to wide-ranging, peripheral metabolic and neural disturbances that could themselves influ‐ ence the progression of HAND and foretell potential mechanisms of toxicity in the CNS [246, 266-276]. While CNS effects of ART are poorly understood, Schweinsburg et al. dem‐ onstrated an association between NRTIs and decreased levels of frontal white matter NAA, which they attributed to NRTI-mediated mitochondrial dysfunction and depletion of cellular respiration [268]. Confounding the issue of direct CNS toxicity of antiretroviral medications is the variability in BBB permeability amongst different drug classes as deter‐ mined by various physicochemical properties such as plasma protein binding, lipophilici‐

Although it is a widely held that ART regimens with higher CNS penetrance generally confer greater neuropsychological outcomes in HIV-positive individuals, numerous clini‐ cal studies have suggested these regimens may negatively impact cognition. In a pro‐ spective study, Marra et al. found a significant association between highly CNS-

HAND vs. AD despite some overlapping pathological features [258].

may account for the varied outcomes of these reports.

ty, and molecular size.

182 Current Perspectives in HIV Infection

The advent of ART has profoundly changed the landscape of disease; however, neurocogni‐ tive impairments continue to be debilitating to patients with the expected life expectancy closer to that of the uninfected population. A better understanding and appreciation of the confounding factors has become more acute as the recent focus in the race to cure AIDS has shifted towards the eradication of latent viral reservoirs, including those in the CNS. It is im‐ perative to anticipate and control the immune responses due to viral reactivation, the poten‐ tial neurotoxicities of viral proteins in the brain parenchyma when latent viral progeny is activated, and the oxidative damage that may be precipitated by viral particles and the acti‐ vated immune cells. These factors will be even more crucial to control in the aging brain with limited cognitive reserves.

### **Author details**

Jennifer M. King, Brigid K. Jensen, Patrick J. Gannon and Cagla Akay\*

\*Address all correspondence to<EMAIL_ADDRESS>
Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, USA

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Philadelphia, USA

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**Section 4**

**Manifestations of HIV Infection**