Glutathione in HIV-Associated Neurocognitive Disorders.

A large portion of patients with Human Immunodeficiency Virus (HIV) have neurologic sequelae. Those with better-controlled HIV via antiretroviral therapies generally have less severe neurologic symptoms. However, for many patients, antiretrovirals do not adequately resolve symptoms. Since much of the pathogenesis of HIV/AIDS (Autoimmune Deficiency Syndrome) involves oxidative stress either directly, through viral interaction, or indirectly, through inflammatory mechanisms, we have reviewed relevant trials of glutathione supplementation in each of the HIV-associated neurocognitive diseases and have found disease-specific results. For diseases for which trials have not been completed, predicted responses to glutathione supplementation are made based on relevant mechanisms seen in the literature. It is not sufficient to conclude that all HIV-associated neurocognitive disorders (HAND) will benefit from the antioxidant effects of glutathione supplementation. The potential effects of glutathione supplementation in patients with HAND are likely to differ based on the specific HIV-associated neurocognitive disease.

HIV-related cognitive disorders in children in Kinshasa (Democratic Republic of Congo).

OBJECTIVES: HIV-infected individuals are at increased risk of neurocognitive disorders compared with the general population. Studies suggest that, despite the combination of antiretroviral drugs, HIV infection causes immune activation leading to significant neural damage; however, there is little data on HIV-infected young people in our country. METHODOLOGY: This is a comparative cross-sectional study conducted between November 2020 and March 2021 on two hundred and sixteen children aged 6-15 years, including 106 HIV-positive children and 108 healthy children. Cognitive performance was assessed using the Differential Ability Scale Second Edition (DAS-II). RESULTS: HIV-infected children showed lower cognitive scores than control children in the subtest group of verbal ability (82.1% vs. 43.5%); non-verbal ability (84.9% vs. 45.4%); spatial ability (79.2% vs. 21.3%) and generall conceptual ability (GCA) (88.7% vs. 43.5%). The children in the control group had significantly higher ability scores in the diagnostic tests and in school achievement, and the difference was statistically significant. CONCLUSION: Cognitive impairment remains a significant complication in HIV-positive children, as suggested by low cognitive scores in more than half of our participants. This is an unresolved issue with implications for survival, quality of life and daily functioning in these children. It is important that clinicians are able to identify and manage these cognitive deficits.

Behavioral Evidence for a Tau and HIV-gp120 Interaction.

Despite successful virologic control with combination antiretroviral therapy (cART), about half of people living with the human immunodeficiency virus-1 (HIV) develop an HIV-associated neurocognitive disorder (HAND). It is estimated that 50% of individuals who are HIV-positive in the United States are aged 50 years or older. Therefore, a new challenge looms as individuals living with HIV increase in age. There is concern that Alzheimer's disease (AD) may become prevalent with an earlier onset of cognitive decline in people living with HIV (PLWH). Clinical data studies reported the presence of AD biomarkers in PLWH. However, the functional significance of the interaction between HIV or HIV viral proteins and AD biomarkers is still not well studied. The main goal of the present study is to address this knowledge gap by determining if the HIV envelope glycoprotein 120 (HIV-gp120) can affect the cognitive functions in the Tau mouse AD model. Male Tau and age-matched, wild-type (WT) control mice were treated intracerebroventricularly (ICV) with HIV-gp120. The animals were evaluated for cognitive function using a Y-maze. We found that HIV-gp120 altered cognitive function in Tau mice. Notably, HIV-gp120 was able to promote a cognitive decline in transgenic Tau (P301L) mice compared to the control (HIV-gp120 and WT). We provide the first in vivo evidence of a cognitive interaction between an HIV viral protein and Tau mice.

HIV-associated neurocognitive disorders at Moi teaching and referral hospital, Eldoret, Kenya.

BACKGROUND: Human Immunodeficiency Virus (HIV) infection causes a myriad of neurological complications including cognitive deficits referred to as HIV-Associated Neurocognitive Disorders (HAND). With the introduction of combination antiretroviral therapy, there has been an epidemiological shift in cognitive disorders with a decline in the more severe HIV-Associated Dementia (HAD) to an increase in the less severe HAND: Asymptomatic Neurocognitive Impairment (ANI) and HIV-associated Mild Neurocognitive Disorder (MND). Central Nervous System (CNS) involvement in HIV interferes with cognitively demanding activities of daily living and hence a worse quality of life. Early diagnosis is delayed until symptoms are overt. METHODS: We conducted a cross sectional analytical study of HIV infected persons on antiretroviral therapy attending HIV clinic. A systematic random sampling was done to select 360 patients. An interviewer administered structured questionnaire was used to collect socio-demographic data while the CD4 count and viral load were retrieved from the Academic Model Providing Access to Healthcare (AMPATH) database. Pearson's Chi Square test was used to compare proportions while independent sample t- test was used to compare continuous variables between the patients diagnosed with HAND and those without HAND. Logistic regression model was used to assess the factors associated with HAND. RESULTS: The mean age of the study participants was 40.2 years. The overall prevalence of HAND was (81.1%) N = 292. Mild HAND (ANI and MND) was present (78.6%) N = 283, Severe HAND (HAD) (2.5%) N = 9. The factors associated with HAND were older age OR: 1.06 (95% CI: 1.03, 1.10), male gender OR: 0.48 (95% CI: 0.24, 0.97), Advanced WHO clinical staging OR: 2.45 (95% CI: 1.20, 5.01) and a higher level of education; secondary/tertiary OR: 0.16 (95% CI: 0.07, 0.38); 0.11 (95% CI: 0.04, 0.35). CONCLUSION: The prevalence of HAND in this study population was found to be high (81.1%). Older age and advanced WHO clinical staging were associated with an increased risk of hand while higher level of education and male gender were protective.

Brain PET Imaging: Value for Understanding the Pathophysiology of HIV-associated Neurocognitive Disorder (HAND).

PURPOSE OF REVIEW: The purpose of this review is to summarize recent developments in PET imaging of neuropathologies underlying HIV-associated neurocognitive dysfunction (HAND). We concentrate on the recent post antiretroviral era (ART), highlighting clinical and preclinical brain PET imaging studies. RECENT FINDINGS: In the post ART era, PET imaging has been used to better understand perturbations of glucose metabolism, neuroinflammation, the function of neurotransmitter systems, and amyloid/tau protein deposition in the brains of HIV-infected patients and HIV animal models. Preclinical and translational findings from those studies shed a new light on the complex pathophysiology underlying HAND. The molecular imaging capabilities of PET in neuro-HIV are great complements for structural imaging modalities. Recent and future PET imaging studies can improve our understanding of neuro-HIV and provide biomarkers of disease progress that could be used as surrogate endpoints in the evaluation of the effectiveness of potential neuroprotective therapies.

Prediction of HIV-associated neurocognitive disorder (HAND) from three genetic features of envelope gp120 glycoprotein.

BACKGROUND: HIV-associated neurocognitive disorder (HAND) remains an important and yet potentially underdiagnosed manifestation despite the fact that the modern combination antiretroviral therapy (cART) has achieved effective viral suppression and greatly reduced the incidence of life-threatening events. Although HIV neurotoxicity is thought to play a central role, the potential of viral genetic signature as diagnostic and/or prognostic biomarker has yet to be fully explored. RESULTS: Using a manually curated sequence metadataset (80 specimens, 2349 sequences), we demonstrated that only three genetic features are sufficient to predict HAND status regardless of sampling tissues; the accuracy reached 100 and 94% in the hold-out testing subdataset and the entire dataset, respectively. The three genetic features stratified HAND into four distinct clusters. Extrapolating the classification to the 1619 specimens registered in the Los Alamos HIV Sequence Database, the global HAND prevalence was estimated to be 46%, with significant regional variations (30-71%). The R package HANDPrediction was implemented to ensure public availability of key codes. CONCLUSIONS: Our analysis revealed three amino acid positions in gp120 glycoprotein, providing the basis of the development of novel cART regimens specifically optimized for HAND-associated quasispecies. Moreover, the classifier can readily be translated into a diagnostic biomarker, warranting prospective validation.

Molecular Signatures of HIV-1 Envelope Associated with HIV-Associated Neurocognitive Disorders.

PURPOSE OF REVIEW: The HIV-1 envelope gene (env) has been an intense focus of investigation in the search for genetic determinants of viral entry and persistence in the central nervous system (CNS). RECENT FINDINGS: Molecular signatures of CNS-derived HIV-1 env reflect the immune characteristics and cellular constraints of the CNS compartment. Although more readily found in those with advanced HIV-1 and HIV-associated neurocognitive disorders (HAND), molecular signatures distinguishing CNS-derived quasispecies can be identified early in HIV-1 infection, in the presence or absence of combination antiretroviral therapy (cART), and are dynamic. Amino acid signatures of CNS-compartmentalization and HAND have been identified across populations. While some significant overlap exists, none are universal. Detailed analyses of CNS-derived HIV-1 env have allowed researchers to identify a number of molecular determinants associated with neuroadaptation. Future investigations using comprehensive cohorts and longitudinal databases have the greatest potential for the identification of robust, validated signatures of HAND in the cART era.

Does the informal caregiver notice HIV associated mild cognitive impairment in people living with HIV?

HIV associated minor neurocognitive disorder (MND) may be difficult to identify as key signs and symptoms (S & S) may be due to other clinical conditions. Using a self-assessment booklet "HIV and associated MND" we recruited 123 people living with HIV (PLHIV) from three sites: two hospital HIV clinics and a sexual health clinic in Sydney, Australia. Patients may down play S & S. Caregivers may notice subtle changes. By including caregivers, we aimed to find whether the caregivers noticed S & S undetected by the PLHIV. This is a sub-study of a prospective observational multi-site study aimed to validate the usefulness of a patient self-assessment tool (HIV-associated MND booklet). Using the booklet, participants and their caregivers subsequently identified S & S of MND. Sixty-four per cent (79) did not nominate a caregiver to be contacted. Participants from 2 sites 44 (36%) nominated caregivers to be contacted. Twenty-five caregivers identified more than four S & S of MND. S & S reported most by caregivers related to participants being more tired at the end of the day (76%). Participants agreed (77%). Participants also reported that they found it more difficult to remember things such as taking medications or attending medical appointments (67%). The most agreed on symptom was the requirement for increased concentration to get the same things done (Kappa P 0.599 <0.001 and McNemar 0.289). For each question at least one caregiver identified a symptom when the PLHIV did not. Caregivers were more likely than participants to report irritability and communication difficulties. It is important to include caregivers when investigating PLHIV for MND, as caregivers may validate the experience of the patient, and may also be uniquely placed to identify S & S not otherwise identified.

HIV-associated neurocognitive disorder in HIV-infected Koreans: the Korean NeuroAIDS Project.

OBJECTIVES: HIV-associated neurocognitive disorder (HAND) is an independent predictor of early mortality and is associated with many difficulties in activities of daily living. We sought to determine the prevalence of and risk factors for HAND in HIV-infected Koreans. In addition, we investigated the performance of screening tools and components of neuropsychological (NP) tests for diagnosing HAND. METHODS: HIV-infected patients were enrolled consecutively from two different urban teaching hospitals in Seoul, South Korea between March 2012 and September 2012. Participants completed a detailed NP assessment of six cognitive domains commonly affected by HIV. The Frascati criteria were used for diagnosing HAND. Four key questions, the International HIV Dementia Scale (IHDS) and Montreal Cognitive Assessment (MoCA)-K were also assessed as potential tools for screening for HAND. RESULTS: Among the 194 participants, the prevalence of HAND was 26.3%. Asymptomatic neurocognitive impairment and minor neurocognitive disorder accounted for 52.9 and 47.1% of the patients with HAND, respectively. In multivariate analysis, haemoglobin (Hb) level ≤ 13 g/dL (P = 0.046) and current use of a protease inhibitor-based regimen (P = 0.031) were independent risk factors for HAND. The sensitivity and specificity of the IHDS were 72.6 and 60.8%, and those of MoCA-K were 52.9 and 73.4%, respectively. The IHDS (P < 0.001) and MoCA-K (P < 0.001) were both useful for screening for HAND. Among NP tests, the sensitivity and specificity of the Grooved Pegboard Test were 90.2 and 72.0%, and those of the Wisconsin Card Sorting Test were 61.2 and 84.4%, respectively. CONCLUSIONS: HAND is a prevalent comorbidity in HIV-infected Koreans. Active screening and diagnosis with effective tools, such as the IHDS, MoCA-K and Grooved Pegboard Test, could be used to identify this important complication.

Cognitive Impairment in People Living with HIV and the Impact of Mood: Results from a Cross-Sectional Study.

Background: Human Immunodeficiency Virus (HIV) infection represents a significant public health concern and, consequently, the incidence of HIV-Associated Neurocognitive Disorder (HAND) has grown over the years. The present study aims to assess HAND with the Montreal Cognitive Assessment (MoCA) in People Living With HIV/AIDS (PLWHA) to find significant associations with cognitive impairment. Methods: The study included 210 PLWHA, aged from 30 to 81 years, of whom, 137 (65.2%) were males. They were assessed at the Immunology Service of the University Hospital of Monserrato, Cagliari, Italy, between November 2022 and April 2023. Results: The sample showed an overall optimal response to antiretroviral therapy, as shown by the excellent levels of CD4+ lymphocytes and HIV RNA copies. A sum of 115 subjects (54.8%) were considered cognitively impaired and the multivariate analysis demonstrated that it was independently associated with duration of infection (OR: 0.96), age (OR: 1.12), alanine aminotransferase (ALT) (OR: 1.02), and depression (OR: 1.33). By dichotomizing the variables, the significance of the association was confirmed for age (65-year threshold) (χ2: 5.142, p = 0.0233) and depression (χ2: 7.834, p = 0.0051). Conclusions: Our study demonstrates that it is hard to find both statistically and clinically significantly associated variables with cognitive impairment in PLWHA, and that the strongest independent association is with depressed mood.

Autophagy Deregulation in HIV-1-Infected Cells Increases Extracellular Vesicle Release and Contributes to TLR3 Activation.

Human immunodeficiency virus type 1 (HIV-1) infection can result in HIV-associated neurocognitive disorder (HAND), a spectrum of disorders characterized by neurological impairment and chronic inflammation. Combined antiretroviral therapy (cART) has elicited a marked reduction in the number of individuals diagnosed with HAND. However, there is continual, low-level viral transcription due to the lack of a transcription inhibitor in cART regimens, which results in the accumulation of viral products within infected cells. To alleviate stress, infected cells can release accumulated products, such as TAR RNA, in extracellular vesicles (EVs), which can contribute to pathogenesis in neighboring cells. Here, we demonstrate that cART can contribute to autophagy deregulation in infected cells and increased EV release. The impact of EVs released from HIV-1 infected myeloid cells was found to contribute to CNS pathogenesis, potentially through EV-mediated TLR3 (Toll-like receptor 3) activation, suggesting the need for therapeutics to target this mechanism. Three HIV-1 TAR-binding compounds, 103FA, 111FA, and Ral HCl, were identified that recognize TAR RNA and reduce TLR activation. These data indicate that packaging of viral products into EVs, potentially exacerbated by antiretroviral therapeutics, may induce chronic inflammation of the CNS observed in cART-treated patients, and novel therapeutic strategies may be exploited to mitigate morbidity.

1H-NMR metabolomics investigation of CSF from children with HIV reveals altered neuroenergetics due to persistent immune activation.

Background: HIV can invade the central nervous system (CNS) early during infection, invading perivascular macrophages and microglia, which, in turn, release viral particles and immune mediators that dysregulate all brain cell types. Consequently, children living with HIV often present with neurodevelopmental delays. Methods: In this study, we used proton nuclear magnetic resonance (1H-NMR) spectroscopy to analyze the neurometabolic profile of HIV infection using cerebrospinal fluid samples obtained from 17 HIV+ and 50 HIV- South African children. Results: Nine metabolites, including glucose, lactate, glutamine, 1,2-propanediol, acetone, 3-hydroxybutyrate, acetoacetate, 2-hydroxybutyrate, and myo-inositol, showed significant differences when comparing children infected with HIV and those uninfected. These metabolites may be associated with activation of the innate immune response and disruption of neuroenergetics pathways. Conclusion: These results elucidate the neurometabolic state of children infected with HIV, including upregulation of glycolysis, dysregulation of ketone body metabolism, and elevated reactive oxygen species production. Furthermore, we hypothesize that neuroinflammation alters astrocyte-neuron communication, lowering neuronal activity in children infected with HIV, which may contribute to the neurodevelopmental delay often observed in this population.

Effects of Morphine on Gp120-induced Neuroinflammation Under Immunocompetent Vs. Immunodeficient Conditions.

HIV-associated neurocognitive disorder (HAND) is a common complication of HIV infection, whose development is known to be facilitated by inflammation and exacerbated by morphine. Previously, using the gp120 transgenic (tg) mouse model in combination with LP-BM5 (a murine retrovirus that can cause systemic immunodeficiency in susceptible mouse strains) we demonstrated differential gp120-associated central nervous system (CNS) neuroinflammatory responses under immunocompetent (-LP-BM5) vs. immunocompromised (+LP-BM5) conditions. Here, we further investigated the effects of morphine on gp120-associated neuroinflammatory response within the hippocampus under differential immune status. First, we confirmed that morphine treatment (2 × 25 mg pellets) did not significantly affect the development of immunodeficiency induced by LP-BM5 and all brain regions examined (hippocampus, striatum, and frontal lobe) had detectable LP-BM5 viral gag genes. Morphine notably reduced the performance of gp120tg+ mice in the alteration T-maze assay when 2-minute retention was used, regardless of LP-BM5 treatment. Morphine further enhanced GFAP expression in gp120tg+ mice regardless of host immune status, while promoted CD11b expression only in immunocompetent mice, regardless of gp120tg expression. In immunocompetent gp120tg+ mice, morphine increased the RNA expression of CCL2, CCL5, CXCL10, IL-12p40, and IFNß; while under the immunodeficient condition, morphine downregulated the expression of CCL2, CCL5, CXCL10, IL-12p40, and IL-1ß. Further, expression of TNFα and IFNγ were enhanced by morphine regardless of host immune status. Altogether, our results suggest that the effects of morphine are complex and dependent on the immune status of the host, and host immune status-specific, targeted anti-neuroinflammatory strategies are required for effective treatment of HAND.

Human Immunodeficiency Virus: Opportunistic Infections and Beyond.

Human immunodeficiency virus (HIV) infection causes substantial morbidity and mortality worldwide. Although antiretroviral therapy (ART) has changed the epidemiology of HIV in the last 20 years with increased survival and decreasing incidence of opportunistic infections (OI), CNS OI remain a major cause of morbidity. Improved survival has also increased neurological presentations due to co morbid conditions, treatment related side effects and inflammatory syndromes. Being familiar with the imaging findings, the impact of ART and interpretation of imaging in the context of clinical and laboratory findings is important for radiologists as well as clinicians in the management of HIV-infected patients.

The role of CCR5 in HIV-associated neurocognitive disorders.

While combination antiretroviral therapy (cART) has successfully increased the lifespan of individuals infected with HIV, a significant portion of this population remains affected by HIV-associated neurocognitive disorder (HAND). C-C chemokine receptor 5 (CCR5) has been well studied in immune response and as a co-receptor for HIV infection. HIV-infected (HIV+) patients experienced mild to significant amelioration of cognitive function when treated with different CCR5 antagonists, including maraviroc and cenicriviroc. Consistent with clinical results, Ccr5 knockout or knockdown rescued cognitive deficits in HIV animal models, with mechanisms of reduced microgliosis and neuroinflammation. Pharmacologic inhibition of CCR5 directly improved cerebral and hippocampal neuronal plasticity and cognitive function. By summarizing the animal and human studies of CCR5 in HIV-associated cognitive deficits, this review aims to provide an overview of the mechanistic role of CCR5 in HAND pathophysiology. This review also discusses the addition of CCR5 antagonists, such as maraviroc, to cART for targeted prevention and treatment of cognitive impairments in patients infected with HIV.

Application of Diffusion Tensor Imaging (DTI) in the Diagnosis of HIV-Associated Neurocognitive Disorder (HAND): A Meta-Analysis and a System Review.

Background: The patients with HIV-associated neurocognitive disorder (HAND) are often accompanied by white matter structure damage. Diffusion tensor imaging (DTI) is an important tool to detect white matter structural damage. However, the changes in DTI values reported in many studies are diverse in different white matter fiber tracts and brain regions. Purpose: Our research is dedicated to evaluating the consistency and difference of the correlation between HAND and DTI measures in different studies. Additionally, the value of DTI in HAND evaluation is used to obtain consensus and independent conclusions between studies. Methods: We searched PubMed and Web of Science to collect relevant studies using DTI for the diagnosis of HAND. After screening and evaluating the search results, meta-analysis is used for quantitative research on data. Articles that cannot collect data but meet the research relevance will be subjected to a system review. Results: The meta-analysis shows that the HAND group has lower fractional anisotropy (standardized mean difference = -0.57 p < 0.0001) and higher mean diffusivity (standardized mean difference = 0.04 p < 0.0001) than the healthy control group in corpus callosum. In other white matter fibers, we found similar changes in fractional anisotropy (standardized mean difference = -1.18 p < 0.0001) and mean diffusivity (standardized mean difference = 0.69 p < 0.0001). However, the heterogeneity (represented by I2) between the studies is high (in corpus callosum 94, 88%, in other matter fibers 95, 81%). After subgroup analysis, the heterogeneity is obtained as 19.5, 40.7% (FA, MD in corpus callosum) and 0, 0% (FA, MD among other white matter fibers). Conclusion: The changes in white matter fibers in patients with HAND are statistically significant at the observation level of DTI compared with healthy people. The differences between the studies are mainly derived from demographics, start and maintenance time of antiretroviral therapy, differences in nadir CD4+T cells, and the use of different neurocognitive function scales. As an effective method to detect the changes in white matter fibers, DTI is of great significance for the diagnosis of HAND, but there are still some shortcomings. In the absence of neurocognitive function scales, independent diagnosis remains difficult.Systematic Review Registration: https://inplasy.com/inplasy-2021-10-0079/.

HIV-Associated Neurocognitive Disorder (HAND): Relative Risk Factors.

This chapter will address the issue of risk for HIV-associated neurocognitive disorder (HAND), focusing on HIV-associated dementia (HAD), among persons living with HIV in relationship to the risk for other dementias. Advances in effective antiretroviral therapy (ART) have led to an increase in the prevalence of older persons surviving with HIV - in addition to older persons who become infected by HIV later in life. Hence, HIV is no longer a disease of younger persons, and additional attention has been brought to bear against the plight of older persons living with HIV - not only as it pertains to treatment but also to prevention. The additional risk caused by aging among older persons living with HIV is complex to asses, and HIV infection is a research area that requires a robust approach to multiple other factors causing neurocognitive impairment with older age. The long-term and potentially neurotoxic exposure to ART and the deleterious consequences of chronic infection with HIV and its associated neuro-inflammation have been described for health. This aids in the understanding of dementia risk factors in this patient population, but the comorbidities (HIV- and non-HIV-associated) occurring among older persons living with HIV must also be addressed to properly assess the overall impact on dementia risk in this group. This need also warrants our examination of the risk factors for other dementias (and comorbid dementias) in persons living with HIV versus the general population through the assessment and quantification of modifiable and non-modifiable risk factors identified as major contributors toward dementia.

Neurocognitive Disorder and Emotional Symptoms in HIV+ Brazilian Elderly: Influence of Gender, Income, Diet, and Sleep.

The purpose of this study was to identify factors associated with HIV-associated neurocognitive disorder (HAND) and symptoms of anxiety and depression in HIV+ Brazilian elderly on antiretroviral treatments. The study included 112 HIV+ elderly who completed a questionnaire, tests for cognitive screening, attention, problem solving, processing speed, visual perception, memory, and anxiety and depression scales. The results showed presence of HAND (89.3%), pathological anxiety (48.2%) and depression (58%) in the sample. Higher income was a protective factor for HAND (OR = 0.33). Waking up well-rested (OR = 0.63) and better diet quality (OR = 0.62) reduced the chance of pathological anxiety. Higher education (OR = 0.74) and waking up well-rested (OR = 0.61) reduced the chance of depression. Being female (OR = 7.73) increased the chance of depression. It can be concluded that it is important to evaluate cognitive and emotional aspects of HIV+ elders and to consider social and educational status, diet, and sleep in interventions, paying special attention to elderly women.

Characterization of HIV-Associated Neurocognitive Impairment in Middle-Aged and Older Persons With HIV in Lima, Peru.

Background: With widespread use of antiretroviral medications, people living with HIV (PWH) are living longer worldwide, increasing their risk of developing neurocognitive impairment (NCI). The proportion of Peruvians over age 60 is expected to increase to 25% of the population by 2050, including PWH. Therefore, the problem of aging and NCI, especially in the setting of HIV infection, is uniquely pressing. We sought to study the rates of and risk factors associated with NCI among middle-aged and older PWH in Lima, Peru. Materials and Methods: Sociodemographic, medical (infectious and non-infectious), and psychiatric comorbidity and laboratory data were collected. We administered a brief neuropsychological battery evaluating seven cognitive domains affected in HIV-associated NCI and a depression screening. Cognitive test raw scores were converted to T-scores that were demographically adjusted. Descriptive statistics were performed together with regression (unadjusted and adjusted) analyses to determine potential risk factors for NCI among PWH. Results: This was a cross-sectional study in which 144 PWH aged ≥40 years attending a large HIV clinic in Lima, Peru, were recruited from September 2019 to March 2020. Mean age was 51.6 ± 7.7 years, and mean years of education were 14.0 ± 3.1 with 15% females. Median [interquartile range (IQR)] current CD4 and nadir CD4 were 554 (371, 723) and 179 (83, 291), respectively, and 10% currently had AIDS. The prevalence of NCI was 28.5%, and many demonstrated difficulty with attention and working memory (70%). One-quarter of PWH had mild depression or worse on Patient Health Questionnaire 9 (PHQ-9 ≥ 5). In bivariate analyses, neither a depression history nor a higher PHQ-9 score correlated with NCI. No other non-communicable medical or psychiatric comorbidity nor HIV characteristic was predictive of NCI. Having a positive lifetime history of hepatitis B infection, pulmonary tuberculosis, or syphilis increased risk of NCI (PR 1.72; 95% CI 1.04-2.86) in unadjusted analyses, but not in adjusted analyses. Conclusions: NCI among older Peruvians with HIV was found to be highly prevalent with levels consistent with prior reports of HIV-associated NCI worldwide. Common latent HIV-associated co-infections, including latent syphilis, hepatitis B infection, or pulmonary tuberculosis, may increase the risk of NCI among middle-aged and older PWH in Peru.