Immunometabolic Reprogramming in Response to HIV Infection Is Not Fully Normalized by Suppressive Antiretroviral Therapy.

BACKGROUND: HIV infection results in immunometabolic reprogramming. While we are beginning to understand how this metabolic reprogramming regulates the immune response to HIV infection, we do not currently understand the impact of ART on immunometabolism in people with HIV (PWH). METHODS: Serum obtained from HIV-infected (n = 278) and geographically matched HIV seronegative control subjects (n = 300) from Rakai Uganda were used in this study. Serum was obtained before and ~2 years following the initiation of ART from HIV-infected individuals. We conducted metabolomics profiling of the serum and focused our analysis on metabolic substrates and pathways assocaited with immunometabolism. RESULTS: HIV infection was associated with metabolic adaptations that implicated hyperactive glycolysis, enhanced formation of lactate, increased activity of the pentose phosphate pathway (PPP), decreased ß-oxidation of long-chain fatty acids, increased utilization of medium-chain fatty acids, and enhanced amino acid catabolism. Following ART, serum levels of ketone bodies, carnitine, and amino acid metabolism were normalized, however glycolysis, PPP, lactate production, and ß-oxidation of long-chain fatty acids remained abnormal. CONCLUSION: Our findings suggest that HIV infection is associated with an increased immunometabolic demand that is satisfied through the utilization of alternative energetic substrates, including fatty acids and amino acids. ART alone was insufficient to completely restore this metabolic reprogramming to HIV infection, suggesting that a sustained impairment of immunometabolism may contribute to chronic immune activation and comorbid conditions in virally suppressed PWH.

Neuropathic pain correlates with worsening cognition in people with human immunodeficiency virus.

Neuropathic pain and cognitive impairment are among the HIV-related conditions that have most stubbornly resisted amelioration by virally suppressive antiretroviral therapy. Overlaps between the regional brain substrates and mechanisms of neuropathic pain and cognitive disorders are increasingly recognized, yet no studies have examined the longitudinal relationship between these two disorders. Participants in the prospective, observational CNS HIV AntiRetroviral Therapy Effects Research (CHARTER) cohort underwent standardized clinical evaluations for clinical examination findings of distal sensory polyneuropathy, reporting distal neuropathic pain and neurocognitive performance at study entry (baseline) and an average of 12 years later. Change in neuropathic pain and neuropathy status from baseline to follow-up was by self-report and repeat examination, and change in neurocognitive performance was assessed using a previously published summary regression-based change score. Relationships between incident or worsened neuropathic pain and neurocognitive change were evaluated using uni- and multivariable regressions, including age at baseline and other relevant covariates. Participants were 385 people with HIV, 91 (23.6%) females, mean ± standard deviation (SD) age at baseline 43.5 (7.81) years, ethnicity 44.9% African American, 10.6% Hispanic, 42.6% non-Hispanic white and 1.82% other. Baseline median (interquartile range) nadir CD4 was 175 (34 309) cells/µl and current CD4 was 454 (279 639). Incident or worsened distal neuropathic pain occurred in 98 (25.5%) over the follow-up period. People with HIV with incident or worsened distal neuropathic pain had significantly worsened neurocognitive performance at follow-up compared to those without incident or worsened distal neuropathic pain (summary regression-based change score mean ± SD -0.408 ± 0.700 versus -0.228 ± 0.613; P = 0.0158). This effect remained significant when considering viral suppression on antiretroviral therapy, incident diabetes and other covariates as predictors. Overall neurocognitive change related to neuropathic pain was driven primarily by changes in the domains of executive function and speed of information processing. Those with incident distal neuropathy signs did not have neurocognitive worsening, nor did individuals who used opioid analgesics or other pain-modulating drugs such as amitriptyline. Worsened neurocognitive performance in people with HIV was associated with worsened neuropathic pain but not with changes in physical signs of neuropathy, and this was not attributable to therapies for pain or depression or to differences in viral suppression. This finding implies that incident or worsened pain may signal increased risk for neurocognitive impairment, and deserves more investigation, particularly if better pain management might stabilize or improve neurocognitive performance.

Legacy effect on neuropsychological function in HIV-infected men on combination antiretroviral therapy.

OBJECTIVE: To determine whether combination antiretroviral therapy (cART) initiation alters the trajectory of cognitive performance in HIV+ men, and whether cognition prior to cART predicts postcART function. DESIGN: Longitudinal cohort study. Multicenter AIDS Cohort Study. METHODS: From an initial set of 3701 men with complete neuropsychological data, men with HIV infection were initially matched with men without infection on cognitive status, race, age, and timeline (T0 defined as cART initiation). Propensity score matching was then used to match pairs on depressive symptoms at T0, education, T0 cognitive scores, and recruitment cohort. There were 506 matched pairs of infected and uninfected men in the final analysis. Mixed effect models were constructed to analyze the trajectories of cognitive functions and to test the effect of cART and HIV on cognitive functions over time. RESULTS: Performance in each cognitive domain did not change following the initiation of cART among HIV-infected men with prior impairment and was comparable to the performance of their matched uninfected men. However, among the infected men who were unimpaired prior to cART, motor function declined significantly faster than it did for uninfected controls. CONCLUSIONS: Cognitive dysfunction is persistent in HIV-infected men and cART does not alter the trajectory of cognitive decline in men who were impaired prior to effective therapy. This suggests that current cognitive impairment in HIV+ men results from a legacy effect, and from factors other than the HIV itself. Furthermore, motor skills may be uniquely vulnerable to the virus, cART, or age-related co-morbidities.

Tablet-Based Cognitive Impairment Screening for Adults With HIV Seeking Clinical Care: Observational Study.

BACKGROUND: Neurological complications including cognitive impairment persist among people with HIV on antiretrovirals; however, cognitive screening is not routinely conducted in HIV clinics. OBJECTIVE: Our objective for this study was 3-fold: (1) to determine the feasibility of implementing an iPad-based cognitive impairment screener among adults seeking HIV care, (2) to examine the psychometric properties of the tool, and (3) to examine predictors of cognitive impairment using the tool. METHODS: A convenience sample of participants completed Brain Baseline Assessment of Cognition and Everyday Functioning (BRACE), which included (1) Trail Making Test Part A, measuring psychomotor speed; (2) Trail Making Test Part B, measuring set-shifting; (3) Stroop Color, measuring processing speed; and (4) the Visual-Spatial Learning Test. Global neuropsychological function was estimated as mean T score performance on the 4 outcomes. Impairment on each test or for the global mean was defined as a T score ≤40. Subgroups of participants repeated the tests 4 weeks or >6 months after completing the first test to evaluate intraperson test-retest reliability and practice effects (improvements in performance due to repeated test exposure). An additional subgroup completed a lengthier cognitive battery concurrently to assess validity. Relevant factors were abstracted from electronic medical records to examine predictors of global neuropsychological function. RESULTS: The study population consisted of 404 people with HIV (age: mean 53.6 years; race: 332/404, 82% Black; 34/404, 8% White, 10/404, 2% American Indian/Alaskan Native; 28/404, 7% other and 230/404, 58% male; 174/404, 42% female) of whom 99% (402/404) were on antiretroviral therapy. Participants completed BRACE in a mean of 12 minutes (SD 3.2), and impairment was demonstrated by 34% (136/404) on Trail Making Test A, 44% (177/404) on Trail Making Test B, 40% (161/404) on Stroop Color, and 17% (67/404) on Visual-Spatial Learning Test. Global impairment was demonstrated by 103 out of 404 (25%). Test-retest reliability for the subset of participants (n=26) repeating the measure at 4 weeks was 0.81 and for the subset of participants (n=67) repeating the measure almost 1 year later (days: median 294, IQR 50) was 0.63. There were no significant practice effects at either time point (P=.20 and P=.68, respectively). With respect for validity, the correlation between global impairment on the lengthier cognitive battery and BRACE was 0.63 (n=61; P<.001), with 84% sensitivity and 94% specificity to impairment on the lengthier cognitive battery. CONCLUSIONS: We were able to successfully implement BRACE and estimate cognitive impairment burden in the context of routine clinic care. BRACE was also shown to have good psychometric properties. This easy-to-use tool in clinical settings may facilitate the care needs of people with HIV as cognitive impairment continues to remain a concern in people with HIV.

Baseline Neurocognitive Impairment (NCI) Is Associated With Incident Frailty but Baseline Frailty Does Not Predict Incident NCI in Older Persons With Human Immunodeficiency Virus (HIV).

BACKGROUND: Neurocognitive impairment (NCI) and frailty are more prevalent among persons with human immunodeficiency virus (HIV, PWH) compared to those without HIV. Frailty and NCI often overlap with one another. Whether frailty precedes declines in neurocognitive function among PWH or vice versa has not been well established. METHODS: AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH. Participants undergo annual assessments for NCI and frailty. ACTG A5322 participants who developed NCI as indexed by tests of impaired executive functioning and processing speed during the first 3 years were compared to persons who maintained normal cognitive function; those who demonstrated resolution of NCI were compared to those who had persistent NCI. Participants were similarly compared by frailty trajectory. We fit multinomial logistic regression models to assess associations between baseline covariates (including NCI) and frailty, and associations between baseline covariates (including frailty) and NCI. RESULTS: In total, 929 participants were included with a median age of 51 years (interquartile range [IQR] 46-56). At study entry, 16% had NCI, and 6% were frail. Over 3 years, 6% of participants developed NCI; 5% developed frailty. NCI was associated with development of frailty (odds ratio [OR] = 2.06; 95% confidence interval [CI] = .94, 4.48; P = .07). Further adjustment for confounding strengthened this association (OR = 2.79; 95% CI = 1.21, 6.43; P = .02). Baseline frailty however was not associated with NCI development. CONCLUSIONS: NCI was associated with increased risk of frailty, but frailty was not associated with development of NCI. These findings suggest that the presence of NCI in PWH should prompt monitoring for the development of frailty and interventions to prevent frailty in this population.

Improvement in depressive symptoms after antiretroviral therapy initiation in people with HIV in Rakai, Uganda.

Depression is common following HIV infection and often improves after ART initiation. We aimed to identify distinct dimensions of depression that change following ART initiation in persons with HIV (PWH) with minimal comorbidities (e.g., illicit substance use) and no psychiatric medication use. We expected that dimensional changes in improvements in depression would differ across PWH. In an observational cohort in Rakai, Uganda, 312 PWH (51% male; mean age = 35.6 years) completed the Center for Epidemiologic Studies-Depression (CES-D) scale before and up to 2 years after ART initiation. Twenty-two percent were depressed (CES-D scores ≥ 16) pre-ART that decreased to 8% after ART. All CES-D items were used in a latent class analysis to identify subgroups with similar change phenotypes. Two improvement phenotypes were identified: affective-symptom improvement (n = 58, 19%) and mixed-symptom improvement (effort, appetite, irritability; n = 41, 13%). The affect-improvement subgroup improved on the greatest proportion of symptoms (76%). A third subgroup was classified as no-symptom changes (n = 213, 68%) as they showed no difference is symptom manifestation from baseline (93% did not meet depression criteria) to post-ART. Factors associated with subgroup membership in the adjusted regression analysis included pre-ART self-reported functional capacity, CD4 count, underweight BMI, hypertension, female sex(P's < 0.05). In a subset of PWH with CSF, subgroup differences were seen on Aß-42, IL-13, and IL-12. Findings support that depression generally improves following ART initiation; however, when improvement is seen the patterns of symptom improvement differ across PWH. Further exploration of this heterogeneity and its biological underpinning is needed to evaluate potential therapeutic implications of these differences.

Assessment, prevalence, and correlates of frailty among middle-aged adults with HIV in rural Uganda.

We investigated the prevalence and risk factors for frailty among people with HIV (PWH) in rural Uganda (n = 55, 47% male, mean age 44 years). Frailty was defined according to the Fried criteria with self-reported physical activity level replacing the Minnesota Leisure Time Activity Questionnaire. Alternate classifications for physical activity utilized were the sub-Saharan Africa Activity Questionnaire and the International Physical Activity Questionnaire. Eleven participants (19%) were frail. Frail participants were older (p < 0.001), less likely to be on antiretroviral therapy (p = 0.03), and had higher rates of depression (p < .001) and HIV-associated neurocognitive disorder (p = 0.003). Agreement between physical activity measures was sub-optimal. Prevalence of frailty was high among PWH in rural Uganda, but larger sample sizes and local normative data are needed.

Longitudinal 5-year prediction of cognitive impairment among men with HIV disease.

BACKGROUND: Although combination antiretroviral therapy reduced the prevalence of HIV-associated dementia, milder syndromes persist. Our goals were to predict cognitive impairment of the Multicenter AIDS Cohort Study (MACS) participants 5 years ahead and from a large pool of factors, select the ones that mostly contributed to our predictions. DESIGN: Longitudinal, natural and treated history of HIV infection among MSM. METHODS: The MACS is a longitudinal study of the natural and treated history of HIV disease in MSM; the neuropsychological substudy aims to characterize cognitive disorders in men with HIV disease. RESULTS: We modeled on an annual basis the risk of cognitive impairment 5 years in the future. We were able to predict cognitive impairment at individual level with high precision and overperform default methods. We found that while a diagnosis of AIDS is a critical risk factor, HIV infection per se does not necessarily convey additional risk. Other infectious processes, most notably hepatitis B and C, are independently associated with increased risk of impairment. The relative importance of an AIDS diagnosis diminished across calendar time. CONCLUSION: Our prediction models are a powerful tool to help clinicians address dementia in early stages for MACS paticipants. The strongest predictors of future cognitive impairment included the presence of clinical AIDS and hepatitis B or C infection. The fact that the pattern of predictive power differs by calendar year suggests a clinically critical change to the face of the epidemic.

Paresthesia Predicts Increased Risk of Distal Neuropathic Pain in Older People with HIV-Associated Sensory Polyneuropathy.

OBJECTIVE: Distal sensory polyneuropathy (DSP) is a disabling consequence of human immunodeficiency virus (HIV), leading to poor quality of life and more frequent falls in older age. Neuropathic pain and paresthesia are prevalent symptoms; however, there are currently no known curative treatments and the longitudinal course of pain in HIV-associated DSP is poorly characterized. METHODS: This was a prospective longitudinal study of 265 people with HIV (PWH) enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study with baseline and 12-year follow-up evaluations. Since pain and paresthesia are highly correlated, statistical decomposition was used to separate the two symptoms at baseline. Multivariable logistic regression analyses of decomposed variables were used to determine the effects of neuropathy symptoms at baseline on presence and worsening of distal neuropathic pain at 12-year follow-up, adjusted for covariates. RESULTS: Mean age was 56 ± 8 years, and 21% were female at follow-up. Nearly the entire cohort (96%) was on antiretroviral therapy (ART), and 82% had suppressed (≤50 copies/mL) plasma viral loads at follow-up. Of those with pain at follow-up (n = 100), 23% had paresthesia at the initial visit. Decomposed paresthesia at baseline increased the risk of pain at follow-up (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.18, 2.07), and decomposed pain at baseline predicted a higher frequency of pain at follow-up (OR 1.96 [95% CI 1.51, 2.58]). CONCLUSIONS: Paresthesias are a clinically significant predictor of incident pain at follow-up among aging PWH with DSP. Development of new therapies to encourage neuroregeneration might take advantage of this finding to choose individuals likely to benefit from treatment preventing incident pain.

Evaluation of a screening tool for the identification of neurological disorders in rural Uganda.

BACKGROUND: Neurological disorders are common in sub-Saharan African, but accurate neuroepidemiologic data are lacking from the region. We assessed a neuroepidemiological screening tool in a rural Ugandan cohort with high HIV prevalence. METHODS: Participants were recruited from the Rakai Neurology Study in rural Rakai District, Uganda. A nurse administered the tool and a sociodemographic survey. 100 participants returned for validation examinations by a neurologist (validation cohort). The diagnostic utility and validity of the instrument were calculated and characteristics of those with and without neurological disorders compared. RESULTS: The tool was administered to 392 participants, 48% female, 33% people with HIV, average age 35.1 ± 8.5 years. 33% of the study cohort screened positive for neurologic disorders. These participants were older [mean (SD): 38.3 (9.7) vs. 33.5 (7.1) years, p < 0.001], had a lower Karnofsky score [89.8 (8.4) vs. 93.9 (7.5), p < 0.001] and had a lower body mass index [21.8 (3.3) vs. 22.8 (3.7), p = 0.007] than those who screened negative. Amongst the validation cohort, 54% had a neurological abnormality of which 46% were symptomatic. The tool was 57% sensitive and 74% specific for detecting any neurological abnormality and 80% sensitive and 69% specific for symptomatic abnormalities. CONCLUSIONS: We found a lower sensitivity and similar specificity for the screening tool compared with two previous studies. The lower validity in this study was likely due in part to the high percentage of asymptomatic neurological abnormalities detected. This screening tool will require further refinement and cultural contextualization before it can be widely implemented across new populations.

Sex-specific associations between cerebrospinal fluid inflammatory marker levels and cognitive function in antiretroviral treated people living with HIV in rural Uganda.

People with HIV (PWH) taking antiretroviral therapy (ART) have persistent cognitive impairment. The prevalence of cognitive impairment is higher in women with HIV (WWH) compared to men with HIV (MWH), possibly due to sex differences in immune function. Here we report sex differences in cerebrospinal fluid (CSF) immune markers in relation to cognitive performance. A subset of 83 PWH on ART (52% WWH; mean age = 37.6 years, SD = 7.9) from the Rakai community cohort study Cohort and Rakai Health Sciences Program supported clinics in rural Uganda completed a neuropsychological (NP) assessment and a lumbar puncture. CSF was used to measure 16 cytokines/chemokines. Individual NP test z-scores were generated based on local normative data. A series of least absolute shrinkage and selection operator (lasso) regressions examined associations between CSF inflammatory markers and NP outcomes. Overall, there were no sex differences in CSF inflammatory marker levels. However, MWH displayed more associations between inflammatory markers and cognitive performance than WWH. Among MWH, inflammatory markers were associated with a number of cognitive domains, including attention, processing speed, fluency, executive function, learning and memory. MIP-1ß, INF-γ, GM-CSF, IL-7 and IL-12p70 were associated with multiple domains. Among WWH, few inflammatory markers were associated cognition. Degree of associations between CSF inflammatory biomarkers and cognitive performance varied by sex in this young, ART-treated, Ugandan cohort. Further investigation into sex-specific inflammatory mechanisms of cognitive impairment among PWH is warranted to inform sex-specific management strategies.

Neurocognitive Complications of HIV Infection in Low-Income Countries.

There is a paucity of information on neurocognitive dysfunction in individuals with HIV in resource-limited regions, despite the fact that these areas have the greatest burden of infection. HIV-associated neurocognitive disorder (HAND) remains a common complication of HIV despite the use of effective antiretroviral therapy (ART). HAND is a major cause of morbidity of HIV+ individuals and is estimated to be the most prevalent form of neurocognitive impairment worldwide in young adults. This finding has drastic implications for the productivity and social engagement of young adults in the development of industry, education, and healthcare, which is particularly relevant in low-income countries. Building an infrastructure to examine the neurological and neuropsychological characteristics of HIV+ individuals in resource-limited settings (RLS) can advance the understanding of the unique contributing factors of HIV-1 clades in these regions of high prevalence, improve neurological monitoring, explore the CNS HIV reservoir, and provide key information on prevention/interventions to help manage/improve these neurological and neuropsychological complications.

NIH Workshop on HIV-Associated Comorbidities, Coinfections, and Complications: Summary and Recommendation for Future Research.

BACKGROUND: With potent antiretroviral therapy and simplified regimens, people living with HIV (PWH) are achieving near-normal lifespans but not necessarily a normal health span or healthy aging. PWH have a higher than expected risk of developing a number of non-AIDS comorbidities, coinfections, and complications (CCC), often against a background of stigma, poverty, and isolation. SETTING: To gain a better understanding of research needs for HIV-associated CCC, the NIH convened a 2-day workshop (HIV-associated CCC, or HIV ACTION). METHODS: A cross-institute NIH planning committee identified 6 key research areas: epidemiology and population research, pathogenesis and basic science research, clinical research, implementation science research, syndemics research and international research in low and middle income countries. Investigators were selected to lead working groups (WGs) to assess the state-of-the-art and identify 3-5 priority areas in each field before the workshop. A 2-day program at the NIH was developed which included presentations by invited experts and WG members. RESULTS: Over 400 participants attended the workshop. After general and individual WG discussions, the most pressing gaps, questions, or proposed action items were identified. Priority lists of pressing research issues were presented by cochairs of each WG. A detailed report is posted at the NHLBI website. This article reports the streamlined priority list and a summary of WG discussions to inform investigators of current priorities in the field. CONCLUSION: Collaborative efforts of many disciplines are needed to improve the health and wellbeing of PWH. Several common themes emerged across WG representing potential priorities for investigators and recommendations for the NIH.

Studying the neuropsychological sequelae of SARS-CoV-2: lessons learned from 35 years of neuroHIV research.

The virology of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the human immune response to the virus are under vigorous investigation. There are now several reports describing neurological symptoms in individuals who develop coronavirus disease 2019 (COVID-19), the syndrome associated with SARS-CoV-2 infection. The prevalence, incidence, and clinical course of these symptoms will become clearer in the coming months and years through epidemiological studies. However, the long-term neurological and cognitive consequence of SARS-CoV-2 infection will remain conjectural for some time and will likely require the creation of cohort studies that include uninfected individuals. Considering the early evidence for neurological involvement in COVID-19 it may prove helpful to compare SARS-CoV-2 with another endemic and neurovirulent virus, human immunodeficiency virus-1 (HIV-1), when designing such cohort studies and when making predictions about neuropsychological outcomes. In this paper, similarities and differences between SARS-CoV-2 and HIV-1 are reviewed, including routes of neuroinvasion, putative mechanisms of neurovirulence, and factors involved in possible long-term neuropsychological sequelae. Application of the knowledge gained from over three decades of neuroHIV research is discussed, with a focus on alerting researchers and clinicians to the challenges in determining the cause of neurocognitive deficits among long-term survivors.

Neurocognitive Effects of Antiretroviral Initiation Among People Living With HIV in Rural Uganda.

BACKGROUND: HIV-associated neurocognitive disorders remain prevalent despite effective antiretroviral therapy (ART), but there are limited longitudinal data on people living with HIV (PLWH) in sub-Saharan Africa. We examined neuropsychological (NP) performance in PLWH in a longitudinal study in Uganda. METHODS: Participants enrolled through the Rakai Community Cohort Study (400 ART-naive PLWH and 400 matched HIV-negative persons) were administered NP assessments. In 2017, PLWH who had initiated ART underwent a 2-year follow-up assessment. Demographically adjusted Z-scores for each NP test were established using data from the HIV- controls. Multivariable linear and logistic regressions were conducted to examine group differences in NP performance. Mixed-effects regressions were conducted to examine ART-related changes in NP outcomes. RESULTS: Of 333 PLWH who returned for their 2-year follow-up visit, 312 (94%) had initiated ART. Those on ART had a mean age of 35.6 years (SD ± 8.5 years) and mean education of 5.4 years (SD ± 3.3 years); 49% were women. ART-associated NP improvements occurred in verbal learning and memory (P's < 0.05), motor (P's < 0.01), and some measures of processing speed (P = 0.002), whereas there were declines in attention/working memory (P's < 0.001) and semantic fluency (P < 0.001). Pre-ART CD4 count and efavirenz use were associated with a more impaired change in NP performance. CONCLUSIONS: PLWH in this resource-limited setting showed improved neurocognitive performance on most NP tests after ART initiation. However, the declines in attention/working memory and fluency performance, as well as relationship to efavirenz, warrant further study.

Predictors of worsening neuropathy and neuropathic pain after 12 years in people with HIV.

OBJECTIVE: Distal sensory polyneuropathy (DSP) and neuropathic pain are important clinical concerns in virally suppressed people with HIV. We determined how these conditions evolved, what factors influenced their evolution, and their clinical impact. METHODS: Ambulatory, community-dwelling HIV seropositive individuals were recruited at six research centers. Clinical evaluations at baseline and 12 years later determined neuropathy signs and distal neuropathic pain (DNP). Additional assessments measured activities of daily living and quality of life (QOL). Factors potentially associated with DSP and DNP progression included disease severity, treatment, demographics, and co-morbidities. Adjusted odds ratios were calculated for follow-up neuropathy outcomes. RESULTS: Of 254 participants, 21.3% were women, 57.5% were non-white. Mean baseline age was 43.5 years. Polyneuropathy prevalence increased from 25.7% to 43.7%. Of 173 participants initially pain-free, 42 (24.3%) had incident neuropathic pain. Baseline risk factors for incident pain included unemployment (OR [95% CI], 5.86 [1.97, 17.4]) and higher baseline body mass index (BMI) (1.78 [1.03, 3.19] per 10-units). Participants with neuropathic pain at follow-up had significantly worse QOL and greater dependence in activities of daily living than those who remained pain-free. INTERPRETATION: HIV DSP and neuropathic pain increased in prevalence and severity over 12 years despite high rates of viral suppression. The high burden of neuropathy included disability and poor life quality. However, substantial numbers remained pain-free despite clear evidence of neuropathy on exam. Protective factors included being employed and having a lower BMI. Implications for clinical practice include promotion of lifestyle changes affecting reversible risk factors.

Beta-amyloid (Aß) uptake by PET imaging in older HIV+ and HIV- individuals.

The causes of cognitive impairment among older HIV+ individuals may overlap with causes among elderly HIV seronegative (HIV-) individuals. The objective of this study was to determine if beta-amyloid (Aß) deposition measured by [18F] AV-45 (florbetapir) positron emission tomography (PET) is increased in older HIV+ individuals compared to HIV- individuals. Forty-eight HIV+ and 25 HIV- individuals underwent [18F] AV-45 PET imaging. [18F] AV-45 binding to Aß was measured by standardized uptake value ratios (SUVR) relative to the cerebellum in 16 cortical and subcortical regions of interest. Global and regional cortical SUVRs were compared by (1) serostatus, (2) HAND stage, and (3) age decade, comparing individuals in their 50s and > 60s. There were no differences in median global cortical SUVR stratified by HIV serostatus or HAND stage. The proportion of HIV+ participants in their 50s with elevated global amyloid uptake (SUVR > 1.40) was significantly higher than the proportion in HIV- participants (67% versus 25%, p = 0.04), and selected regional SUVR values were also higher (p < 0.05) in HIV+ compared to HIV- participants in their 50s. However, these group differences were not seen in participants in their 60s. In conclusion, PET imaging found no differences in overall global Aß deposition stratified by HIV serostatus or HAND stage. Although there was some evidence of increased Aß deposition in HIV+ individuals in their 50s compared to HIV- individuals which might indicate premature aging, the most parsimonious explanation for this is the relatively small sample size in this cross-sectional cohort study.

The neurologic phenotype of South African patients with HIV-associated neurocognitive impairment.

BACKGROUND: The neurologic manifestations of HIV include a spectrum of HIV-associated neurocognitive disorders, as well as a cluster of neurologic symptoms and signs. The neurologic manifestations have been modified but not eradicated by antiretroviral therapy (ART). We describe the neurologic phenotype in South African patients with predominant HIV-1 subtype C infection on ART and its association with neurocognitive impairment and efavirenz and 8-hydroxy-efavirenz concentrations. METHODS: We conducted a cross-sectional analysis of the neurologic examination findings of HIV+ patients with neurocognitive impairment and used multiple linear regression to explore associations with neurocognitive impairment, efavirenz, and 8-hydroxy-efavirenz pharmacokinetics (plasma and CSF). RESULTS: We included 80 participants established on ART (median 40 months) of which 72 (90%) were female. The median age was 35 (interquartile range [IQR], 32-42) and the median Global Deficit Score was 0.94 (IQR 0.63-1.36). We found associations between neurocognitive impairment and neurologic signs: gait (slow walking speed [p = 0.03; R2 = 0.06], gait ataxia [p < 0.01; R2 = 0.21], and abnormal gait appearance [p < 0.01; R2 = 0.18]); coordination (upper limb bradykinesia [p < 0.01; R2 = 0.10] and lower limb bradykinesia [p = 0.01; R2 = 0.10]); reflexes (jaw jerk [p = 0.04; R2 = 0.05] and palmomental response [p = 0.03; R2 = 0.06]); ocular signs (impaired smooth pursuit [p = 0.01; R2 = 0.09] and impaired saccades [p < 0.01; R2 = 0.15]); and motor signs (spasticity [p ≤ 0.01; R2 = 0.15] and muscle weakness [p = 0.01; R2 = 0.08]). No significant associations were found between plasma and CSF efavirenz or 8-hydroxy efavirenz concentrations and any neurologic sign. CONCLUSION: We found that individual neurologic signs were associated with neurocognitive impairment in South African HIV+ patients with predominant HIV-1 subtype C infection on ART and could be used in clinical practice to assess severity. REGISTRATION NUMBER: PACTR201310000635418.

Utility of the International HIV Dementia Scale for HIV-Associated Neurocognitive Disorder.

BACKGROUND: We assessed the utility of the International HIV Dementia Scale (IHDS) in detecting HIV-associated neurocognitive disorder (HAND) in Uganda in antiretroviral (ART)-naïve and ART-experienced adults. SETTING: A longitudinal observational cohort study in Rakai, Uganda. METHODS: Three hundred ninety-nine HIV+ ART-naïve adults underwent neurological, functional status, and neuropsychological assessments including the IHDS. Three hundred twelve participants who initiated ART were re-evaluated after 2 years. HAND stages [asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia (HAD)] were determined based on Frascati criteria using local normative data. Sensitivity, specificity, and area under the ROC curve were determined for various IHDS thresholds (≤9, ≤ 9.5, and ≤10). RESULTS: At baseline, the participants' mean age was 35 years (SD ± 8), 53% were men, and 84% had less than a high school education. At baseline, sensitivity for detecting any HAND stage, symptomatic HAND [mild neurocognitive disorder, HAD], and HAD alone were maximized at IHDS ≤10 (81%, 83%, 92%, respectively). Among 312 individuals who returned for the 2-year follow-up and had initiated ART, a score of ≤10 provided a lower or equal sensitivity for detecting different stages of HAND (all HAND: 70%; symptomatic HAND: 75%; HAD: 94%). The area under the ROC curve was higher for ART-experienced versus ART-naïve individuals. CONCLUSIONS: The IHDS is a potentially useful screening tool for neurocognitive impairment in rural Uganda for both ART-naïve and ART-experienced adults. A cutoff ≤10 demonstrates higher sensitivity for more severe HAND stages compared with less severe HAND. Future studies should focus on potential modifications to the IHDS to improve its specificity.

Higher levels of plasma inflammation biomarkers are associated with depressed mood and quality of life in aging, virally suppressed men, but not women, with HIV.

BACKGROUND AND OBJECTIVES: People with HIV (PWH) often suffer from depressive symptoms which have a deleterious impact on numerous domains including antiretroviral adherence and quality of life. In the general population, a treatment-resistant phenotype of depression is associated with systemic inflammation, which is of considerable importance as it responds favorably to anti-inflammatory medications. Aging PWH experience increasing inflammation. We sought to evaluate the impact of chronic inflammation in aging PWH on depressed mood. METHODS: PWH were recruited at 6 U.S. academic medical centers. Depressed mood was assessed using the Beck Depression Inventory (BDI)-II. Inflammatory biomarkers measured at the 12-year follow-up visit in blood plasma using immunoassays were neopterin, sTNFRII, d-dimer, IL-6, CRP, MCP-1, sCD14 and sCD40L. Factor analyses with oblique Equamax rotation were employed to reduce the dimensionality of the biomarkers. RESULTS: Participants were 78 PWH, 14 (17.9%) women, 40 (51.3%) non-White, mean age 55.3 (±SD 8.29), with a nadir and current CD4 of 134 (IQR 36, 204) and 567 (316, 797), respectively. 80.5% were virally suppressed. A factor analysis of the eight inflammatory biomarkers in plasma at the 12-year follow-up visit yielded 3 Factors, with Factor 1 loading on neopterin and sTNFRII, Factor 2 loading on d-dimer, IL-6 and CRP, and Factor 3 loading on sCD40L (MCP-1 and sCD14 did not appear in any of the factors). Univariate regressions of each factor vs BDI-II scores yielded significance only for Factor 2 (r â€‹= â€‹0.295; p â€‹= â€‹0.0083 (Bonferroni-adjusted p â€‹= â€‹0.0261). Of the Factor 2 component biomarkers, BDI-II scores correlated significantly with d-dimer and IL-6, but not CRP. Women had worse BDI-II scores (p â€‹= â€‹0.0127). In a logistic regression with sex and Factor 2, both variables were significant (sex p â€‹= â€‹0.0246, Factor 2 p â€‹= â€‹0.0168). The relationship between Factor 2 and BDI was significant for men (r â€‹= â€‹0.348 [95% CI 0.111, 0.547]; p â€‹= â€‹0.0049), but not women (r â€‹= â€‹0.0580 95% CI -0.488, 0.571]; p â€‹= â€‹0.844). Viral suppression was not significant in the multivariate model. CONCLUSIONS: Some PWH with depressed mood have elevated markers of inflammation in blood. Men showed this relationship, while women did not. Together with previous findings that an inflammatory depression phenotype responds to treatment with anti-inflammatory medications, our findings suggest that treatment with anti-inflammatory medications might benefit at least a subset of depressed PWH who have a high inflammatory biomarker profile, as well as poor response to antidepressant medications alone, and that the pathophysiology of depression in men and women with HIV may differ.