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Background The prevalence and mortality risk of depression in people with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART) is higher than in the general population, yet biomarkers for therapeutic targeting are unknown. In the current study, we aimed to identify plasma metabolites associated with depressive symptoms in people with HIV receiving ART. Methods This is a prospective study of ART-treated HIV-infected adults with or without depressive symptoms assessed using longitudinal Beck Depression Inventory scores. Plasma metabolite profiling was performed in 2 independent cohorts (total n = 99) using liquid and gas chromatography and tandem mass spectrometry. Results Participants with depressive symptoms had lower neuroactive steroids (dehydroepiandrosterone sulfate [DHEA-S], androstenediols, and pregnenolone sulfate) compared with those without depressive symptoms. The cortisol/DHEA-S ratio, an indicator of hypothalamic-pituitary-adrenal axis imbalance, was associated with depressive symptoms (P < .01) because of low DHEA-S levels, whereas cortisol was similar between groups. The odds of having depressive symptoms increased with higher cortisol/DHEA-S ratios (adjusted odds ratio, 2.5 per 1-unit increase in z score; 95% confidence interval, 1.3–4.7), independent of age and sex. The kynurenine-to-tryptophan ratio showed no significant associations. Conclusions These findings suggest that altered neuroactive steroid metabolism may contribute to the pathophysiological mechanisms of depression in ART-treated HIV-infected adults, representing a potential biological pathway for therapeutic targeting., Depression is a major challenge for people with human immunodeficiency virus (HIV). Adults with depressive symptoms had lower neuroactive steroid metabolites than those without depressive symptoms, highlighting the importance of hypothalamic-pituitary-adrenal axis dysregulation in HIV-infected adults with depression.

Background Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression. Objectives To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352). Methods Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA Results Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA Conclusions A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.

Objective Neurocognitive performance among older persons, including those living with HIV (people living with HIV [PLWH]), exhibits significant heterogeneity, suggesting subpopulations with differing profiles of neurocognitive impairment (NCI). Metabolic factors are associated with NCI, but their relationships to cluster-derived NCI profiles are unknown. Method Participants (144 PLWH and 102 HIV uninfected) aged 50+ years completed a neuropsychological battery assessing seven cognitive domains. Latent class analysis (LCA) identified NCI profiles separately by HIV serostatus and in a combined sample. Obtained classes were examined against the Montreal Cognitive Assessment (MoCA) and diagnoses of HIV-associated neurocognitive disorders (HAND). Multinomial regression identified metabolic predictors of classification. Results LCA identified three latent classes in each participant sample: Class1Multidomain NCI (high probability of impairment across multiple domains), Class 2Learning & Recall NCI (high probability of impairment in learning and recall), and Class 3NC Unimpaired (low probability of NCI across all domains). Severity of NCI implied by classes corresponded with MoCA scores and HAND diagnoses. In analyses on the combined sample, compared to HIV-uninfected individuals, PLWH were more likely to be in Class1Multidomain NCI. Among PLWH, those with dyslipidemia and hypertension had greater odds of classification in Class 1Multidomain NCI while those with central obesity had higher odds of classification in Class 2Learning & Recall NCI; metabolic syndrome approached significance as a differential predictor. Regardless of HIV status, individuals with diabetes were more likely to be in Class 1Multidomain NCI. Conclusions Metabolic risk factors confer heightened risk of NCI in HIV infection. Interventions to reduce metabolic risk may improve neurocognitive outcomes among PLWH.

Background Human immunodeficiency virus (HIV) infection leads to blood–brain barrier (BBB) dysfunction that does not resolve despite viral suppression on antiretroviral therapy (ART) and is associated with adverse clinical outcomes. In preclinical models, cannabis restores BBB integrity. Methods We studied persons with HIV (PWH) and HIV-negative (HIV−) individuals who had used cannabis recently. We assessed 2 biomarkers of BBB permeability: the cerebrospinal fluid (CSF) to serum albumin ratio (CSAR) and CSF levels of soluble urokinase plasminogen activator receptor (suPAR), a receptor for uPA, a matrix-degrading proteolytic enzyme that disrupts the BBB. A composite index of the BBB markers was created using principal components analysis. Neural injury was assessed using neurofilament light (NFL) in CSF by immunoassay. Results Participants were 45 PWH and 30 HIV− individuals of similar age and ethnicity. Among PWH, higher CSF suPAR levels correlated with higher CSAR values (r = 0.47, P Conclusions Cannabis may have a beneficial impact on HIV-associated BBB injury. Since BBB disruption may permit increased entry of toxins such as microbial antigens and inflammatory mediators, with consequent CNS injury, these results support a potential therapeutic role of cannabis among PWH and may have important treatment implications for ART effectiveness and toxicity.

Protease inhibitors were independent predictors of cerebrospinal fluid (CSF) escape in antiretroviral therapy (ART)–experienced human immunodeficiency virus–infected adults. M184V/I combined with thymidine analog mutations were more frequent in adults with CSF escape compared to no escape. These findings suggest optimizing ART may reduce likelihood of CSF escape., Background Cerebrospinal fluid (CSF) viral escape occurs in 4%–20% of human immunodeficiency virus (HIV)–infected adults, yet the impact of antiretroviral therapy (ART) on CSF escape is unclear. Methods A prospective study of 1063 participants with baseline plasma viral load (VL) ≤400 copies/mL between 2005 and 2016. The odds ratio (OR) for ART regimens (protease inhibitor with nucleoside reverse transcriptase inhibitor [PI + NRTI] vs other ART) and CSF escape was estimated using mixed-effects models. Results Baseline mean age was 46 years, median plasma VL, and CD4 count were 50 copies/mL, and 424 cells/μL, respectively. During median follow-up of 4.4 years, CSF escape occurred in 77 participants (7.2%). PI + NRTI use was an independent predictor of CSF escape (OR, 3.1; 95% confidence interval, 1.8–5.0) in adjusted analyses and models restricted to plasma VL ≤50 copies/mL (P < .001). Regimens that contained atazanavir (ATV) were a stronger predictor of CSF viral escape than non-ATV PI + NRTI regimens. Plasma and CSF M184V/I combined with thymidine-analog mutations were more frequent in CSF escape vs no escape (23% vs 2.3%). Genotypic susceptibility score–adjusted central nervous system (CNS) penetration-effectiveness (CPE) values were calculated for CSF escape with M184V/I mutations (n = 34). Adjusted CPE values were low (

New tools are needed to understand human immunodeficiency virus central nervous system involvement. Testing 15 cerebrospinal fluid (CSF) samples for p24 antigen, using a high-sensitivity assay, we found a strong correlation trend between CSF p24 concentration and worse neuropsychological performance.

Author(s): Bharti, Ajay R; McCutchan, Allen; Deutsch, Reena; Smith, Davey M; Ellis, Ronald J; Cherner, Mariana; Woods, Steven P; Heaton, Robert K; Grant, Igor; Letendre, Scott L | Abstract: Background Human immunodeficiency virus (HIV)-associated neurocognitive disorders persist despite suppressive antiretroviral therapy (ART). Because latent Toxoplasma infection (LTI) may adversely impact brain function, we investigated its impact on neurocognitive impairment (NCI) in people living with HIV disease.Methods Two hundred sixty-three HIV-infected adults underwent comprehensive neurocognitive assessments and had anti-Toxoplasma gondii immunoglobulin G (anti-Toxo IgG) measured by qualitative and quantitative enzyme-linked immunosorbent assays.Results Participants were mostly middle-aged white men who were taking ART (70%). LTI was detected in 30 (11.4%) participants and was associated with a significantly greater prevalence of global NCI (LTI positive [LTI+] = 57% and LTI negative [LTI-] = 34%) (odds ratio, 1.67; 95% confidence interval, 1.17-2.40; P = .017). Deficits were more prevalent in the LTI+ vs the LTI- group in 6 of 7 cognitive domains with statistical significance reached for delayed recall (P l .01). The probability of NCI increased with higher CD4+ T-cell counts among LTI+ individuals but with lower CD4+ T-cell counts in LTI- persons. A strong correlation (r = .93) between anti-Toxo IgG levels and global deficit score was found in a subgroup of 9 patients. Biomarkers indicative of central nervous system inflammation did not differ between LTI+ and LTI- participants.Conclusions In this cross-sectional analysis, LTI was associated with NCI, especially in those with higher CD4+ T-cell counts. Longitudinal studies to investigate the role of neuroinflammation and neuronal injury in LTI patients with NCI and trials of anti-Toxoplasma therapy should be pursued.

Background: Neurocognitive impairment (NCI) remains an important complication in persons infected with human immunodeficiency virus (HIV). Ancestry-related mitochondrial DNA (mtDNA) haplogroups have been associated with outcomes of HIV infection and combination antiretroviral therapy (CART), and with neurodegenerative diseases. We hypothesize that mtDNA haplogroups are associated with NCI in HIV-infected adults and performed a genetic association study in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. Methods: CHARTER is an observational study of ambulatory HIV-infected adults. Haplogroups were assigned using mtDNA sequence, and principal components were derived from ancestry-informative nuclear DNA variants. Outcomes were cross-sectional global deficit score (GDS) as a continuous measure, GDS impairment (GDS ≥ 0.50), and HIV-associated neurocognitive disorder (HAND) using international criteria. Multivariable models were adjusted for comorbidity status (incidental vs contributing), current CART, plasma HIV RNA, reading ability, and CD4 cell nadir. Results: Haplogroups were available from 1027 persons; median age 43 years, median CD4 nadir 178 cells/mm(3), 72% on CART, and 46% with HAND. The 102 (9.9%) persons of genetically determined admixed Hispanic ancestry had more impairment by GDS or HAND than persons of European or African ancestry (P < .001 for all). In multivariate models including persons of admixed Hispanic ancestry, those with haplogroup B had lower GDS (β = -0.34; P = .008) and less GDS impairment (odds ratio = 0.16; 95% confidence interval, .04, .63; P = .009) than other haplogroups. There were no significant haplogroup associations among persons of European or African ancestry. Conclusions: In these mostly CART-treated persons, mtDNA haplogroup B was associated with less NCI among persons of genetically determined Hispanic ancestry. mtDNA variation may represent an ancestry-specific factor influencing NCI in HIV-infected persons.

Objective Investigate the discrepancy between subjective and chronologic age by HIV-serostatus, and the association of this discrepancy with subjective neurocognitive functioning (NCF) and objective NCF. Methods One hundred nineteen persons living with HIV (PWLH) and 98 HIV-uninfected (HIV-) adults (Mage = 50.9; SDage = 7.9) completed a comprehensive neurobehavioral battery. Subjective age was assessed using a single-item question (i.e., “how old do you feel?”). The difference between chronologic and subjective age resulted in subjective age discrepancy scores (SADS). Subjective NCF was measured using the Patient’s Assessment of Own Functioning Inventory; objective NCF was measured using global demographically-corrected T-scores. Linear regressions examined the association between subjective and objective NCF with SADS, covarying for significant PLWH and HIV- group differences (i.e., education, sex, ethnicity, and lifetime Major Depressive Disorder). Results PLWH reported lower SADS (indicating closer correspondence between chronologic and subjective age) than their HIV- counterparts, who reported feeling much younger (p = .05; 95% CI: -5.4, .001). Among PLWH, better subjective NCF was significantly related to greater SADS (p = .0002; 95% CI: -.48, -.16). Objective NCF was not associated with SADS among persons with and without HIV. Conclusions Adults without HIV reported feeling younger than their chronologic age, whereas PLWH felt significantly closer to their chronologic age. SADS were negatively associated with only subjective NCF, among only PLWH. This suggests perceived cognitive functioning has a greater impact on psychological well-being among this group. Future research is warranted to delineate the relationship between HIV, subjective neurocognition, and psychosocial factors related to daily functioning to improve successful aging outcomes among this vulnerable population.

Objective Despite potential for dependence and adverse neurological effects, long-term benzodiazepine (BDZ) use is common among persons living with HIV (PLWH). As PLWH are at risk for CNS dysfunction, we retrospectively examined the association between BDZ use and HIV-associated neurocognitive disorders (HAND). Methods 306 PLWH (mean age = 45.1 years) underwent comprehensive neurobehavioral evaluations. Current BDZ use (BDZ+) was determined via self-report. Using propensity scores, 153 BDZ- individuals were matched to 153 BDZ+ participants on demographics, HIV disease characteristics, and comorbidities. Multiple regression models examined HAND and demographically-adjusted neurocognitive T-scores as a function of BDZ group, adjusting for estimated premorbid ability, current affective symptoms, and nadir CD4 count. Secondary analyses explored neurocognitive correlates of positive BDZ urine toxicology screens (TOX+). Results Median BDZ use was 24 months. Compared to BDZ-, BDZ+ had higher likelihood of HAND (OR = 2.14; p = .003) and poorer global (d = -0.33, p = .005), processing speed (d = -0.29, p = .013), and motor T-scores (d = -0.35, p = 0.003). Compared to BDZ+/TOX-, BDZ+/TOX+ users exhibited additional decrements in global (p = .033), executive function (p = .019), and delayed recall T-scores (p = .006). Conclusions BDZ use may elevate risk for HAND, potentially through diffuse neurocognitive slowing and acute compromise of recall and higher-order capacities. These effects are robust to psychosocial and HIV-specific factors and occur in comparison to a tightly-matched BDZ- group. Indications for BDZs (e.g., insomnia) may also impact neurocognition and/or manifest from latent neuropathology. Longitudinal studies should evaluate potential causal associations between HAND and BDZs. Given the extent of BDZ use and possibility of neurocognitive recovery post-abstinence, interventional studies should explore treatment alternatives to BDZs in PLWH.

Background Although antiretroviral therapy (ART) has improved survival and morbidity, HIV-infected adults still have higher rates of non-AIDS disorders, such as neurocognitive impairment, than HIV-uninfected adults. (1–3)-b-D-Glucan (BDG) is a fungal cell wall component which serves as a plasma biomarker for fungal infection and—in the absence of fungal infections—for gut barrier integrity failure and microbial translocation. The objective of this study was to determine whether higher plasma and cerebrospinal fluid (CSF) levels of BDG are associated with neurocognitive impairment [evaluated by global deficit score (GDS)] in HIV-infected adults. Methods We measured levels of BDG in paired plasma and CSF samples, and compared levels with GDS, soluble urokinase plasminogen activator receptor (suPAR; a marker of monocyte activation and chronic inflammation that has previously been associated with non-AIDS disorders) and plasma CD4/CD8 ratio in a cohort of 61 HIV+ adults on suppressive ART. Study samples were collected as part of the prospective CHARTER study between 2005 and 2015 at the University of California San Diego and were stored at −80°C on the day of collection. BDG testing of blood plasma and CSF supernatant was performed at the Associates of Cape Cod, Inc., research laboratories using the Fungitell assay. Results Median plasma BDG level was 18 pg/mL (range: 2–60 pg/mL), median CSF BDG level was 20 pg/mL (range: 0–830 pg/mL). Higher levels of plasma BDG were associated with more severe cognitive impairment as measured by the GDS (Spearman r = 0.35; P = 0.006, Figure). Individuals with neurocognitive impairment (i.e., GDS > 0.5, n = 33) had higher plasma BDG levels compared with unimpaired individuals (P = 0.027). Plasma levels of BDG and suPAR correlated significantly (r = 0.31, P = 0.016), while all other correlations were nonsignificant (e.g., CSF BDG and GDS [r = 0.23], plasma suPAR and GDS [r = 0.19], CSF suPAR and GDS [r = −0.022], CD4/CD8 ratio and GDS [r = −0.028]). Conclusion Elevated plasma levels of BDG may be an indicator of gut barrier integrity failure and an independent biomarker associated with neurocognitive functioning in HIV+ adults on suppressive ART. Disclosures M. Finkelman, Associated of Cape Cod: Employee, Salary.

Objectives: Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90% inhibitory concentration (IC90). Methods: Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography–tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir. Results: Twenty-nine matched CSF– plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5%. Median fractional penetrance was 1.4% of median total and 9.4% of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC90 for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma. Conclusions: Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.

Background. Sleep disturbances are reportedly common among persons infected with human immunodeficiency virus (HIV), but recent data, including comparisons with HIV-uninfected persons, are limited. Methods. We performed a cross-sectional study among early-treated HIV-infected military beneficiaries (n = 193) to determine the prevalence and factors associated with insomnia (Pittsburgh Sleep Quality Index [PSQI]) and daytime sleepiness (Epworth Sleepiness Scale [ESS]). Data were compared with HIV-uninfected persons (n = 50) matched by age, sex, race or ethnicity, and military rank. Results. Forty-six percent of HIV-infected persons had insomnia (PSQI >5), and 30% reported daytime drowsiness (ESS ≥10). The prevalence of insomnia and daytime sleepiness was not significantly higher compared with the HIV-uninfected group (38% [P = .30] and 20% [P = .18], respectively). In the multivariate model, factors associated with insomnia among HIV infected patients included depression (odds ratio [OR], 16.8; 95% confidence interval [CI], 2.0–142.1; P = .01), increased waist size (OR, 2.7; 95% CI, 1.4–5.1; P = .002), and fewer years of education (OR, 0.8; 95% CI, .7–.95; P = .006). Neurocognitive impairment (diagnosed in 19% of HIV-infected participants) was not associated with insomnia; however, HIV-infected persons with insomnia were 3.1-fold more likely to have a decline in activities of daily living than those without insomnia (23% vs 9%; P = .01). Only 18% of HIV-infected persons reported using a sleep medication at least weekly. Conclusions. HIV-infected persons have a high prevalence of insomnia, but among an early-treated cohort this rate was not significantly higher compared with HIV-uninfected persons. Factors associated with insomnia among HIV-infected patients include depression and increased waist size. Prompt diagnosis and treatment of sleep disturbances are advocated and may improve quality of life.

We investigated the interactions between human immunodeficiency virus (HIV) infection and aging and their effects on brain function demands by means of functional magnetic resonance imaging (fMRI). A multiple-regression model was used to study the association and interaction between fMRI measures, HIV serostatus, and age for 26 HIV-infected subjects and 25 seronegative subjects. Although HIV serostatus and age independently affected fMRI measures, no interaction occurred. Functional brain demands in HIV-positive subjects were equivalent to those of HIV-negative subjects who were 15-20 years older. Frailty parallels between HIV infection and aging could result from continued immunological challenges depleting resources and triggering increased metabolic demands. In the future, fMRI could be a noninvasive biomarker to assess HIV infection in the brain.

Background. Combination antiretroviral (ARV) therapy can reduce human immunodeficiency virus (HIV) RNA levels in cerebrospinal fluid (CSF) and plasma and improve immunocompetence. However, HIV-associated neurocognitive disorders persist, possibly because some ARV drugs do not reach therapeutic concentrations in the brain. The primary objective of this study was to determine whether lopinavir plus ritonavir (LPV-rtv) used alone reduced the HIV RNA level in CSF. Methods. The study was an open-label, 24-week trial of sequential ARV therapy. Fifteen subjects were enrolled and received LPV-rtv therapy. Ten subjects reached the primary study end point at week 3, before at least 2 other ARV drugs were added to the treatment regimen. CSF and blood samples were obtained before treatment and after 3, 12, and 24 weeks of treatment. Results. LPV-rtv therapy alone reduced the HIV RNA level in CSF in all subjects (median change in HIV RNA level, -1.42 log 10 copies/mL), including 5 who had slower decreases in HIV RNA level in CSF than in plasma-an indicator of autonomous central nervous system infection. Among 9 subjects who completed 12 weeks of LPV-rtv-containing therapy, the HIV RNA level was below quantitation in the CSF samples from 8 subjects and in the plasma samples from 6 subjects. By week 24, HIV RNA levels were below quantitation in samples of both fluids from all 8 subjects. Conclusions. LPV-rtv therapy alone for 3 weeks consistently reduces the HIV RNA level in CSF by at least 10-fold in most individuals, including those likely to have autonomous HIV replication in the central nervous system. Because it penetrates the central nervous system in therapeutic concentrations and appears to reduce HIV replication in the central nervous system, LPV-rtv may benefit subjects who receive a diagnosis of or are at risk for HIV-associated neurocognitive disorders.

opment of immunosuppression [5]. Once in the CNS [6], HIV establishes a chronic infection that predominantly involves monocytes, perivascular macrophages, microglial cells, and, to some extent, a restricted infection of astrocytes [7, 8]. Since the earliest years of the HIV epidemic, there has been great interest in studying cerebrospinal fluid (CSF) in HIV infection, because this compartment represents a "window" into HIV replication, treatment response, and damage in brain parenchyma. Th study by Spudich et al. [9] in this issue of the Journal of Infectious Diseases provides new information about the virological responses to ART in the CSE It represents a cross-sectional analysis of 139 HIV-positive subjects categorized as having therapeutic success or failure on the basis of their virological response to ART. The estimated blood-brain barrier penetration of antiretroviral regimens was categorized using 2 methods, including one used in an ongoing National Institutes of Health-funded study of the effects of antiretroviral therapy on CNS HIV infection-the CNS HIV Antiretroviral Effects

Macrophages express the chemokine receptor CCR-5, a coreceptor for human immunodeficiency virus (HIV) entry. This receptor is ligated by beta chemokines, which influence HIV type 1 (HIV-1) replication in CCR-5-bearing cells in vitro and could influence the course of infection in the central nervous system. Cerebrospinal fluid (CSF) samples from 73 HIV-infected men were assayed for macrophage inflammatory protein-1 alpha (MIP-1alpha), MIP-1beta, and regulated upon activation, normal T cell expressed and secreted (RANTES). Distributions of all three were positively skewed. CSF chemokine concentrations were correlated with each other and were higher in demented patients. In a multivariate analysis, demented subjects were more likely to have detectable CSF MIP-1alpha, elevated CSF HIV RNA levels, and lower CD4+ cell counts. However, among those with detectable CSF MIP-1alpha, levels were lower in demented patients. CSF beta chemokine elevation is consistent with the macrophage activation known to occur in dementia and with studies of beta chemokine mRNA expression in the brain. Low, but detectable, levels of CSF MIP-1alpha were strongly associated with dementia, suggesting that higher levels may have neuroprotective effects.