CCR2 on Peripheral Blood CD14+CD16+ Monocytes Correlates with Neuronal Damage,HIV-Associated Neurocognitive Disorders,and Peripheral HIV DNA: reseeding of CNS reservoirs?

HIV-associated neurocognitive disorders (HAND) occur in ~50% of HIV infected individuals despite combined antiretroviral therapy. Transmigration into the CNS of CD14⁺CD16⁺ monocytes, particularly those that are HIV infected and express increased surface chemokine receptor CCR2, contributes to neuroinflammation and HAND. To examine whether in HIV infected individuals CCR2 on CD14⁺CD16⁺ monocytes serves as a potential peripheral blood biomarker of HAND, we examined a cohort of 45 HIV infected people. We correlated CCR2 on CD14⁺CD16⁺ monocytes with cognitive status, proton magnetic resonance spectroscopy (¹H-MRS) measured neurometabolite levels, and peripheral blood mononuclear cell (PBMC) HIV DNA copies. We determined that CCR2 was increased specifically on CD14⁺CD16⁺ monocytes from people with HAND (median [interquartile range (IQR)]) (63.3 [51.6, 79.0]), compared to those who were not cognitively impaired (38.8 [26.7, 56.4]) or those with neuropsychological impairment due to causes other than HIV (39.8 [30.2, 46.5]). CCR2 was associated with neuronal damage, based on the inverse correlation of CCR2 on CD14⁺CD16⁺ monocytes with total N-Acetyl Aspartate (tNAA)/total Creatine (tCr) (r² = 0.348, p = 0.01) and Glutamine-Glutamate (Glx)/tCr (r² = 0.356, p = 0.01) in the right and left caudate nucleus, respectively. CCR2 on CD14⁺CD16⁺ monocytes also correlated with PBMC HIV DNA copies (ρ = 0.618, p = 0.02) that has previously been associated with HAND. These findings suggest that CCR2 on CD14⁺CD16⁺ monocytes may be a peripheral blood biomarker of HAND, indicative of increased HIV infected CD14⁺CD16⁺ monocyte entry into the CNS that possibly increases the macrophage viral reservoir and contributes to HAND.

     

APOE ��4 allele and CSF APOE on Cognition in HIV-Infected Subjects

The significance of the cerebrospinal fluid (CSF) Apolipoprotein E (APOE) level and whether it might have differential effects on brain function due to the presence of APOE ??4 allele(s) in HIV-infected patients are unknown. However, APOE ??4 allele has been associated with greater incidence of HIV-associated dementia and accelerated progression of HIV infection. Here, we show further evidence for the role of APOE ??4 in promoting cognitive impairment. We measured the APOE levels in the CSF of HIV-infected individuals. HIV+ subjects showed lower CSF APOE proteins than SN controls (?19%, p?=?0.03). While SN subjects with or without ??4 allele showed no difference in CSF APOE levels, ??4+ HIV+ subjects had similar levels to the SN subjects but higher levels than ??4? HIV+ subjects (+34%, p?=?0.01). Furthermore, while HIV+ subjects with ??2 or ??3 allele(s) showed a positive relationship between their CSF APOE levels and cognitive performance on the speed of processing domain (r?=?+0.35, p?=?0.05), ??4+ HIV+ subjects, in contrast, exhibited a negative relationship such that those with higher levels of CSF APOE(4) performed worse on the HIV Dementia Scale (r?=??0.61, p?=?0.02), had lower Global Cognitive Scores (r?=??0.57, p?=?0.03), and had poorer performance on tests involving learning (??4 allele x [APOE] interaction, p?=?0.01). Our findings also suggest that the relatively higher levels of CSF APOE in ??4+ HIV+ (having primarily APOE4 isoforms) may negatively impact the brain and lead to poorer cognitive outcomes, while those individuals without the ??4 allele (with primarily APOE2 or APOE3 isoforms) may show compensatory responses that lead to better cognitive performance.     

Transgenerational sublethal effects of abamectin and pyridaben on demographic traits of Phytonemus pallidus (Banks) (Acari: Tarsonemidae)

In addition to determining the lethal effects, identifying sublethal effects of a pesticide is crucial to understanding the total impact a pesticide may have on a pest population. We determined the sublethal effects the two pesticides, abamectin and pyridaben, have on the cyclamen mite, Phytonemus pallidus (Banks) (Acari: Tarsonemidae)—a major pest of strawberry. Demographic traits of the P. pallidus progeny (F1 generation) produced by parents (F0 generation) treated with a low lethal concentration (LC₁₅) of abamectin and pyridaben were assessed using the age-stage, two-sex life table theory. The total longevity of the F1 generation (males = 10.78 days; female = 14.35 days) was the shortest in the progeny of the abamectin treated parents, differing significantly from the progeny of mites treated with pyridaben (males = 11.50 days, females = 15.63 days), and the control population (males = 13.50 days, females = 17.81 days). The intrinsic rates of increase (r) and the finite rates of increase (λ) of the progeny of abamectin (r = 0.0854 day⁻¹, λ = 1.0891 day⁻¹) and pyridaben (r = 0.0951 day⁻¹, λ = 1.0997 day⁻¹) treated parents were significantly lower than in the control mites (r = 0.1455 day⁻¹, λ = 1.1567 day⁻¹). The lowest fecundity (5.35 eggs/female), occurred in F1 female offspring of parents treated with LC₁₅ concentrations of abamectin, which was significantly lower than in the pyridaben (6.11 eggs/female) and control treatments (11.45 eggs/female). Transgenerational sublethal effects of abamectin and pyridaben in P. pallidus can be effectively used to for optimizing IPM programs against this pest on strawberries.

     

HIV and Chronic Methamphetamine Dependence Affect Cerebral Blood Flow

Human immunodeficiency virus (HIV) and methamphetamine (METH) dependence are independently associated with neuronal dysfunction. The coupling between cerebral blood flow (CBF) and neuronal activity is the basis of many task-based functional neuroimaging techniques. We examined the interaction between HIV infection and a previous history of METH dependence on CBF within the lenticular nuclei (LN). Twenty-four HIV−/METH−, eight HIV−/METH+, 24 HIV+/METH−, and 15 HIV+/METH+ participants performed a finger tapping paradigm. A multiple regression analysis of covariance assessed associations and two-way interactions between CBF and HIV serostatus and/or previous history of METH dependence. HIV+ individuals had a trend towards a lower baseline CBF (−10%, p = 0.07) and greater CBF changes for the functional task (+32%, p = 0.01) than HIV− subjects. Individuals with a previous history of METH dependence had a lower baseline CBF (−16%, p = 0.007) and greater CBF changes for a functional task (+33%, p = 0.02). However, no interaction existed between HIV serostatus and previous history of METH dependence for either baseline CBF (p = 0.53) or CBF changes for a functional task (p = 0.10). In addition, CBF and volume in the LN were not correlated. A possible additive relationship could exist between HIV infection and a history of METH dependence on CBF with a previous history of METH dependence having a larger contribution. Abnormalities in CBF could serve as a surrogate measure for assessing the chronic effects of HIV and previous METH dependence on brain function.     

Lower Glial Metabolite Levels in Brains of Young Children with Prenatal Nicotine Exposure

Many pregnant women smoke cigarettes during pregnancy, but the effect of nicotine on the developing human brain is not well understood, especially in young children. This study aims to determine the effects of prenatal nicotine exposure (PNE) on brain metabolite levels in young (3–4 years old) children, using proton magnetic resonance spectroscopy (¹H MRS). Twenty-six children with PNE and 24 nicotine-unexposed children (controls) were evaluated with a structured examination, a battery of neuropsychological tests, and MRI/¹H MRS (without sedation). Concentrations of N-acetyl compounds (NA), total creatine (tCR), choline-containing compounds (CHO), myo-inositol (MI), and glutamate+glutamine (GLX) were measured in four brain regions. Children with PNE had similar performance to controls on neuropsychological testing. However, compared to controls, the PNE group had lower MI (repeated measures ANOVA—p = 0.03) and tCr levels (repeated measures ANOVA–p = 0.003), especially in the basal ganglia of the girls (−19.3%, p = 0.01). In contrast, GLX was elevated in the anterior cingulate cortex of the PNE children (+9.4%, p = 0.03), and those with the highest GLX levels had the poorest performance on vocabulary (r = −0.67; p < 0.001) and visual motor integration (r = −0.53; p = 0.01). The amount of prenatal nicotine exposure did not correlate with metabolite concentrations. These findings suggest that PNE may lead to subclinical abnormalities in glial development, especially in the basal ganglia, and regionally specific changes in other neurometabolites. These alterations were not influenced by the amount of nicotine exposure prenatally. However, the effects of PNE on energy metabolism may be sex specific, with greater alterations in girls.     

Combined and Independent Effects of Chronic Marijuana Use and HIV on Brain Metabolites

The effects of chronic marijuana (MJ) use on brain function remain controversial. Because MJ is often used by human immunodeficiency virus (HIV) patients, the aim of this study was to evaluate whether chronic MJ use and HIV infection are associated with interactive or additive effects on brain chemistry and cognitive function. We evaluated 96 subjects (30 seronegative nondrug users, 24 MJ users, 21 HIV without MJ use, 21 HIV + MJ) using proton magnetic resonance spectroscopy and a battery of neuropsychological tests. The two primarily abstinent MJ user groups showed no significant differences on calculated estimates of lifetime grams of delta9-tetrahydrocannabinol exposure, despite some differences in usage pattern. The two HIV groups also had similar HIV disease severity (CD4 cell count, plasma viral load, HIV dementia staging, Karnofsky score). On two-way analyses of covariance, HIV infection (independent of MJ) was associated with trends for reduced N-acetyl aspartate (NA) in the parietal white matter and increased choline compounds (CHO) in the basal ganglia. In contrast, MJ (independent of HIV) was associated with decreased basal ganglia NA (−5.5%, p = 0.05), CHO (−10.6%, p = 0.04), and glutamate (−9.5%, p = 0.05), with increased thalamic creatine (+6.1%, p = 0.05). HIV + MJ was associated with normalization of the reduced glutamate in frontal white matter (interaction p = 0.01). After correction for age, education, or mood differences, MJ users had no significant abnormalities on neuropsychological test performance, and HIV subjects only had slower reaction times. These findings suggest chronic MJ use may lead to decreased neuronal and glial metabolites, but may normalize the decreased glutamate in HIV patients.     

In a Model of Neuroinflammation Designed to Mimic Delirium,Quetiapine Reduces Cortisol Secretion and Preserves Reversal Learning in the Attentional Set Shifting Task

Quetiapine, an atypical antipsychotic medication has lacked pre-clinical validation for its purported benefits in the treatment of delirium. This laboratory investigation examined the effects of quetiapine on the attentional set shifting task (ASST), a measure of cognitive flexibility and executive functioning, in a rodent model of lipopolysaccharide (LPS) mediated neuroinflammation. 19 Sprague Dawley female rats were randomly selected to receive intraperitoneal placebo (N = 5), LPS and placebo (N = 7) or LPS and quetiapine (n = 7) and performed the ASST. We measured trials to criterion, errors, non-locomotion episodes and latency to criterion, serum cortisol and tumor necrosis factor alpha (TNF-α) levels. TNF-α levels were not different between groups at 24 h. Cortisol levels in the LPS + Quetiapine group were reduced compared to LPS + Placebo (P < 0.001) and did not differ from the placebo group (P = 0.15). Analysis between LPS + Quetiapine and LPS + Placebo treated rats demonstrated improvement in the compound discrimination reversal (CD Rev1) (P = 0.016) and the intra-dimensional reversal (ID Rev2) (P = 0.007) discriminations on trials to criterion. LPS + Quetiapine treated rats had fewer errors than LPS + Placebo treated animals in the compound discrimination (CD) (P = 0.007), CD Rev1 (P = 0.005), ID Rev2 (P < 0.001) discriminations. There was no difference in non-locomotion frequency or latency to criterion between the three groups in all discriminations (P > 0.0167). We demonstrated preserved reversal learning, no effect on attentional set shifting and normalized cortisol levels in quetiapine-treated rats in this neuroinflammatory model of delirium. This suggests that quetiapine’s beneficial effects in delirium may be related to the preservation of reversal learning and potential downstream effects related to reduction in cortisol production.

Graphical Abstract

     

Clinical sleep patterns in human immune virus infection

Clinical sleep patterns were recorded in 45 HIV +ve patients, using a 5-item questionnaire concerned with: sleep onset, nocturnal wakings, early morning awakening, duration of sleep and well-being on final waking. These were quantified to give a total ‘insomnia score’ and compared to matched normal controls. Sleep was significantly worse in the HIV patients in relation to: delayed onset and early morning awakening (p < 0.5), nocturnal wakings and wellbeing on waking (p < 0.0001), although not significant for duration of sleep. The mean total score for the HIV patients was 3.8 and for the controls 2.1 (p < 0.0001). There was an almost significant correlation between insomnia score and duration HIV +ve (p = 0.055). AIDS status did not affect the results but the insomnia score was greater in the absence of anti-viral chemotherapy (p = 0.052). In the controls insomnia severity almost correlated to stress (p = 0.052). The results showed that the HIV patients had significantly more sleep disturbance than the matched controls, with resultant implications for improving quality of life in this respect.     

Greater Than Age-Related Changes in Brain Diffusion of HIV Patients After 1 Year

Chronic infection with HIV is associated with neuroinflammation. Prior diffusion tensor imaging (DTI) studies demonstrated increased mean diffusion (MD) and decreased fractional anisotropy (FA) in the white matter (WM) and subcortical brain regions of HIV patients. The current study aims to detect whether there are greater than age-related brain changes in HIV patients after a 1-year follow-up period using DTI. Thirty-nine antiretroviral-stable HIV subjects and 32 HIV-seronegative (SN) controls were evaluated, with neuropsychological tests and DTI, at baseline and after 1 year. MD and FA in the genu and splenium of the corpus callosum and in six other subcortical and white matter regions were evaluated bilaterally. Compared to SN controls, HIV subjects had significantly higher MD in the frontal WM (p = 0.0104) and lower FA in the parietal WM (p = 0.006). After 1 year, HIV subjects showed increase in MD in frontal and parietal WM, putamen, and genu; HIV subjects also showed greater increased genu diffusion than SN controls (p = 0.005). Changes in global cognitive deficit score correlated with changes in MD in the genu and FA in the parietal and frontal WM and putamen (multiple regression, p = 0.0008). Lastly, normal age-dependent changes in frontal WM diffusion and FA in genu and putamen were not observed in HIV subjects. Since increased MD may reflect increased neuroinflammation, our findings suggest greater than normal age-related inflammatory changes in the genu of these HIV patients, which may contribute to the cognitive deficits. Measurements of MD in the genu may be useful for monitoring disease progression in HIV brain infection.     

Cocaine Potentiates Cathepsin B Secretion and Neuronal Apoptosis from HIV-Infected Macrophages

Substance abuse is a risk factor for HIV infection and progression to AIDS. Recent evidence establishes that cocaine use promotes brain perivascular macrophage infiltration and microglia activation. The lysosomal protease cathepsin B is increased in monocytes from patients with HIV dementia and its secretion induces 10–15 % of neurotoxicity. Here we asked if cocaine potentiates cathepsin B secretion from HIV-infected monocyte-derived macrophages (MDM) and its effect in neuronal apoptosis. Samples of plasma, CSF, and post-mortem brain tissue from HIV positive patients that used cocaine were tested for cathepsin B and its inhibitors to determine the in vivo relevance of these findings. MDM were inoculated with HIV-1_ADA, exposed to cocaine, and the levels of secreted and bioactive cathepsin B and its inhibitors were measured at different time-points. Cathepsin B expression (p?p?p?Cathepsin B was significantly increased in the plasma and post-mortem brain tissue of HIV/cocaine users over non-drug users. Our results demonstrated that cocaine potentiates cathepsin B secretion in HIV-infected MDM and increase neuronal apoptosis. These findings provide new evidence that cocaine synergize with HIV-1 infection in increasing cathepsin B secretion and neurotoxicity.     

Altered Associations between Pain Symptoms and Brain Morphometry in the Pain Matrix of HIV-Seropositive Individuals

Pain remains highly prevalent in HIV-seropositive (HIV+) patients despite their well-suppressed viremia with combined antiretroviral therapy. Investigating brain abnormalities within the pain matrix, and in relation to pain symptoms, in HIV+ participants may provide objective biomarkers and insights regarding their pain symptoms. We used Patient-Reported Outcome Measurement Information System (PROMIS®) pain questionnaire to evaluate pain symptoms (pain intensity, pain interference and pain behavior), and structural MRI to assess brain morphometry using FreeSurfer (cortical area, cortical thickness and subcortical volumes were evaluated in 12 regions within the pain matrix). Compared to seronegative (SN) controls, HIV+ participants had smaller surface areas in prefrontal pars triangularis (right: p = 0.04, left: p = 0.007) and right anterior cingulate cortex (p = 0.03) and smaller subcortical regions (thalamus: p ≤ 0.003 bilaterally; right putamen: p = 0.01), as well as higher pain scores (pain intensity-p = 0.005; pain interference-p = 0.008; pain-behavior-p = 0.04). Furthermore, higher pain scores were associated with larger cortical areas, thinner cortices and larger subcortical volumes in HIV+ participants; but smaller cortical areas, thicker cortices and smaller subcortical volumes in SN controls (interaction-p = 0.009 to p = 0.04). These group differences in the pain-associated brain abnormalities suggest that HIV+ individuals have abnormal pain responses. Since these abnormal pain-associated brain regions belong to the affective component of the pain matrix, affective symptoms may influence pain perception in HIV+ patients and should be treated along with their physical pain symptoms. Lastly, associations of lower pain scores with better physical or mental health scores, regardless of HIV-serostatus (p < 0.001), suggest adequate pain treatment would lead to better quality of life in all participants.     

Association of Marijuana Use with Changes in Cognitive Processing Speed and Flexibility for 17 Years in HIV-Seropositive and HIV-Seronegative Men

Background: The long-term effects of marijuana on cognition, particularly in the context of HIV is not clear, as extant research shows mixed findings. Objective: To determine associations between current and cumulative exposure to marijuana and changes in cognitive processing speed and flexibility in 788 HIV-seropositive (HIV+) and 1,132 HIV-seronegative (HIV?) men followed for up to 17 years in the Multicenter AIDS Cohort Study. Results: Among HIV+ men only, current daily marijuana use compared to none-use, was significantly associated with a greater annual percentage decline in cognitive processing speed assessed with the Trail Making Test A (TMTA) (β=?0.41, 95% confidence interval (CI): ?0.88, ?0.03, p=0.03)] and Symbol Digit Modalities Test (SDMT) (β= ?0.14, 95% CI: ?0.28, ?0.01, p=0.04). Further, monthly marijuana use was associated with greater annual percentage decline in cognitive flexibility assessed with the Trail Making Test B (TMTB) (β= ?0.70, 95% CI: ?1.34, ?0.05; p=0.03] and cognitive processing speed (SDMT) (β= ?0.21, 95% CI: ?0.40, ?0.01, p=0.03). Among the HIV? men only, each 5-marijuana use-years (equivalent to 5-years of daily marijuana use) was significantly associated with a 0.17 annual percentage decline in cognitive processing speed only (TMTA) (β= ?0.18, 95% CI: ?0.36, ?0.01; p=0.04). Conclusions: Our findings suggest that marijuana use, particularly current use, may be associated with worse cognitive processing speed, but the magnitude of the estimates was not clinically meaningful.     

Identifying Risk Factors for HIV-Associated Neurocognitive Disorders Using the International HIV Dementia Scale

HIV-associated neurocognitive disorders (HAND) persist despite great advancements in combination antiretroviral therapy (cART). The gold standard for diagnosing cognitive impairment consists of a time-consuming neuropsychological battery of tests given by a trained neuropsychologist, however in the outpatient HIV clinic this is not feasible. The International HIV Dementia Scale (IHDS) was developed to help identify individuals with cognitive impairment in the outpatient setting. The IHDS is moderately sensitive for detecting more symptomatic forms of HAND but sensitivity has been shown to be poor in mild impairment. The IHDS has not been evaluated in developed countries in large cohort populations. We conducted a prospective cross-sectional study of only HIV+ individuals in an urban clinic and evaluated the prevalence of HAND and associated risk factors for cognitive impairment using the IHDS. A total of 507 HIV+ individuals participated in the study of which the majority were male (65 %) and African American (68 %); and 41 % had cognitive impairment. On multivariate analysis, African American race (p?=?2.21), older age (p?=?1.03), high school education or less (p?=?2.03) and depression (p?=?1.05) were associated with cognitive impairment. The high prevalence of HAND in this group suggests that more severe forms of HAND persist despite cART. Identified risk factors were non-HIV-related and suggest that environmental and sociodemographic factors have a significant impact on cognitive functioning and should be given more attention. The IHDS should be further evaluated in large cohort HIV+ and HIV- populations in the United States, as there remains a significant need to identify an effective brief screening tool for cognitive impairment.     

Feather mercury concentrations in North American raptors sampled at migration monitoring stations

We assessed total mercury (THg) concentrations in breast feathers of diurnal North American raptors collected at migration monitoring stations. For 9 species in the Pacific Flyway, we found species and age influenced feather THg concentrations whereas sex did not. Feather THg concentrations µg/g dry weight (dw) averaged (least squares mean ± standard error) higher for raptors that generally consume > 75% avian prey (sharp-shinned hawk Accipiter striatus: n = 113; 4.35 ± 0.45 µg/g dw, peregrine falcon Falco peregrinus: n = 12; 3.93 ± 1.11 µg/g dw, Cooper’s hawk Accipiter cooperii: n = 20; 2.35 ± 0.50 µg/g dw, and merlin Falco columbarius: n = 59; 1.75 ± 0.28 µg/g dw) than for raptors that generally consume < 75% avian prey (northern harrier Circus hudsonius: n = 112; 0.75 ± 0.10 µg/g dw, red-tailed hawk Buteo jamaicensis: n = 109; 0.56 ± 0.06 µg/g dw, American kestrel Falco sparverius: n = 16; 0.57 ± 0.14 µg/g dw, prairie falcon Falco mexicanus: n = 10; 0.41 ± 0.13 µg/g dw) except for red-shouldered hawks Buteo lineatus: n = 10; 1.94 ± 0.61 µg/g dw. Feather THg concentrations spanning 13-years (2002–2014) in the Pacific Flyway differed among 3 species, where THg increased for juvenile northern harrier, decreased for adult red-tailed hawk, and showed no trend for adult sharp-shinned hawk. Mean feather THg concentrations in juvenile merlin were greater in the Mississippi Flyway (n = 56; 2.14 ± 0.18 µg/g dw) than those in the Pacific Flyway (n = 49; 1.15 ± 0.11 µg/g dw) and Intermountain Flyway (n = 23; 1.14 ± 0.16 µg/g dw), and Atlantic Flyway (n = 38; 1.75 ± 0.19 µg/g dw) averaged greater than the Pacific Flyway. Our results indicate that raptor migration monitoring stations provide a cost-effective sampling opportunity for biomonitoring environmental contaminants within and between distinct migration corridors and across time.

     

Independent and Combined Effects of Chronic HIV-Infection and Tobacco Smoking on Brain Microstructure

HIV-infected individuals (HIV+) have 2–3 times higher prevalence of tobacco smoking than the general U.S. population. This study aims to evaluate the independent and combined effects of tobacco-smoking and HIV-infection on brain microstructure and cognition using a 2?×?2 design. 21 HIV?+?Smokers, 25 HIV?+?Nonsmokers, 25 Seronegative (SN)-Smokers and 23 SN-Nonsmokers were evaluated using diffusion tensor imaging. Fractional anisotropy (FA), mean (MD), radial (RD) and axial (AD) diffusivity were assessed in 8 major cerebral fiber tracts and 5 subcortical regions. Cognitive performance in 7 neurocognitive domains was also assessed. Compared to SN, HIV+ had higher AD in genu of corpus callosum (GCC, p?=?0.002). Smokers also had higher diffusivities in GCC, splenium of corpus callosum (SCC), anterior corona radiata (ACR), sagittal stratum (SS) and superior fronto-occipital fasciculus (SFO), than Nonsmokers (p-values<0.001–0.003). Tobacco-Smoking and HIV-infection showed synergistic effects on AD_SS (p?=?0.002) and RD_SFO (p?=?0.02), but opposite effects in FA_putamen (p?=?0.024). Additive effects from HIV+ and Tobacco-Smoking were observed in 9 other white matter tracts, with highest diffusivities and lowest FA in HIV?+?Smokers. Higher diffusivities in the GCC, SCC, ACR and SS predicted poorer cognitive performance across all participants (p?≤?0.001). Higher AD_GCC also predicted slower Speed of information processing and poorer Fluency and Attention only in HIV?+?Smokers (p?=?0.001–0.003). Chronic tobacco smoking and HIV-infection appear to have additive and synergistic adverse effects on brain diffusivities, suggesting greater neuroinflammation, which may contribute to poorer cognition. Therefore, chronic tobacco-smoking may be a risk factor for HIV-associated neurocognitive disorders.

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Graphical Abstract ?

     

Triple nucleoside treatment with abacavir plus the lamivudine/ zidovudine combination tablet (COM) compared to indinavir/COM in antiretroviral therapy-naïve adults: results of a 48-week open-label,equivalence trial (CNA3014)

SUMMARY

Objective: An equivalence (non-inferiority) trial comparing antiviral response, tolerability, and adherence with a triple nucleoside regimen containing abacavir 300?mg (ABC) plus a lamivudine 150-mg/zidovudine 300-mg combination tablet (COM) twice daily vs. a regimen containing the protease inhibitor indinavir (IDV) 800?mg three times daily plus COM twice daily (IDV/COM) in antiretroviral-naïve, HIV-infected patients.

Methods: Adult patients with plasma HIV-1 RNA levels ≥ 5000?copies/mL and CD4+ cell counts ≥ 100?cells/mm³ were randomized to receive open-label ABC/COM (n = 169) or IDV/COM (n = 173) for 48?weeks. The intent-to-treat (ITT) population was the primary population evaluated. ITT: switch/missing equals failure (ITT: S/M = F) and as-treated (AT) analyses were used for assessing the proportion of patients achieving plasma HIV-1 RNA level < 400 and < 50?copies/mL at each clinic visit. In the ITT: S/M = F analysis, patients who switched treatment or had missing values were considered treatment failures; the AT analysis examined virologic data only while patients received study treatment. ABC/COM was considered equivalent (non-inferior) to IDV/COM if the lower limit of the 95% confidence intervals (CIs) about the difference in proportions of ABC/COM- vs. IDV/COM-treated patients attaining plasma HIV-1 RNA < 400?copies/mL exceeded –15% at week 48.

Results: The study population was diverse with respect to ethnicity (38% Asian, 27% Hispanic, 28% white, 3% black, 4% other) and gender (39% women, 61% men). Baseline median HIV-1 RNA was 4.80?log₁₀?copies/mL and CD4+ cell count was 315?cells/mm³. ABC/COM met the criterion of equivalence to IDV/COM. In the ITT: S/M = F analysis at Week 48, a greater proportion of ABC/COM-treated patients achieved HIV-1 RNA < 400?copies/mL (66% [109/164] vs. 50% [82/165]; treatment difference 16.6%, 95% CI (6.0, 27.2), p = 0.002) and HIV-1 RNA < 50?copies/mL (60% [99/164] vs. 50% [83/165]; treatment difference 9.6%, 95% CI [–1.1, 20.2]), whereas the AT analysis showed similar proportions achieving these endpoints (< 400?copies/mL: 85 vs. 83%; < 50?copies/mL: 79 vs 81%). Comparable proportions of patients with screening HIV-1 RNA values > 100?000?copies/mL achieved HIV-1 RNA < 400?copies/mL (ABC/COM: 60% [35/58]; IDV/COM: 51% [33/65]; treatment difference 9.6%, 95% CI [–7.9, 27.1]; ITT: S/M = F analysis). A significantly greater proportion taking ABC/COM were ≥ 95% adherent (72% [109/151] vs. 45% [70/154] with IDV/COM, p < 0.001). Median increases from baseline in CD4+ cell counts were similar in the two treatment groups (+148 vs. +152?cells/mm³). Significantly more patients on IDV/COM reported drug-related adverse events (87% [142/165] vs. 65% [108/164] with ABC/COM, p < 0.001), similar proportions discontinued treatment due to adverse events (13 vs. 10%), and a slightly greater proportion in the ABC/COM group reported serious adverse events (13 vs. 8%). About half of the latter comprised suspected ABC-related hypersensitivity reactions (overall rate, 6%). Most adverse events were gastrointestinal in nature in both treatment groups.

Conclusion: ABC/COM was at least equivalent to IDV/COM over 48?weeks in the treatment of antiretroviral-naïve patients. ABC/COM was associated with a significantly higher adherence rate and lower incidence of drug-related adverse events than IDV/COM. The study was limited in that it was not powered to determine equivalence of treatments within high vs. low viral load strata, adherence was not monitored electronically, and bias could not be ruled out due to the open-label study design.     

Neurometabolite Abnormalities in Simian Immunodeficiency Virus-Infected Macaques with Chronic Morphine Administration

Opiate abuse increases the risk for human immunodeficiency virus (HIV) infection, while both opiates and HIV may impact the immune and nervous systems. To model potential interactions between opiate drugs and HIV on the brain, neurometabolite levels were evaluated in simian immunodeficiency virus (SIV)-infected macaques with or without chronic morphine administration. Over the course of the study, 58% of these SIV-infected animals progressed to acquired immune deficiency syndrome (AIDS). Brain extracts from four brain regions were evaluated with proton magnetic resonance spectroscopy. Animals with AIDS had lower N-acetyl-aspartate in all four brain regions (p ≤ 0.05) as well as lower frontal gray matter total creatine (p = 0.03), lower frontal white matter (p = 0.003) and caudate (p = 0.002) glutamate, and higher frontal white matter myo-inositol (p = 0.05) than the healthier non-AIDS macaques. Morphine-dependent animals had higher levels of myo-inositol in the putamen (p = 0.003), especially those with AIDS. In the animals with AIDS, those with morphine dependence had higher total creatine in the frontal white matter (p = 0.04) than those treated with saline, which in turn had lower creatine than saline-injected animals without AIDS (p = 0.04), leading to an interaction between the effects of morphine and AIDS on total creatine in this brain region (ANOVA p = 0.02). The majority of these brain metabolites correlated with viral counts indicating more severe metabolite abnormalities in animals with higher viral loads or set points. Collectively, these findings suggest that chronic morphine may protect against the neurotoxic effect of AIDS and reinforce the importance of maintaining a low viral load in AIDS.     

Magnetic Resonance Spectroscopy to Assess NeuroInflammation and Neuropathic Pain

Proton magnetic resonance spectroscopy (¹H MRS) has been applied to numerous clinical studies, especially for neurological disorders. This technique can non-invasively evaluate brain metabolites and neurochemicals in selected brain regions and is particularly useful for assessing neuroinflammatory disorders. Neurometabolites assessed with MRS include the neuronal markers N-acetylaspartate (NAA) and glutamate (Glu), as well as the glial marker myo-inositol (MI). Therefore, the concentrations of these metabolites typically correspond to disease severity and often correlate well with clinical variables in the various brain disorders. Neuroinflammation with activated astrocytes and microglia in brain disorders are often associated with elevated MI, and to a lesser extent elevated total creatine (tCr) and choline containing compounds (Cho), which are found in higher concentrations in glia than neurons, while neuronal injury is indicated by lower than normal levels of NAA and Glu. This review summarizes the neurometabolite abnormalities found in MRS studies performed in patients with neuroinflammatory disorders or neuropathic pain, which also may be associated with neuroinflammation. These brain disorders include multiple sclerosis, neuroviral infections (including Human Immunodeficiency virus and Hepatitis C), degenerative brain disorders (including Alzheimer’s disease and Parkinson’s disease), stimulant abuse (including methamphetamine and cocaine) as well as several chronic pain syndromes.     

Predictors of adherence and virologic outcome in HIV-infected patients treated with abacavir- or indinavir-based triple combination HAART also containing lamivudine/zidovudine

SUMMARY

Objectives: To compare dosing convenience and adherence with abacavir (ABC) 300?mg plus a fixed-dose lamivudine 150?mg/zidovudine 300?mg combination tablet (COM) twice daily versus indinavir (IDV) plus COM twice daily in treatment-naïve, HIV-1-infected adults; and to evaluate the association among difficulty taking antiretroviral regimens, adherence, and virologic efficacy.

Methods: An open-label, randomized, multicenter, international study compared the COM/ABC and IDV/COM regimens with respect to self-reported adherence and regimen convenience over 48?weeks. Logistic regression analysis (LRA) was done on a patient sub-sample from both groups to evaluate predictors of adherence and virologic response at last time-point on randomized therapy (LTORT).

Results: The study population was diverse with respect to ethnicity (38% Asian, 27% Hispanic, 28% white, 3% black, 4% other) and gender (39% women, 61% men). Baseline median HIV-1 RNA was 4.80?log₁₀ copies/mL and CD4+ cell count was 315?cells/mm³. Of 329 patients who were randomized and received treatment, 315 (96%) provided adherence data. Significantly more patients in the ABC/COM group than in the IDV/COM group reported ≥ 95% adherence to therapy (76 vs 58%, p < 0.001) and no difficulty in taking their regimen (91 vs 61%, p < 0.001). In both groups, the highest probability of HIV-1 RNA < 400 copies/mL occurred when median adherence was ≥ 95%. The probability of HIV-1 RNA < 400?copies/mL declined more rapidly in the IDV/COM group as adherence rates decreased. LRA showed that no difficulty taking any of the drugs in the regimen, ABC/COM treatment group, and male gender were independent significant predictors of ≥ 95% adherence (?p < 0.05). Median adherence and baseline HIV-1 RNA were significant predictors of HIV-1 RNA < 400?copies/mL (?p < 0.05).

Conclusions: Patients reported greater ease of use and superior adherence to ABC/COM than IDV/COM. Patient-reported difficulty taking drugs in a regimen was predictive of reduced adherence, and both of the latter factors were predictive of poorer virologic outcome. Adherence levels of ≥ 95% in both treatment groups maximized the probability of patients achieving an HIV-1 RNA < 400?copies/mL.