Functional Connectivity in Virally Suppressed Patients with HIV-Associated Neurocognitive Disorder: A Resting-State Analysis.

BACKGROUND AND PURPOSE: HIV-associated neurocognitive disorder still occurs despite virally suppressive combination antiretroviral therapy. In the pre-combination antiretroviral era and in patients without HIV suppression, HIV-associated neurocognitive disorder was caused by synaptodendritic injury resulting in impairment of neural networks, characterized by decreased attention, psychomotor slowing, and working memory deficits. Whether similar pathogenesis is true for HIV-associated neurocognitive disorder in the context of viral suppression is not clear. Resting-state fMRI has been shown to be efficient in detecting impaired neural networks in various neurologic illnesses. This pilot study aimed to assess resting-state functional connectivity of the brain in patients with active HIV-associated neurocognitive disorder in the context of HIV viral suppression in both blood and CSF. MATERIALS AND METHODS: Eighteen patients with active HIV-associated neurocognitive disorder (recent diagnosis with progressing symptoms) on combination antiretroviral therapy with viral suppression in both blood and CSF and 9 demographically matched control subjects underwent resting-state functional MR imaging. The connectivity in the 6 known neural networks was assessed. To localize significant ROIs within the HIV and control group, we performed a seed-based correlation for each known resting-state network. RESULTS: There were significant group differences between the control and HIV-associated neurocognitive disorder groups in the salience (0.26 versus 0.14, t = 2.6978, df = 25, P = .0123) and executive networks (0.52 versus 0.32, t = 2.2372, df = 25, P = .034). The covariate analysis with neuropsychological scores yielded statistically significant correlations in all 6 studied functional networks, with the most conspicuous correlation in salience networks. CONCLUSIONS: Active HIV-associated neurocognitive disorder in virally suppressed patients is associated with significantly decreased connectivity in the salience and executive networks, thereby making it potentially useful as a biomarker.

CNS-specific regulatory elements in brain-derived HIV-1 strains affect responses to latency-reversing agents with implications for cure strategies.

Latency-reversing agents (LRAs), including histone deacetylase inhibitors (HDACi), are being investigated as a strategy to eliminate latency in HIV-infected patients on suppressive antiretroviral therapy. The effectiveness of LRAs in activating latent infection in HIV strains derived from the central nervous system (CNS) is unknown. Here we show that CNS-derived HIV-1 strains possess polymorphisms within and surrounding the Sp transcription factor motifs in the long terminal repeat (LTR). These polymorphisms result in decreased ability of the transcription factor specificity protein 1 to bind CNS-derived LTRs, reducing the transcriptional activity of CNS-derived viruses. These mutations result in CNS-derived viruses being less responsive to activation by the HDACi panobinostat and romidepsin compared with lymphoid-derived viruses from the same subjects. Our findings suggest that HIV-1 strains residing in the CNS have unique transcriptional regulatory mechanisms, which impact the regulation of latency, the consideration of which is essential for the development of HIV-1 eradication strategies.

Consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New Zealand.

Encephalitis is a complex neurological syndrome caused by inflammation of the brain parenchyma. The management of encephalitis is challenging because: the differential diagnosis of encephalopathy is broad; there is often rapid disease progression; it often requires intensive supportive management; and there are many aetiologic agents for which there is no definitive treatment. Patients with possible meningoencephalitis are often encountered in the emergency care environment where clinicians must consider differential diagnoses, perform appropriate investigations and initiate empiric antimicrobials. For patients who require admission to hospital and in whom encephalitis is likely, a staged approach to investigation and management is preferred with the potential involvement of multiple medical specialties. Key considerations in the investigation and management of patients with encephalitis addressed in this guideline include: Which first-line investigations should be performed?; Which aetiologies should be considered possible based on clinical features, risk factors and radiological features?; What tests should be arranged in order to diagnose the common causes of encephalitis?; When to consider empiric antimicrobials and immune modulatory therapies?; and What is the role of brain biopsy?

HIV eradication symposium: will the brain be left behind?

On 18 July 2014, the National Institute of Mental Health in collaboration with ViiV Health Care and Boehringer Ingelheim supported a symposium on HIV eradication and what it meant for the brain. The symposium was an affiliated event to the 20th International AIDS Conference. The meeting was held in Melbourne, Australia, and brought together investigators currently working on HIV eradication together with investigators who are working on the neurological complications of HIV. The purpose of the meeting was to bring the two fields of HIV eradication and HIV neurology together to foster dialogue and cross talk to move the eradication field forward in the context of issues relating to the brain as a potential reservoir of HIV. The outcomes of the symposium were that there was substantive but not definitive evidence for the brain as an HIV reservoir that will provide a challenge to HIV eradication. Secondly, the brain as a clinically significant reservoir for HIV is not necessarily present in all patients. Consequently, there is an urgent need for the development of biomarkers to identify and quantify the HIV reservoir in the brain. Lastly, when designing and developing eradication strategies, it is critical that approaches to target the brain reservoir be included.

Factors associated with neurocognitive test performance at baseline: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: We describe neuropsychological test performance (NP) in antiretroviral treatment (ART)-naïve HIV-positive individuals with CD4 cell counts above 500 cells/µL. METHODS: In a neurology substudy of the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) Strategic Timing of AntiRetroviral Treatment (START) study, eight neurocognitive tests were administered. The primary measure of NP was the quantitative NP z-score (QNPZ-8), the average of the z-scores for the eight tests. Associations of baseline factors with QNPZ-8 scores were assessed by multiple regression. Mild neurocognitive impairment (NCI) was defined as z-scores < -1 in at least two of six cognitive domains. RESULTS: A total of 608 participants had a median age of 34 years; 11% were women and 15% were black; the median time since HIV diagnosis was 0.9 years; the median CD4 cell count was 633 cells/µL; 19.9% had mild NCI. Better NP was independently associated with younger age, being white, higher body mass index (0.10 per 10 kg/m(2) higher), and higher haematocrit percentage (0.19 per 10% higher). Worse NP was associated with longer time since HIV diagnosis (-0.17 per 10 years), diabetes (-0.29) and higher Framingham risk score (-0.15 per 10 points higher). QNPZ-8 scores differed significantly between geographical locations, with the lowest scores in Brazil and Argentina/Chile. CONCLUSIONS: This is the largest study of NP in ART-naïve HIV-positive adults with CD4 counts > 500 cells/µL. Demographic factors and diabetes were most strongly associated with NP. Unmeasured educational/sociocultural factors may explain geographical differences. Poorer NP was independently associated with longer time since HIV diagnosis, suggesting that untreated HIV infection might deleteriously affect NP, but the effect was small.

Treatment of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome with intravenous immunoglobulin in a patient with multiple sclerosis treated with fingolimod after discontinuation of natalizumab.

We report a case of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome in a multiple sclerosis (MS) patient 3.5 months after fingolimod commencement and 4.5 months after natalizumab (NTZ) cessation. Three cerebrospinal fluid analyses were required before a definitive diagnosis of progressive multifocal leukoencephalopathy was reached. Intravenous immunoglobulin (IVIG) was subsequently given as the sole MS treatment along with mirtazapine and mefloquine. There has been improvement and subsequent clinical stabilization. The notable features are the difficult timing of fingolimod commencement in the context of previous NTZ therapy, the role of repeated cerebrospinal fluid John Cunningham virus analyses in progressive multifocal leukoencephalopathy diagnosis, and the role of IVIG.

Symptoms of depression and rates of neurocognitive impairment in HIV positive patients in Beijing, China.

BACKGROUND: In China an estimated 780,000 people are living with HIV (PLWH). In high-income countries PLWH are at increased risk of depression, with subsequent adverse consequences for quality of life, and HIV-related morbidity and mortality. There are few data from low-and middle-income countries. The aims of this country-specific investigation of the Asia Pacific NeuroAIDS Consortium (APNAC) study were to establish the point prevalence, severity and HIV-related and non-HIV related correlates of depressive symptoms in PLWH, in Beijing, China. METHOD: PLWH attending an outpatient clinic at Ditan Hospital, Beijing were recruited consecutively. Data sources were: study-specific questions about demographic characteristics, and health behaviours, the Centre for Epidemiological Studies Depression Scale (CES-D), the World Health Organisation Self-Reporting Questionnaire (SRQ-20) translated into Mandarin and administered as structured individual interviews, and a screen battery of four standard neuropsychological tests. RESULTS: In total 50/51 (98%) eligible patients agreed to participate. Overall 28% scored CES-D≥16 or SRQ20≥10 and 18% in these clinical ranges on both measures; 69% were classified as being neuropsychologically impaired (scoring below 1 SD of the control value on at least two tests). Higher depressive symptom scores were associated with lower education, alcohol overuse and diminished motor ability (all p<0.05), but not neuropsychological impairment CONCLUSION: Clinically significant depressive symptoms among this cohort of PLWH in Beijing occurred at 5 times the rate reported among a general Chinese urban population. No participants had been assessed for depression prior to the study and none were treated, indicating that consideration of psychological morbidity and its consequences for health behaviours should be incorporated into routine HIV care in China.

Raltegravir resistance in the cerebrospinal fluid.

We report the first published case of integrase inhibitor resistance in the central nervous system compartment in the absence of evidence of integrase inhibitor resistance in the plasma of a patient without human immunodeficiency virus (HIV)-encephalitis in the context of other HIV-associated central nervous system infections.

Does use of antiretroviral therapy regimens with high central nervous system penetration improve survival in HIV-infected adults?

OBJECTIVES: The aim of the study was to determine whether combination antiretroviral therapy (cART) with high central nervous system penetration-effectiveness (CPE) rank (neurocART) is associated with increased survival benefit compared with non-neurocART. METHODS: Prospective data were examined for HIV-positive patients in the Asia Pacific HIV Observational Database who had commenced cART. CPE rank was calculated using the 2010 rankings process. NeurocART status was assigned to regimens with a CPE rank of 8 or more. Survival was analysed using Cox proportional hazards models with covariates updated at changes in cART regimen and with deaths up to 90 days after regimen cessation attributed to that regimen. Sensitivity analyses were conducted to examine the robustness of analysis assumptions. RESULTS: Among 5882 patients, 308 deaths occurred. The hazard ratio (HR) for neurocART use was 0.89 (P=0.35) when data were stratified by cohort and adjusted for age, mode of HIV exposure, hepatitis B virus coinfection, AIDS-defining illness, CD4 count (cells/µL) and regimen count. Sensitivity analyses showed similar nonsignificant results. We also examined a composite endpoint of AIDS-defining illness or death (HR=0.93; P=0.61), baseline regimen as neurocART (HR=0.95; P=0.69), CPE category (P=0.71) and prior neurocART duration (P=0.16). No association between CD4 cell count and neurocART use was observed (P=0.52). CONCLUSIONS: Our findings do not show a significant overall survival benefit associated with neurocART compared with cART. The potential benefit associated with neurocART in terms of prevention of neurocognitive impairment did not translate into an improvement in overall survival in this population. These findings were limited by the low incidence of associated mortality. Further studies and more extensive data are needed to address these limitations.

Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons.

OBJECTIVE: To determine factors associated with baseline neurocognitive performance in HIV-infected participants enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) neurology substudy. METHODS: Participants from Australia, North America, Brazil, and Thailand were administered a 5-test neurocognitive battery. Z scores and the neurocognitive performance outcome measure, the quantitative neurocognitive performance z score (QNPZ-5), were calculated using US norms. Neurocognitive impairment was defined as z scores <-2 in two or more cognitive domains. Associations of test scores, the QNPZ-5, and impairment with baseline factors including demographics and risk factors for HIV-associated dementia (HAD) and cardiovascular disease (CVD) were determined in multiple regression. RESULTS: The 292 participants had a median CD4 cell count of 536 cells/mm(3), 88% had an HIV viral load < or =400 copies/mL, and 92% were taking antiretrovirals. Demographics, HIV, and clinical factors differed between locations. The mean QNPZ-5 score was -0.72; 14% of participants had neurocognitive impairment. For most tests, scores and z scores differed significantly between locations, with and without adjustment for age, sex, education, and race. Prior CVD was associated with neurocognitive impairment. Prior CVD, hypercholesterolemia, and hypertension were associated with poorer neurocognitive performance but conventional HAD risk factors and the CNS penetration effectiveness rank of antiretroviral regimens were not. CONCLUSIONS: In this HIV-positive population with high CD4 cell counts, neurocognitive impairment was associated with prior CVD. Lower neurocognitive performance was associated with prior CVD, hypertension, and hypercholesterolemia, but not conventional HAD risk factors. The contribution of CVD and cardiovascular risk factors to the neurocognition of HIV-positive populations warrants further investigation.

Hepatitis C seropositivity is not a risk factor for sensory neuropathy among patients with HIV.

BACKGROUND: Sensory neuropathy (SN) is common in patients with HIV. Hepatitis C (HCV) coinfection is often cited as an HIV-SN risk factor, but data to support this are lacking. This collaboration aimed to examine the association between HCV serostatus and SN risk among ambulatory HIV-positive patients. METHODS: Patients with HIV were assessed in cross-sectional studies in Baltimore, Jakarta, Johannesburg, Kuala Lumpur, Melbourne, and Sydney for SN (defined by both supportive symptoms and signs). HCV seropositivity was assessed as an SN risk using a chi(2) test, followed by logistic regression modeling to correct for treatment exposures and demographics. RESULTS: A total of 837 patients of African, Asian, and Caucasian descent were studied. HCV seroprevalence varied by site (Baltimore n = 104, 61% HCV+; Jakarta 96, 51%; Johannesburg 300, 1%; Kuala Lumpur 97, 10%; Melbourne 206, 16%; Sydney 34, 18%). HCV seropositivity was not associated with increased SN risk at any site, but was associated with reduced SN risk in Melbourne (p = 0.003). On multivariate analyses, the independent associations with SN were increasing age, height, and stavudine exposure. HCV seropositivity was not independently associated with an increased SN risk at any site, but associated independently with reduced SN risk in Baltimore (p = 0.04) and Melbourne (p = 0.06). CONCLUSIONS: Hepatitis C (HCV) seropositivity was not associated with increased sensory neuropathy risk among HIV-positive patients at any site. While we were unable to assess HCV RNA or liver damage, the data suggest that HCV coinfection is not a major contributor to HIV-SN. HCV = hepatitis C; SN = sensory neuropathy.

A screening algorithm for HIV-associated neurocognitive disorders.

BACKGROUND: HIV physicians have limited time for cognitive screening. Here we developed an extra-brief, clinically based tool for predicting HIV-associated neurocognitive impairment (HAND) in order to determine which HIV-positive individuals require a more comprehensive neurological/neuropsychological (NP) assessment. METHODS: Ninety-seven HIV-positive individuals with advanced disease recruited in an HIV out-patient clinic received standard NP testing. A screening algorithm was developed using support vector machines, an optimized prediction procedure for classifying individuals into two groups (here NP-impaired and NP-normal) based on a set of predictors. RESULTS: The final algorithm utilized age, current CD4 cell count, past central nervous system HIV-related diseases and current treatment duration and required approximately 3 min to complete, with a good overall prediction accuracy of 78% (against the gold standard; NP-impairment status derived from standard NP testing) and a good specificity of 70%. CONCLUSION: This noncognitive-based algorithm should prove useful to identify HIV-infected patients with advanced disease at high risk of HAND who require more formal assessment. We propose staged guidelines, using the algorithm, for improved HAND therapeutic management. Future larger, international studies are planned to test the predictive effect of nadir CD4 cell count, hepatitis C virus infection, gender, ethnicity and HIV viral clade. We recommend the use of this first version for HIV-infected Caucasian men with advanced disease.

The relationship between ApoE, TNFA, IL1a, IL1b and IL12b genes and HIV-1-associated dementia.

OBJECTIVES: Host genetic factors implicated in AIDS dementia complex (ADC) were studied. METHODS: DNA from ADC patients (n=56), unselected HIV-seropositive patients (n=112, 171, 185 and 204) and HIV-seronegative controls (n=204, 60, 60, 96 and 624) were typed for polymorphic loci in genes encoding tumour necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, IL-1beta, IL-12 and Apolipoprotein E (ApoE). Diagnosis of ADC was based on neurological symptoms, signs and neuroimaging findings with other causes of dementia excluded. Patients selected had ADC stage > or =1 and CD4 counts of <500 cells/microL. RESULTS: Allele 2 of TNFA-308 was more common in ADC patients compared to HIV-positive or HIV-negative controls (P=0.005, 0.024). No other differences between ADC patients and control groups were significant. Meta-analyses confirmed these results. CONCLUSIONS: This study suggests that TNFA-308 allele 2 or an allele in linkage disequilibrium with this locus influences ADC.

Serotonin decreases HIV-1 replication in primary cultures of human macrophages through 5-HT(1A) receptors.

BACKGROUND AND PURPOSE: 5-HT (serotonin) is known to be involved in neuroinflammation and immunoregulation. The human immunodeficiency virus (HIV) targets cells such as monocytes/macrophages, which colocalize with 5-HT-releasing cell types, mostly platelets. In this study, we investigated the effects of 5-HT on HIV-1-infected macrophages in vitro. EXPERIMENTAL APPROACH: Human macrophages cultured in serum-free medium were treated over 7 days with 5-HT at three concentrations (0.01, 1 and 100 microM) with or without agonists and antagonists of 5-HT(1A) and 5-HT(2) receptors. After 7 days of treatment, macrophages were infected with HIV-1/Ba-L and virus replication was monitored over 16 days and expression of proviral HIV DNA was investigated by PCR after 24 h of infection. Cell surface expression of HIV-1/Ba-L receptor (CD4) and coreceptor (CCR5) was investigated by flow cytometry. The CCR5 ligand, macrophage inflammatory protein-1alpha (MIP-1alpha), was quantified by ELISA in cell culture supernatants and MIP-1alpha mRNA expression was assessed by reverse transcriptase-PCR. KEY RESULTS: In vitro, 5-HT downregulated the membranous expression of CCR5 and led to a decrease of HIV-1 infection, probably through its action on 5-HT(1A) receptors. 5-HT (100 microM) was also able to induce overexpression of MIP-1alpha mRNA leading to an increase of MIP-1alpha secretion by human macrophages. CONCLUSIONS AND IMPLICATIONS: The effects of 5-HT on HIV infection could be a consequence of the increase in MIP-1alpha concentrations and/or CCR5 receptor downregulation. These results suggest that 5-HT can inhibit the replication of HIV-1 in primary culture of human macrophages through its action on 5-HT(1A) receptors.

Updated research nosology for HIV-associated neurocognitive disorders.

In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND.

Improved cognitive function as a consequence of hepatitis C virus treatment.

OBJECTIVE: The aim of the study was to investigate the impact of treatment-related clearance of hepatitis C virus (HCV) on cognitive function. METHODS: A prospective study was conducted in 19 HCV-monoinfected and 15 HIV/HCV-coinfected individuals undergoing pegylated interferon alpha-2a and ribavirin therapy between April 2003 and August 2005. Neuropsychological, mood, and health-related quality of life (HRQOL) effects were assessed using computer-based battery, Trail Making Tests, Depression Anxiety Stress Scales and the Short Form-36 health survey. RESULTS: Pretreatment cognitive function, mood status, and HRQOL were similar between the HCV patient groups. Sustained virological response (SVR) rates were similar between HCV-monoinfected (68%) and HIV/HCV-coinfected (73%) groups. SVR was associated with significant improvements in some measures of cognitive function, independent of HRQOL improvement. CONCLUSIONS: Our findings provide evidence to support cognitive effects of HCV independent of mood status and HRQOL profiles.

Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection.

OBJECTIVE: Increased levels of the light-chain neurofilament protein (NFL) in CSF provide a marker of CNS injury in several neurodegenerative disorders and have been reported in the AIDS dementia complex (ADC). We examined the effects of highly active antiretroviral treatment (HAART) on CSF NFL in HIV-1-infected subjects with and without ADC who underwent repeated lumbar punctures (LPs). METHOD: NFL was measured by ELISA (normal reference value < 250 ng/L) in archived CSF samples from 53 patients who had undergone LPs before and after initiation of HAART. RESULTS: Twenty-one of the subjects had increased CSF NFL at baseline, with a median level of 780 ng/L and an intraquartile range (IQR) of 480 to 7300. After 3 months of treatment, NFL concentrations had fallen to normal in 48% (10/21), and the median decreased to 340 ng/L (IQR < 250 to 4070) (p < 0.001), whereas at 1 year, only 4 of 16 of the 21 subjects observed for this length still had elevated NFL levels. Thirty-two subjects had normal NFL at baseline, and all but one remained normal at follow-up. These effects on CSF NFL were seen in association with clinical improvement in ADC patients, decreases in plasma and CSF HIV-1 RNA and CSF neopterin, and increases in blood CD4 T cell counts. CONCLUSION: HAART seems to halt the neurodegenerative process(es) caused by HIV-1, as shown by the significant decrease in CSF NFL after treatment initiation. CSF NFL may serve as a useful marker in monitoring CNS injury in HIV-1 infection and in evaluating CNS efficacy of antiretroviral therapy.

Human immunodeficiency virus-associated progressive multifocal leucoencephalopathy: epidemiology and predictive factors for prolonged survival.

We performed a retrospective review of cases of human immunodeficiency virus-associated progressive multifocal leucoencephalopathy in four hospitals (three in Australia and one in Hong Kong) between 1987 and 2003 in order to describe the local experience with this disease and to evaluate parameters impacting upon survival. Eighty-seven cases were identified and demographic details, baseline parameters and treatment methods and response were described. Survival was substantially increased in the post-highly active antiretroviral therapy (HAART) era with a median survival increase from 14 to 64 weeks. On multivariate analysis, variables associated with prolonged survival included a CD4 count of >100 cells/mul at diagnosis and the use of HAART post-diagnosis, with no significant additional advantage from the use of neuroactive antiretrovirals.

Neural transplantation of human MSC and NT2 cells in the twitcher mouse model.

BACKGROUND: Accumulating evidence has demonstrated that the NT2 embryonal carcinoma cell line and multipotential stem cells found in BM, mesenchymal stromal cells (MSC), have the ability to differentiate into a wide variety of cell types. This study was designed to explore the efficacy of these two human stem cell types as a graft source for the treatment of demyelinating disorders such as Krabbe's disease and multiple sclerosis (MS). METHODS: We examined the engraftment and in vivo differentiation of adult MSC and NT2 cells after transplantation into two demyelinating environments, the neonatal and postnatal twitcher mouse brain. RESULTS: Both types of xenografts led to anatomical integration, without tumor formation, and remained viable in the normal and twitcher mouse brain, showing differentiation into neurons, astrocytes and oligodendrocytes. DISCUSSION: This study represents a platform for further stem cell transplantation studies in the twitcher model and potentially has important therapeutic implications.