Clea E. Ribeiro

Neurocognitive Impairment in HIV-1 Clade C versus B Infected Individuals in Southern Brazil

HIV-1 clade C isolates show reduced Tat protein chemoattractant activity compared with clade B. This might influence neuropathogenesis by altering trafficking of monocytes into the CNS. A previous study suggested low rates of HIV-associated dementia in clade C-infected individuals. The present study evaluated neurocognitive impairment rates in clade B- and C-infected individuals from the same local population. HIV+ and HIV− participants were recruited from the same geographic region in Southern Brazil. We evaluated neuropsychological (NP) impairment using a screening instrument (the International HIV Dementia Scale (IHDS)), as well as a Brazilian Portuguese adaptation of a comprehensive battery that has demonstrated sensitivity to HIV-associated neurocognitive disorders (HAND) internationally. NP performance in controls was used to generate T scores and impairment ratings by the global deficit score (GDS) method. Clade assignments were ascertained by sequencing pol and env. Blood and cerebrospinal fluid were collected from all HIV+ participants. HIV+ and HIV− participants were comparable on demographic characteristics. HIV+ participants overall were more likely to be impaired than HIV− by the IHDS and the GDS. Clade B- and C-infected individuals were demographically similar and did not differ significantly in rates of impairment. The prevalence of pleocytosis, a marker of intrathecal cellular chemotaxis, also did not differ between clade B and C infections. Clade B and C HIV-infected individuals from the same geographic region, when ascertained using comparable methods, did not differ in their rates of neurocognitive impairment, and there was no evidence of differences in CNS chemotaxis.

Implications of apathy and depression for everyday functioning in HIV/AIDS in Brazil

BACKGROUND Brazil accounts for the largest number of HIV+ persons in Latin America, and this epidemic poses a significant public health burden in this country. Little is known about the neuropsychiatric and functional consequences of HIV infection in this population. METHODS Participants were 43 HIV+ and 29 HIV- individuals who underwent a neuropsychological, psychiatric and neurological evaluation that included self-report measures of mood (Beck Depression Inventory-II; BDI-II), neurocognitive complaints (Patients Assessment of Own Functioning Inventory) and declines in instrumental activities of daily living (Activities of Daily Living questionnaire). The MINI-Plus generated major depressive disorder (MDD) diagnoses. Apathy, defined as social withdrawal, decision-making difficulty, loss of interest and pleasure, was measured using items from the BDI-II and the neurological evaluation. RESULTS When compared with seronegative participants, HIV+ individuals endorsed higher levels of apathy spectrum symptoms. After adjusting for mood and other covariates, apathy significantly predicted worse everyday functioning. LIMITATIONS The small sample size, along with the self-report measures used to evaluate apathy and functional difficulties limit the inferences that may be drawn from our findings. CONCLUSIONS Our Brazilian HIV+ cohort endorsed apathy and depression as well as significant functional complaints. Although correlated with depression, apathy was uniquely associated with functional difficulties. Clinical attention to apathy and depression in HIV-infected Brazilians may help identify patients at risk for functional difficulties who may benefit from additional support to maintain independence.

Molecular epidemiology of HIV-1 clades in Southern Brazil

Human immunodeficiency virus (HIV) clades B and C account for more than 60% of the HIV-1 infections worldwide. In this paper, we describe the profiles of patients infected with subtypes of HIV-1 from the state of Paraná, Southern Brazil, and correlate them with demographic and epidemiological findings. A retrospective analysis of HIV cases reported from 1999-2007 was also performed. Data from 293 patients were reviewed and 245 were older than 13 (58% female). The distribution of clades was as follows: B 140 (57%), C 67 (23%), F 24 (10%) and mosaic or unique recombinant forms (URFs) 24 (10%). Of the 48 patients younger than 13 years of age (62.5% male), vertical transmission occurred in 46 and the distribution of clades was as follows: B 14 (29%), C 24 (50%), F 7 (15%) and URFs 6 (13%). There was no significant difference in mortality between HIV-1 subtypes. In both groups, patients infected with clade C tended to have higher rates of injection drug use exposure risk.

Quantification of cerebrospinal fluid lactic acid in the differential diagnosis between HIV chronic meningitis and opportunistic meningitis.

Abstract Background: Approximately 40% of HIV infected patients have chronic meningitis at various stages during the infection, 59% are asymptomatic. This is a diagnosis of exclusion and a confounding factor in cerebrospinal fluid (CSF) analysis, any other causes of chronic meningitis by opportunistic or co-infection must be ruled out. The aim of this study was to analyze CSF lactic acid (LA) as an adjuvant biomarker in chronic meningitis due to HIV. Methods: CSF LA was quantified in 223 CSF samples by the Dimension AR (Dade Behring, Deerfield, IL, USA), distributed into nine groups: 1) HIV positive with an increase in CSF WBCs (n=17); 2) HIV positive with normal CSF (n=20); 3) enterovirus meningitis (n=33); 4) Herpesviridae meningoencephalitis (n=30); 5) fungal meningitis (n=25); 6) tuberculosis (TB) meningitis (n=17); 7) toxoplasmosis (n=18); 8) neurosyphilis (n=6); 9) control group (n=57). Results: CSF LA (median; IQR) was higher in samples with TB meningitis (5.5; 2.9–7.5 mmol/L) and Cryptococcus neoformans meningitis (3.9; 2.7–5.8 mmol/L) compated with samples with HIV chronic meningitis (1.7; 1.4–1.9 mmol/L) and other groups (p≤0.0001). For the diagnosis of HIV chronic meningitis, using a cut-off of 3.5 mmol/L, CSF LA showed high sensitivity and negative predictive value, although low specificity. Conclusions: CSF LA helps to discriminate between C. neoformans or TB meningitis and HIV chronic meningitis: CSF LA can be included with the methods currently used to identify these specific pathogens, though it does not replace them. It is rapid, inexpensive and easy to perform, and can be used in developing countries.

Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization—case study

Despite the effective suppression of viremia with antiretroviral therapy, HIV can still replicate in the central nervous system (CNS). This was a longitudinal study of the cerebrospinal fluid (CSF) and serum dynamics of several biomarkers related to inflammation, the blood-brain barrier, neuronal injury, and IgG intrathecal synthesis in serial samples of CSF and serum from a patient infected with HIV-1 subtype C with CNS compartmentalization.The phylogenetic analyses of plasma and CSF samples in an acute phase using next-generation sequencing and F-statistics analysis of C2-V3 haplotypes revealed distinct compartmentalized CSF viruses in paired CSF and peripheral blood mononuclear cell samples. The CSF biomarker analysis in this patient showed that symptomatic CSF escape is accompanied by CNS inflammation, high levels of cell and humoral immune biomarkers, CNS barrier dysfunction, and an increase in neuronal injury biomarkers with demyelization. Independent and isolated HIV replication can occur in the CNS, even in HIV-1 subtype C, leading to compartmentalization and development of quasispecies distinct from the peripheral plasma. These immunological aspects of the HIV CNS escape have not been described previously. To our knowledge, this is the first report of CNS HIV escape and compartmentalization in HIV-1 subtype C.

Blood-CSF barrier and compartmentalization of CNS cellular immune response in HIV infection.

HIV infection is persistent in the CNS, to evaluate the compartmentalization of the CNS immune response to HIV, we compared soluble markers of cellular immunity in the blood and CSF among HIV- (n=19) and HIV+ (n=68), as well as among HIV participants with or without CSF pleocytosis. Dysfunction of the blood cerebrospinal fluid barrier (BCSFB) was common in HIV participants. CSF levels of TNFα, IFNγ, IL-2, IL-6, IL-7, IL-10, IP-10, MIP-1α, MIP-1β, and RANTES were significantly higher in participants with CSF pleocytosis (P<0.05); serum levels of these biomarkers were comparable. The CNS immune response is compartmentalized, and remains so despite the BCSFB dysfunction during HIV infection; it is markedly reduced by virology suppression, although BCSFB dysfunction persists on this subgroup.

Estimation of HIV incidence in two Brazilian municipalities, 2013

ABSTRACT OBJECTIVE To estimate HIV incidence in two Brazilian municipalities, Recife and Curitiba, in the year of 2013. METHODS The method for estimating incidence was based on primary information, resulting from the Lag-Avidity laboratory test for detection of recent HIV infections, applied in a sample of the cases diagnosed in the two cities in 2013. For the estimation of the HIV incidence for the total population of the cities, the recent infections detected in the research were annualized and weighted by the inverse of the probability of HIV testing in 2013 among the infected and not diagnosed cases. After estimating HIV incidence for the total population, the incidence rates were estimated by sex, age group, and exposure category. RESULTS In Recife, 902 individuals aged 13 years and older were diagnosed with HIV infection. From these, 528 were included in the study, and the estimated proportion of recent infections was 13.1%. In Curitiba, 1,013 people aged 13 years and older were diagnosed, 497 participated in the study, and the proportion of recent infections was 10.5%. In Recife, the estimated incidence rate was 53.1/100,000 inhabitants of 13 years and older, while in Curitiba, it was 41.1/100,000, with male-to-female ratio of 3.5 and 2.4, respectively. We observed high rates of HIV incidence among men who have sex with men, of 1.47% in Recife and 0.92% in Curitiba. CONCLUSIONS The results obtained in the two cities showed that the group of men who have sex with men are disproportionately subject to a greater risk of new infections, and indicate that strategies to control the spread of the epidemic in this population subgroup are essential and urgent.

Cerebrospinal fluid can be used for HIV genotyping when it fails in blood

Blood plasma specimens are the clinical standard for HIV-1 pol gene genotyping from viral populations; however, it is not always successful, often from low viral loads or the presence of polymerase chain reaction (PCR) inhibitors. Objective To describe the successful of HIV-1 genotyping in two samples of cerebrospinal fluid (CSF), after genotype procedures failed from blood. Method Two HIV-infected patients enrolled in a neurocognitive research study were evaluated when standard HIV-1 genotyping failed from blood plasma samples. Genotyping was performed using the commercial system TRUGENE HIV-1 Genotyping Kit and the OpenGene DNA Sequencing System (Siemens Healthcare Diagnostics, Tarrytown, NY, USA). Results CSF genotyping was performed via the same commercial platform and was successful in both cases. Conclusion This report demonstrates that CSF could be used as an alternate clinical specimen for HIV-1 genotyping when it fails from blood.

Acute bacterial meningitis in HIV, patients in southern Brazil: Curitiba, Paraná, Brazil.

Acute communitarian bacterial meningitis and AIDS are prevalent infectious disease in Brazil. The objective of this study was to evaluate the frequency of acute communitarian bacterial meningitis in AIDS patients, the clinical and cerebrospinal fluid (CSF) characteristics. It was reviewed the Health Department data from city of Curitiba, Southern Brazil, from 1996 to 2002. During this period, 32 patients with AIDS fulfilled criteria for acute bacterial meningitis, representing 0.84% of the AIDS cases and 1.85% of the cases of bacterial meningitis. S. pneumoniae was the most frequent bacteria isolated. The number of white blood cells and the percentage of neutrophils were higher and CSF glucose was lower in the group with no HIV co-infection (p 0.12; 0.008; 0.04 respectively). Bacteria not so common causing meningitis can occur among HIV infected patients. The high mortality rate among pneumococcus meningitis patients makes pneumococcus vaccination important.

Improving detection of HIV-associated cognitive impairment: Comparison of the International HIV Dementia Scale and a Brief Screening Battery.

Objectives: The International HIV Dementia Scale (IHDS) was developed to screen for HIV-associated dementia, but it has been used more generally for HIV-associated neurocognitive disorder (HAND). This study sought to examine the accuracy of the IHDS in a cohort of Brazilian HIV-infected individuals and compare its performance to an alternative screening battery for detecting HAND. Methods: A total of 108 participants (including 60 HIV-infected persons) completed the IHDS and a gold standard neuropsychological (NP) battery of 17 tests. As alternative screening method, all possible 3-test combinations from the NP battery were examined and a superiority index (a marker of specificity and sensitivity) was calculated. Results: Sensitivity and specificity to HAND using the standard IHDS cutpoint of 10 were 36% and 75%, respectively. The best balance between sensitivity and specificity was accomplished with a modified cutpoint of 11.5, which yielded sensitivity of 72% and specificity of 58%. The top two most sensitive test combinations, compared with the gold standard NP battery, were Trail Making Test A, Wechsler Adult Intelligence Scale III Digit Symbol and Hopkins Verbal Learning Test—Revised Total Recall (sensitivity 91%, specificity 96%), and Digit Symbol, Brief Visuospatial Memory Test—Revised Total Recall and Grooved Pegboard Test—dominant hand (sensitivity 94%, specificity 91%). Conclusions: Both test combinations can be administered in less than 10 minutes and were more accurate than the IHDS in classifying HIV+ participants as NP impaired or unimpaired. These data suggest that demographically corrected T-scores from commonly used NP measures with modest time and material demands can improve identification of patients with HAND who may benefit from a more extensive NP examination.