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Peripheral Blood Mitochondrial DNA Copy Number Obtained From Genome-Wide Genotype Data Is Associated With Neurocognitive Impairment in Persons With Chronic HIV Infection.
Hulgan T, Kallianpur AR, Guo Y, Barnholtz-Sloan JS, Gittleman H, Brown TT, Ellis R, Letendre S, Heaton RK, Samuels DC, CHARTER Study
(2019) J Acquir Immune Defic Syndr 80: e95-e102
MeSH Terms: AIDS Dementia Complex, Adult, Anti-Retroviral Agents, DNA Copy Number Variations, DNA, Mitochondrial, Female, Genome-Wide Association Study, Genotype, HIV Infections, Humans, Male, Middle Aged, Mitochondria, Neurocognitive Disorders, Neuropsychological Tests
Show Abstract · Added December 11, 2019
BACKGROUND - Mitochondrial DNA (mtDNA) copy number varies by cell type and energy demands. Blood mtDNA copy number has been associated with neurocognitive function in persons without HIV. Low mtDNA copy number may indicate disordered mtDNA replication; high copy number may reflect a response to mitochondrial dysfunction. We hypothesized that blood mtDNA copy number estimated from genome-wide genotyping data is related to neurocognitive impairment (NCI) in persons with HIV.
METHODS - In the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, peripheral blood mtDNA copy number was obtained from genome-wide genotyping data as a ratio of mtDNA single-nucleotide polymorphism probe intensities relative to nuclear DNA single-nucleotide polymorphisms. In a multivariable regression model, associations between mtDNA copy number and demographics, blood cell counts, and HIV disease and treatment characteristics were tested. Associations of mtDNA copy number with the global deficit score (GDS), GDS-defined NCI (GDS ≥ 0.5), and HIV-associated neurocognitive disorder (HAND) diagnosis were tested by logistic regression, adjusting for potential confounders.
RESULTS - Among 1010 CHARTER participants, lower mtDNA copy number was associated with longer antiretroviral therapy duration (P < 0.001), but not with d-drug exposure (P = 0.85). mtDNA copy number was also associated with GDS (P = 0.007), GDS-defined NCI (P < 0.001), and HAND (P = 0.002). In all analyses, higher mtDNA copy number was associated with poorer cognitive performance.
CONCLUSIONS - Higher mtDNA copy number estimated from peripheral blood genotyping was associated with worse neurocognitive performance in adults with HIV. These results suggest a connection between peripheral blood mtDNA and NCI, and may represent increased mtDNA replication in response to mitochondrial dysfunction.
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15 MeSH Terms
Precision HIV care: responding to old questions and meeting new challenges.
Hulgan T, Dash C, Haas DW, Phillips EJ
(2018) Pharmacogenomics 19: 1299-1302
MeSH Terms: AIDS Vaccines, Anti-Retroviral Agents, HIV, HIV Infections, Humans, Pharmacogenetics, Precision Medicine
Added December 11, 2019
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Lower Concentrations of Circulating Medium and Long-Chain Acylcarnitines Characterize Insulin Resistance in Persons with HIV.
Bailin SS, Jenkins CA, Petucci C, Culver JA, Shepherd BE, Fessel JP, Hulgan T, Koethe JR
(2018) AIDS Res Hum Retroviruses 34: 536-543
MeSH Terms: Adult, Anti-Retroviral Agents, Blood Chemical Analysis, CD4 Lymphocyte Count, Carnitine, Chromatography, Gas, Chromatography, Liquid, Female, HIV Infections, Humans, Insulin Resistance, Male, Mass Spectrometry, Metabolomics, Middle Aged, Viral Load
Show Abstract · Added December 11, 2019
In human immunodeficiency virus (HIV)-negative individuals, a plasma metabolite profile, characterized by higher levels of branched-chain amino acids (BCAA), aromatic amino acids, and C3/C5 acylcarnitines, is associated with insulin resistance and increased risk of diabetes. We sought to characterize the metabolite profile accompanying insulin resistance in HIV-positive persons to assess whether the same or different bioenergetics pathways might be implicated. We performed an observational cohort study of 70 nondiabetic, HIV-positive individuals (50% with body mass index ≥30 kg/m) on efavirenz, tenofovir, and emtricitabine with suppressed HIV-1 RNA levels (<50 copies/mL) for at least 2 years and a CD4 count over 350 cells/μL. We measured fasting insulin resistance using the homeostatic model assessment 2, plasma free fatty acids (FFA) using gas chromatography, and amino acids, acylcarnitines, and organic acids using liquid chromatography/mass spectrometry. We assessed the relationship of plasma metabolites with insulin resistance using multivariable linear regression. The median age was 45 years, median CD4 count was 701 cells/μL, and median hemoglobin A1c was 5.2%. Insulin resistance was associated with higher plasma C3 acylcarnitines (p = .01), but not BCAA or C5 acylcarnitines. However, insulin resistance was associated with lower plasma levels of C18, C16, C12, and C2 acylcarnitines (p ≤ .03 for all), and lower C18 and C16 acylcarnitine:FFA ratios (p = .002, and p = .03, respectively). In HIV-positive persons, lower levels of plasma acylcarnitines, including the C2 product of complete fatty acid oxidation, are a more prominent feature of insulin resistance than changes in BCAA, suggesting impaired fatty acid uptake and/or mitochondrial oxidation is a central aspect of glucose intolerance in this population.
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Outcomes of HIV-positive patients with cryptococcal meningitis in the Americas.
Crabtree Ramírez B, Caro Vega Y, Shepherd BE, Le C, Turner M, Frola C, Grinsztejn B, Cortes C, Padgett D, Sterling TR, McGowan CC, Person A
(2017) Int J Infect Dis 63: 57-63
MeSH Terms: Adult, Americas, Anti-Retroviral Agents, CD4 Lymphocyte Count, Female, Follow-Up Studies, HIV Infections, Humans, Male, Meningitis, Cryptococcal, Middle Aged, Patient Compliance, Retrospective Studies, Treatment Outcome
Show Abstract · Added March 14, 2018
BACKGROUND - Cryptococcal meningitis (CM) is associated with substantial mortality in HIV-infected patients. Optimal timing of antiretroviral therapy (ART) in persons with CM represents a clinical challenge, and the burden of CM in Latin America has not been well described. Studies suggest that early ART initiation is associated with higher mortality, but data from the Americas are scarce.
METHODS - HIV-infected adults in care between 1985-2014 at participating sites in the Latin America (the Caribbean, Central and South America network (CCASAnet)) and the Vanderbilt Comprehensive Care Clinic (VCCC) and who had CM were included. Survival probabilities were estimated. Risk of death when initiating ART within the first 2 weeks after CM diagnosis versus initiating between 2-8 weeks was assessed using dynamic marginal structural models adjusting for site, age, sex, year of CM, CD4 count, and route of HIV transmission.
FINDINGS - 340 patients were included (Argentina 58, Brazil 138, Chile 28, Honduras 27, Mexico 34, VCCC 55) and 142 (42%) died during the observation period. Among 151 patients with CM prior to ART 56 (37%) patients died compared to 86 (45%) of 189 with CM after ART initiation (p=0.14). Patients diagnosed with CM after ART had a higher risk of death (p=0.03, log-rank test). The probability of survival was not statistically different between patients who started ART within 2 weeks of CM (7/24, 29%) vs. those initiating between 2-8 weeks (14/53, 26%) (p=0.96), potentially due to lack of power.
INTERPRETATION - In this large Latin-American cohort, patients with CM had very high mortality rates, especially those diagnosed after ART initiation. This study reflects the overwhelming burden of CM in HIV-infected patients in Latin America.
Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.
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14 MeSH Terms
Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults.
Patton SM, Wang Q, Hulgan T, Connor JR, Jia P, Zhao Z, Letendre SL, Ellis RJ, Bush WS, Samuels DC, Franklin DR, Kaur H, Iudicello J, Grant I, Kallianpur AR
(2017) Fluids Barriers CNS 14: 11
MeSH Terms: Adult, Anti-Retroviral Agents, Apoferritins, Blood-Brain Barrier, Cohort Studies, Demography, Female, HIV Infections, Humans, Iron, Male, Middle Aged, Transferrin, Viral Load
Show Abstract · Added March 21, 2018
BACKGROUND - HIV-associated neurocognitive disorder (HAND) remains common, despite antiretroviral therapy (ART). HIV dysregulates iron metabolism, but cerebrospinal fluid (CSF) levels of iron and iron-transport proteins in HIV-infected (HIV+) persons are largely unknown. The objectives of this study were to characterize CSF iron-related biomarkers in HIV+ adults and explore their relationships to known predictors of HAND.
METHODS - We quantified total iron, transferrin and heavy-chain (H)-ferritin by immunoassay in CSF sampled by lumbar puncture in 403 HIV+ participants in a multi-center, observational study and evaluated biomarker associations with demographic and HIV-related correlates of HAND [e.g., age, sex, self-reported race/ethnicity, ART, and detectable plasma virus and CSF viral load (VL)] by multivariable regression. In a subset (N = 110) with existing CSF: serum albumin (Q) measurements, Q and comorbidity severity were also included as covariates to account for variability in the blood-CSF-barrier.
RESULTS - Among 403 individuals (median age 43 years, 19% women, 56% non-Whites, median nadir CD4+ T cell count 180 cells/µL, 46% with undetectable plasma virus), men had 25% higher CSF transferrin (median 18.1 vs. 14.5 µg/mL), and 71% higher H-ferritin (median 2.9 vs. 1.7 ng/mL) than women (both p-values ≤0.01). CSF iron was 41% higher in self-reported Hispanics and 27% higher in (non-Hispanic) Whites than in (non-Hispanic) Blacks (median 5.2 and 4.7 µg/dL in Hispanics and Whites, respectively, vs. 3.7 µg/dL in Blacks, both p ≤ 0.01); these findings persisted after adjustment for age, sex, and HIV-specific factors. Median H-ferritin was 25% higher (p < 0.05), and transferrin 14% higher (p = 0.06), in Whites than Blacks. Transferrin and H-ferritin were 33 and 50% higher, respectively, in older (age > 50 years) than in younger persons (age ≤ 35 years; both p < 0.01), but these findings lost statistical significance in subset analyses that adjusted for Q and comorbidity. After these additional adjustments, associations were observed for CSF iron and transferrin with race/ethnicity as well as CSF VL, for transferrin with sex and ART, and for H-ferritin with plasma virus detectability and significant comorbidity (all p < 0.05).
CONCLUSIONS - CSF iron biomarkers are associated with demographic factors, ART, and CSF VL in HIV+ adults. Future studies should investigate a role for CNS iron dysregulation, to which an altered blood-CSF barrier may contribute, in HAND.
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The metabolic and cardiovascular consequences of obesity in persons with HIV on long-term antiretroviral therapy.
Koethe JR, Grome H, Jenkins CA, Kalams SA, Sterling TR
(2016) AIDS 30: 83-91
MeSH Terms: Adult, Alkynes, Anti-Retroviral Agents, Benzoxazines, Cardiovascular Diseases, Cohort Studies, Cyclopropanes, Emtricitabine, Female, HIV Infections, Humans, Male, Metabolic Diseases, Middle Aged, Obesity, Risk Assessment, Tenofovir
Show Abstract · Added February 17, 2016
OBJECTIVE - This study assessed the effect of obesity on metabolic and cardiovascular disease risk factors in HIV-infected adults on antiretroviral therapy with sustained virologic suppression.
DESIGN - Observational, comparative cohort study with three group-matched arms: 35 nonobese and 35 obese HIV-infected persons on efavirenz, tenofovir and emtricitabine with plasma HIV-1 RNA  less than  50  copies/ml for more than 2 years, and 30 obese HIV-uninfected controls. Patients did not have diabetes or known cardiovascular disease.
METHODS - We compared glucose tolerance, serum lipids, brachial artery flow-mediated dilation, carotid intima-media thickness, and soluble inflammatory and vascular adhesion markers between nonobese and obese HIV-infected patients, and between obese HIV-infected and HIV-uninfected patients, using Wilcoxon rank-sum tests and multivariate linear regression.
RESULTS - The cohort was 52% men and 48% nonwhite. Nonobese and obese HIV-infected patients did not differ by clinical or demographic characteristics. Obese HIV-uninfected controls were younger than obese HIV-infected patients and less likely to smoke (P < 0.03 for both). Among HIV-infected patients, obesity was associated with greater insulin release, lower insulin sensitivity, and higher serum high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 1 levels (P < 0.001), but similar lipid profiles, sCD14, sCD163, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, and carotid intima-media thickness and flow mediated dilation. In contrast, Obese HIV-infected patients had adverse lipid changes, and greater circulating intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and sCD14, compared with obese HIV-uninfected controls after adjusting for age and other factors.
CONCLUSION - Obesity impairs glucose metabolism and contributes to circulating high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 1 levels, but has few additive effects on dyslipidemia and endothelial activation, in Obese HIV-infected adults on long-term antiretroviral therapy.
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Effects on mortality of a nutritional intervention for malnourished HIV-infected adults referred for antiretroviral therapy: a randomised controlled trial.
NUSTART (Nutritional Support for Africans Starting Antiretroviral Therapy) Study Team, Filteau S, PrayGod G, Kasonka L, Woodd S, Rehman AM, Chisenga M, Siame J, Koethe JR, Changalucha J, Michael D, Kidola J, Manno D, Larke N, Yilma D, Heimburger DC, Friis H, Kelly P
(2015) BMC Med 13: 17
MeSH Terms: Adult, Anti-Retroviral Agents, Body Mass Index, CD4 Lymphocyte Count, Dietary Supplements, Electrolytes, Female, HIV Infections, Humans, Male, Malnutrition, Middle Aged, Tanzania, Vitamins, Zambia
Show Abstract · Added February 12, 2015
BACKGROUND - Malnourished HIV-infected African adults are at high risk of early mortality after starting antiretroviral therapy (ART). We hypothesized that short-course, high-dose vitamin and mineral supplementation in lipid nutritional supplements would decrease mortality.
METHODS - The study was an individually-randomised phase III trial conducted in ART clinics in Mwanza, Tanzania, and Lusaka, Zambia. Participants were 1,815 ART-naïve non-pregnant adults with body mass index (BMI) <18.5 kg/m² who were referred for ART based on CD4 count <350 cells/μL or WHO stage 3 or 4 disease. The intervention was a lipid-based nutritional supplement either without (LNS) or with additional vitamins and minerals (LNS-VM), beginning prior to ART initiation; supplement amounts were 30 g/day (150 kcal) from recruitment until 2 weeks after starting ART and 250 g/day (1,400 kcal) from weeks 2 to 6 after starting ART. The primary outcome was mortality between recruitment and 12 weeks of ART. Secondary outcomes were serious adverse events (SAEs) and abnormal electrolytes throughout, and BMI and CD4 count at 12 weeks ART.
RESULTS - Follow-up for the primary outcome was 91%. Median adherence was 66%. There were 181 deaths in the LNS group (83.7/100 person-years) and 184 (82.6/100 person-years) in the LNS-VM group (rate ratio (RR), 0.99; 95% CI, 0.80-1.21; P = 0.89). The intervention did not affect SAEs or BMI, but decreased the incidence of low serum phosphate (RR, 0.73; 95% CI, 0.55-0.97; P = 0.03) and increased the incidence of high serum potassium (RR, 1.60; 95% CI, 1.19-2.15; P = 0.002) and phosphate (RR, 1.23; 95% CI, 1.10-1.37; P <0.001). Mean CD4 count at 12 weeks post-ART was 25 cells/μL (95% CI, 4-46) higher in the LNS-VM compared to the LNS arm (P = 0.02).
CONCLUSIONS - High-dose vitamin and mineral supplementation in LNS, compared to LNS alone, did not decrease mortality or clinical SAEs in malnourished African adults initiating ART, but improved CD4 count. The higher frequency of elevated serum potassium and phosphate levels suggests high-level electrolyte supplementation for all patients is inadvisable but the addition of micronutrient supplements to ART may provide clinical benefits in these patients.
TRIAL REGISTRATION - PACTR201106000300631, registered on 1st June 2011.
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Perspectives on pharmacogenomics of antiretroviral medications and HIV-associated comorbidities.
Haas DW, Tarr PE
(2015) Curr Opin HIV AIDS 10: 116-22
MeSH Terms: Anti-Retroviral Agents, Comorbidity, HIV Infections, Humans, Pharmacogenetics
Show Abstract · Added March 13, 2015
PURPOSE OF REVIEW - To summarize current knowledge and provide perspective on relationships between human genetic variants, antiretroviral medications, and aging-related complications of HIV-1 infection.
RECENT FINDINGS - Human genetic variants have been convincingly associated with interindividual variability in antiretroviral toxicities, drug disposition, and aging-associated complications in HIV-1 infection. Screening for HLA-B5701 to avoid abacavir hypersensitivity reactions has become a routine part of clinical care, and has markedly improved drug safety. There are well established pharmacogenetic associations with other agents (efavirenz, nevirapine, atazanavir, dolutegravir, and others), but this knowledge has yet to have substantial impact on HIV-1 clinical care. As metabolic complications including diabetes mellitus, dyslipidemia, osteoporosis, and cardiovascular disease are becoming an increasing concern among individuals who are aging with well controlled HIV-1 infection, human genetic variants that predispose to these complications also become more relevant in this population.
SUMMARY - Pharmacogenetic knowledge has already had considerable impact on antiretroviral prescribing. With continued advances in the field of human genomics, the impact of pharmacogenomics on HIV-1 clinical care and research is likely to continue to grow in importance and scope.
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Summaries for patients. Nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1.
Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, Godfrey C, Kuritzkes DR, Sagar M, Brown TT, Cohn SE, McComsey GA, Aweeka F, Fichtenbaum CJ, Presti RM, Koletar SL, Haas DW, Patterson KB, Benson CA, Baugh BP, Leavitt RY, Rooney JF, Seekins D, Currier JS, ACTG A5257 Team
(2014) Ann Intern Med 161: I-22
MeSH Terms: Anti-Retroviral Agents, Drug Therapy, HIV Infections, HIV-1, Humans, Reverse Transcriptase Inhibitors
Added March 13, 2015
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Genetic variation in iron metabolism is associated with neuropathic pain and pain severity in HIV-infected patients on antiretroviral therapy.
Kallianpur AR, Jia P, Ellis RJ, Zhao Z, Bloss C, Wen W, Marra CM, Hulgan T, Simpson DM, Morgello S, McArthur JC, Clifford DB, Collier AC, Gelman BB, McCutchan JA, Franklin D, Samuels DC, Rosario D, Holzinger E, Murdock DG, Letendre S, Grant I, CHARTER Study Group
(2014) PLoS One 9: e103123
MeSH Terms: Adult, Aged, Anti-Retroviral Agents, Female, Genetic Variation, Genotype, HIV Infections, Humans, Iron, Iron Regulatory Protein 1, Linkage Disequilibrium, Male, Middle Aged, Multivariate Analysis, Neuralgia, Young Adult
Show Abstract · Added February 13, 2015
HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p<0.05) and 5 variants in 4 genes (p<0.01) were nominally associated with DNP: polymorphisms in TF, TFRC, BMP6, ACO1, SLC11A2, and FXN conferred reduced risk (adjusted odds ratios [ORs] ranging from 0.2 to 0.7, all p<0.05); other variants in TF, CP, ACO1, BMP6, and B2M conferred increased risk (ORs ranging from 1.3 to 3.1, all p<0.05). Risks associated with some variants were statistically significant either in black or white subgroups but were consistent in direction. ACO1 rs2026739 remained significantly associated with DNP in whites (permutation p<0.0001) after correction for multiple tests. Several of the same iron-regulatory-gene polymorphisms, including ACO1 rs2026739, were also associated with severity of DNP (all p<0.05). Common polymorphisms in iron-management genes are associated with DNP and with DNP severity in HIV-infected persons receiving cART. Consistent risk estimates across population subgroups and persistence of the ACO1 rs2026739 association after adjustment for multiple testing suggest that genetic variation in iron-regulation and transport modulates susceptibility to DNP.
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16 MeSH Terms