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Cerebrospinal fluid cell-free mitochondrial DNA is associated with HIV replication, iron transport, and mild HIV-associated neurocognitive impairment.
Mehta SR, Pérez-Santiago J, Hulgan T, Day TR, Barnholtz-Sloan J, Gittleman H, Letendre S, Ellis R, Heaton R, Patton S, Suben JD, Franklin D, Rosario D, Clifford DB, Collier AC, Marra CM, Gelman BB, McArthur J, McCutchan A, Morgello S, Simpson D, Connor J, Grant I, Kallianpur A
(2017) J Neuroinflammation 14: 72
MeSH Terms: AIDS Dementia Complex, Adult, Biomarkers, Cell-Free Nucleic Acids, Cohort Studies, Cross-Sectional Studies, DNA, Mitochondrial, Female, HIV, Humans, Iron, Male, Middle Aged, Viral Load, Virus Replication
Show Abstract · Added December 11, 2019
BACKGROUND - Mitochondria are abundant organelles critical for energy metabolism and brain function. Mitochondrial DNA (mtDNA), released during cellular injury and as part of the innate immune response to viral pathogens, contains CpG motifs that act as TLR-9 ligands. We investigated relationships between cerebrospinal fluid (CSF) cell-free mtDNA levels and HIV viral load (VL), biomarkers of inflammation and iron transport, and neurocognitive (NC) function in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort.
METHODS - We quantified cell-free mtDNA in CSF by droplet digital PCR in 332 CHARTER participants who underwent comprehensive neuropsychiatric evaluation. NC performance was assessed using the global deficit score (GDS) as either a continuous or a binary measure (GDS ≥ 0.5, impaired vs. GDS < 0.5, unimpaired). CSF, clinical, and biomarker data from the earliest available time point were analyzed. Cell-free mtDNA associations with CSF inflammation and iron-related biomarkers [CXCL10, IL-6, IL-8, TNF-a, transferrin (TF), ceruloplasmin (CP), and vascular endothelial growth factor (VEGF)], VL, and GDS were evaluated by multivariable regression.
RESULTS - CSF cell-free mtDNA levels were significantly lower in participants with undetectable (vs. detectable) VL in either plasma (p < 0.001) or CSF (p < 0.001) and in those on antiretroviral therapy (ART; p < 0.001). Participants on ART with undetectable VL in both CSF and plasma had lower mtDNA levels than those with detectable VL in both compartments (p = 0.001). Higher mtDNA levels were observed in participants in the highest vs. lowest tertile (T3 vs. T1) of CSF CXCL10 (T3 vs. T1, p < 0.001) and TNF-a (T3 vs. T1, p < 0.05) in unadjusted analyses. MtDNA levels also correlated with CSF leukocyte count. After adjusting for CSF leukocyte count and VL, mtDNA levels were also associated with other inflammation- and iron-related biomarkers in CSF, including TF (T3 vs. T1, p < 0.05) and CP (T3 vs. T1, p < 0.05). With additional correction for ART use, mtDNA was also negatively associated with CSF VEGF (p < 0.05) and IL-6 (p = 0.05). We observed no associations of CSF mtDNA levels with age or GDS-defined NC impairment.
CONCLUSIONS - CSF cell-free mtDNA levels were associated with HIV RNA and ART status, as well as with biomarkers of iron transport and VEGF, a growth factor with known effects on mitochondrial integrity and autophagy. CSF mtDNA may be a biomarker of iron dysregulation and/or neuroinflammation during HIV infection.
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Therapy with CTLA4-Ig and an antiviral monoclonal antibody controls chikungunya virus arthritis.
Miner JJ, Cook LE, Hong JP, Smith AM, Richner JM, Shimak RM, Young AR, Monte K, Poddar S, Crowe JE, Lenschow DJ, Diamond MS
(2017) Sci Transl Med 9:
MeSH Terms: Abatacept, Animals, Antibodies, Neutralizing, Antibodies, Viral, Antiviral Agents, Arthritis, Infectious, Chemokines, Chikungunya Fever, Cytokines, Leukocytes, Mice, Mice, Inbred C57BL, Viral Load
Show Abstract · Added April 13, 2017
In 2013, chikungunya virus (CHIKV) transmission was documented in the Western Hemisphere, and the virus has since spread throughout the Americas with more than 1.8 million people infected in more than 40 countries. CHIKV targets the joints, resulting in symmetric polyarthritis that clinically mimics rheumatoid arthritis and can endure for months to years. At present, no approved treatment is effective in preventing or controlling CHIKV infection or disease. We treated mice with eight different disease-modifying antirheumatic drugs and identified CLTA4-Ig (abatacept) and tofacitinib as candidate therapies based on their ability to decrease acute joint swelling. CTLA4-Ig reduced T cell accumulation in the joints of infected animals without affecting viral infection. Whereas monotherapy with CTLA4-Ig or a neutralizing anti-CHIKV human monoclonal antibody provided partial clinical improvement, therapy with both abolished swelling and markedly reduced levels of chemokines, proinflammatory cytokines, and infiltrating leukocytes. Thus, combination CTLA4-Ig and antiviral antibody therapy controls acute CHIKV infection and arthritis and may be a candidate for testing in humans.
Copyright © 2017, American Association for the Advancement of Science.
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13 MeSH Terms
Respiratory Viral Detections During Symptomatic and Asymptomatic Periods in Young Andean Children.
Howard LM, Johnson M, Williams JV, Zhu Y, Gil AI, Edwards KM, Griffin MR, Lanata CF, Grijalva CG, RESPIRA-PERU Group
(2015) Pediatr Infect Dis J 34: 1074-80
MeSH Terms: Child, Humans, Peru, Random Allocation, Respiratory Tract Infections, Reverse Transcriptase Polymerase Chain Reaction, Viral Load, Viruses
Show Abstract · Added July 27, 2018
BACKGROUND - Viruses are commonly detected in children with acute respiratory illnesses (ARIs) and in asymptomatic children. Longitudinal studies of viral detections during asymptomatic periods surrounding ARI could facilitate interpretation of viral detections but are currently scant.
METHODS - We used reverse transcription polymerase chain reaction to analyze respiratory samples from young Andean children for viruses during asymptomatic periods within 8-120 days of index ARI (cough or fever). We compared viral detections over time within children and explored reverse transcription polymerase chain reaction cycle thresholds (CTs) as surrogates for viral loads.
RESULTS - At least 1 respiratory virus was detected in 367 (43%) of 859 samples collected during asymptomatic periods, with more frequent detections in periods with rhinorrhea (49%) than those without (34%, P < 0.001). Relative to index ARI with human rhinovirus (HRV), adenovirus (AdV), respiratory syncytial virus (RSV) and parainfluenza virus detected, the same viruses were also detected during 32, 22, 10 and 3% of asymptomatic periods, respectively. RSV was only detected 8-30 days after index RSV ARI, whereas HRV and AdV were detected throughout asymptomatic periods. Human metapneumovirus and influenza were rarely detected during asymptomatic periods (<3%). No significant differences were observed in the CT for HRV or AdV during asymptomatic periods relative to ARI. For RSV, CTs were significantly lower during ARI relative to the asymptomatic period (P = 0.03).
CONCLUSIONS - These findings indicate that influenza, human metapneumovirus, parainfluenza virus and RSV detections in children with an ARI usually indicate a causal relationship. When HRV or AdV is detected during ARI, the causal relationship is less certain.
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Injection Drug Use and Hepatitis C as Risk Factors for Mortality in HIV-Infected Individuals: The Antiretroviral Therapy Cohort Collaboration.
May MT, Justice AC, Birnie K, Ingle SM, Smit C, Smith C, Neau D, Guiguet M, Schwarze-Zander C, Moreno S, Guest JL, Monforte Ad, Tural C, Gill MJ, Bregenzer A, Kirk O, Saag M, Sterling TR, Crane HM, Sterne JA
(2015) J Acquir Immune Defic Syndr 69: 348-54
MeSH Terms: Adolescent, Adult, Anti-HIV Agents, CD4 Lymphocyte Count, Cohort Studies, Female, HIV Infections, Hepatitis C, Humans, Male, Middle Aged, Risk Factors, Substance Abuse, Intravenous, Survival Analysis, Treatment Outcome, Viral Load, Young Adult
Show Abstract · Added February 17, 2016
BACKGROUND - HIV-infected individuals with a history of transmission through injection drug use (IDU) have poorer survival than other risk groups. The extent to which higher rates of hepatitis C (HCV) infection in IDU explain survival differences is unclear.
METHODS - Adults who started antiretroviral therapy between 2000 and 2009 in 16 European and North American cohorts with >70% complete data on HCV status were followed for 3 years. We estimated unadjusted and adjusted (for age, sex, baseline CD4 count and HIV-1 RNA, AIDS diagnosis before antiretroviral therapy, and stratified by cohort) mortality hazard ratios for IDU (versus non-IDU) and for HCV-infected (versus HCV uninfected).
RESULTS - Of 32,703 patients, 3374 (10%) were IDU; 4630 (14%) were HCV+; 1116 (3.4%) died. Mortality was higher in IDU compared with non-IDU [adjusted HR 2.71; 95% confidence interval (CI): 2.32 to 3.16] and in HCV+ compared with HCV- (adjusted HR 2.65; 95% CI: 2.31 to 3.04). The effect of IDU was substantially attenuated (adjusted HR 1.57; 95% CI: 1.27 to 1.94) after adjustment for HCV, while attenuation of the effect of HCV was less substantial (adjusted HR 2.04; 95% CI: 1.68 to 2.47) after adjustment for IDU. Both IDU and HCV were strongly associated with liver-related mortality (adjusted HR 10.89; 95% CI: 6.47 to 18.3 for IDU and adjusted HR 14.0; 95% CI: 8.05 to 24.5 for HCV) with greater attenuation of the effect of IDU (adjusted HR 2.43; 95% CI: 1.24 to 4.78) than for HCV (adjusted HR 7.97; 95% CI: 3.83 to 16.6). Rates of CNS, respiratory and violent deaths remained elevated in IDU after adjustment for HCV.
CONCLUSIONS - A substantial proportion of the excess mortality in HIV-infected IDU is explained by HCV coinfection. These findings underscore the potential impact on mortality of new treatments for HCV in HIV-infected people.
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Identification of residues in the human respiratory syncytial virus fusion protein that modulate fusion activity and pathogenesis.
Hotard AL, Lee S, Currier MG, Crowe JE, Sakamoto K, Newcomb DC, Peebles RS, Plemper RK, Moore ML
(2015) J Virol 89: 512-22
MeSH Terms: Animals, Cell Line, DNA Mutational Analysis, Disease Models, Animal, Female, Histocytochemistry, Humans, Lung, Mice, Inbred BALB C, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus, Human, Viral Fusion Proteins, Viral Load, Virus Internalization, Weight Loss
Show Abstract · Added January 20, 2015
UNLABELLED - Human respiratory syncytial virus (RSV) lower respiratory tract infection can result in inflammation and mucus plugging of airways. RSV strain A2-line19F induces relatively high viral load and mucus in mice. The line 19 fusion (F) protein harbors five unique residues compared to the non-mucus-inducing strains A2 and Long, at positions 79, 191, 357, 371, and 557. We hypothesized that differential fusion activity is a determinant of pathogenesis. In a cell-cell fusion assay, line 19 F was more fusogenic than Long F. We changed the residues unique to line 19 F to the corresponding residues in Long F and identified residues 79 and 191 together as responsible for high fusion activity. Surprisingly, mutation of residues 357 or 357 with 371 resulted in gain of fusion activity. Thus, we generated RSV F mutants with a range of defined fusion activity and engineered these into recombinant viruses. We found a clear, positive correlation between fusion activity and early viral load in mice; however, we did not detect a correlation between viral loads and levels of airway mucin expression. The F mutant with the highest fusion activity, A2-line19F-K357T/Y371N, induced high viral loads, severe lung histopathology, and weight loss but did not induce high levels of airway mucin expression. We defined residues 79/191 as critical for line 19 F fusion activity and 357/371 as playing a role in A2-line19F mucus induction. Defining the molecular basis of the role of RSV F in pathogenesis may aid vaccine and therapeutic strategies aimed at this protein.
IMPORTANCE - Human respiratory syncytial virus (RSV) is the most important lower respiratory tract pathogen of infants for which there is no vaccine. Elucidating mechanisms of RSV pathogenesis is important for rational vaccine and drug design. We defined specific amino acids in the fusion (F) protein of RSV strain line 19 critical for fusion activity and elucidated a correlation between fusion activity and viral load in mice. Further, we identified two distinct amino acids in F as contributing to the mucogenic phenotype of the A2-line19F virus. Taken together, these results illustrate a role for RSV F in virulence.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial.
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: 461-71
MeSH Terms: Adenine, Adult, Atazanavir Sulfate, Darunavir, Deoxycytidine, Drug Combinations, Drug Therapy, Combination, Emtricitabine, Female, HIV Infections, HIV Protease Inhibitors, HIV-1, Humans, Male, Oligopeptides, Organophosphonates, Pyridines, RNA, Viral, Reverse Transcriptase Inhibitors, Sulfonamides, Tenofovir, Therapeutic Equivalency, Viral Load
Show Abstract · Added March 13, 2015
BACKGROUND - Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.
OBJECTIVE - To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability.
DESIGN - A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954).
SETTING - 57 sites in the United States and Puerto Rico.
PATIENTS - Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors.
INTERVENTION - Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d.
MEASUREMENTS - Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability.
RESULTS - Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir.
LIMITATION - The trial was open-label, and ritonavir was not provided.
CONCLUSION - Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen.
PRIMARY FUNDING SOURCE - National Institute of Allergy and Infectious Diseases.
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23 MeSH Terms
Current drug use and lack of HIV virologic suppression: point-of-care urine drug screen versus self-report.
Qian HZ, Mitchell VJ, Bebawy S, Cassell H, Perez G, McGowan CC, Sterling TR, Vermund SH, D'Aquila R, Hulgan T
(2014) BMC Infect Dis 14: 508
MeSH Terms: Adult, Aged, Anti-HIV Agents, CD4 Lymphocyte Count, Cross-Sectional Studies, Disease Progression, Drug Users, Female, HIV Infections, HIV-1, Humans, Illicit Drugs, Interviews as Topic, Male, Middle Aged, Point-of-Care Systems, Self Report, Substance-Related Disorders, Viral Load, Young Adult
Show Abstract · Added February 17, 2016
BACKGROUND - There have been inconsistent findings on the association between current drug use and HIV disease progression and virologic suppression. Drug use was often measured using self-report of historical use. Objective measurement of current drug use is preferred.
METHODS - In this cross-sectional study, we assessed drug use through Computer-Assisted Self Interviews (CASI) and point-of-care urine drug screen (UDS) among 225 HIV-infected patients, and evaluated the association between current drug use and virologic suppression.
RESULTS - About half (54%) of participants had a positive UDS, with a lower self-reported rate by CASI (42%) (Kappa score = 0.59). By UDS, 36.0% were positive for marijuana, 25.8% for cocaine, 7.6% for opiates, and 2.2% for methamphetamine or amphetamine. Factors associated with virologic suppression (plasma HIV RNA <50 copies/mL) were Caucasian race (P = 0.03), higher CD4 count (P < 0.01), current use of antiretroviral therapy (ART) (P < 0.01), and a negative UDS (P < 0.01). Among 178 current ART users, a positive UDS remained significantly associated with lower likelihood of virologic suppression (P = 0.04).
CONCLUSIONS - UDS had good agreement with CASI in detecting frequently used drugs such as marijuana and cocaine. UDS at routine clinic visits may provide "real-time" prognostic information to optimize management.
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Pharmacokinetics of efavirenz and treatment of HIV-1 among pregnant women with and without tuberculosis coinfection.
Dooley KE, Denti P, Martinson N, Cohn S, Mashabela F, Hoffmann J, Haas DW, Hull J, Msandiwa R, Castel S, Wiesner L, Chaisson RE, McIlleron H, TSHEPISO Study Team
(2015) J Infect Dis 211: 197-205
MeSH Terms: Adolescent, Adult, Anti-HIV Agents, Benzoxazines, Cohort Studies, Coinfection, Female, HIV Infections, HIV-1, Humans, Plasma, Pregnancy, Pregnancy Complications, Infectious, Prospective Studies, South Africa, Tuberculosis, Viral Load, Young Adult
Show Abstract · Added March 13, 2015
BACKGROUND - Pregnancy and tuberculosis treatment or prophylaxis can affect efavirenz pharmacokinetics, maternal human immunodeficiency virus type 1 (HIV-1) treatment outcomes, and mother-to-child transmission (MTCT) risk.
METHODS - We evaluated a prospective cohort of pregnant, HIV-infected women with and without tuberculosis in Soweto, South Africa. Pharmacokinetic sampling was performed at gestation week 37 and during the postpartum period. Efavirenz trough concentrations (Cmin) were predicted using population pharmacokinetic models. HIV-viral load was measured at delivery for mothers and at 6 weeks of age for infants.
RESULTS - Ninety-seven women participated; 44 had tuberculosis. Median efavirenz Cmin during pregnancy was 1.35 µg/mL (interquartile range [IQR], 0.90-2.07 µg/mL; 27% had an efavirenz Cmin of < 1 µg/mL), compared with a median postpartum value of 2.00 µg/mL (IQR, 1.40-3.59 µg/mL; 13% had an efavirenz Cmin of < 1 µg/mL). A total of 72% of pregnant women with extensive CYP2B6 genotypes had an efavirenz Cmin of <1 µg/mL. Rifampin did not reduce the efavirenz Cmin. Isoniazid (for prophylaxis or treatment), though, reduced the rate of efavirenz clearance. At delivery, median durations of ART were 13 weeks (IQR, 9-18 weeks) and 21 weeks (IQR, 13-64 weeks) for women with and those without tuberculosis, respectively; 55% and 83%, respectively, had a viral load of <20 copies/mL (P = .021). There was 1 case of MTCT.
CONCLUSIONS - Pregnancy increased the risk of low efavirenz concentrations, but MTCT was rare. A detectable HIV-viral load at delivery was more common among pregnant women with tuberculosis, in whom ART was generally initiated later.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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A randomized controlled trial of palifermin (recombinant human keratinocyte growth factor) for the treatment of inadequate CD4+ T-lymphocyte recovery in patients with HIV-1 infection on antiretroviral therapy.
Jacobson JM, Wang H, Bordi R, Zheng L, Gross BH, Landay AL, Spritzler J, Routy JP, Benson C, Aberg J, Tebas P, Haas DW, Tiu J, Coughlin K, Purdue L, Sekaly RP, AIDS Clinical Trials Group (ACTG) A5212 Protocol Team
(2014) J Acquir Immune Defic Syndr 66: 399-406
MeSH Terms: Adult, Anti-HIV Agents, CD4 Lymphocyte Count, Dose-Response Relationship, Drug, Double-Blind Method, Female, Fibroblast Growth Factor 7, HIV Infections, HIV-1, Humans, Male, Middle Aged, RNA, Viral, Recombinant Proteins, Thymus Gland, Viral Load
Show Abstract · Added March 13, 2015
BACKGROUND - Poor CD4 lymphocyte recovery on antiretroviral therapy (ART) is associated with reduced function of the thymus. Palifermin (keratinocyte growth factor), by providing support to the thymic epithelium, promotes lymphopoiesis in animal models of bone marrow transplantation and graft-versus-host disease.
METHODS - In AIDS Clinical Trials Group A5212, a randomized, double-blind, placebo-controlled study, 99 HIV-infected patients on ART with plasma HIV-1 RNA levels ≤200 copies per milliliter for ≥6 months and CD4 lymphocyte counts <200 cells per cubic milliliter were randomized 1:1:1:1 to receive once daily intravenous administration of placebo or 20, 40, or 60 μg/kg of palifermin on 3 consecutive days.
RESULTS - The median change in the CD4 T-cell count from baseline to week 12 was not significantly different between the placebo arm [15 (-16, 23) cells/mm] and the 20-μg/kg dose [11 (2, 32) cells/mm], the 40-μg/kg dose [12 (-2, 25) cells/mm], or the 60-μg/kg dose arm [8 (-13, 35) cells/mm] of palifermin. No significant changes were observed in thymus size or in the number of naive T cells or recent thymic emigrants.
CONCLUSIONS - Palifermin in the doses studied was not effective in improving thymic function and did not raise CD4 lymphocyte counts in HIV-infected patients with low CD4 cell counts despite virologically effective ART.
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Disparities in the quality of HIV care when using US Department of Health and Human Services indicators.
Althoff KN, Rebeiro P, Brooks JT, Buchacz K, Gebo K, Martin J, Hogg R, Thorne JE, Klein M, Gill MJ, Sterling TR, Yehia B, Silverberg MJ, Crane H, Justice AC, Gange SJ, Moore R, Kitahata MM, Horberg MA, North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD)
(2014) Clin Infect Dis 58: 1185-9
MeSH Terms: Adult, Aged, Aged, 80 and over, Anti-Retroviral Agents, Cohort Studies, Continuity of Patient Care, Cross-Sectional Studies, Female, HIV Infections, Healthcare Disparities, Humans, Male, Middle Aged, United States, United States Dept. of Health and Human Services, Viral Load
Show Abstract · Added May 29, 2014
We estimated US Department of Health and Human Services (DHHS)-approved human immunodeficiency virus (HIV) indicators. Among patients, 71% were retained in care, 82% were prescribed treatment, and 78% had HIV RNA ≤200 copies/mL; younger adults, women, blacks, and injection drug users had poorer outcomes. Interventions are needed to reduce retention- and treatment-related disparities.
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16 MeSH Terms