80 results on '"Jagodzinski LL"'
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2. Neurological Response to cART vs. cART plus integrase inhibitor and ccr5 antagonist initiated during acute HIV
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Valcour, Victor, Valcour, VG, Spudich, SS, Sailasuta, N, Phanuphak, N, Lerdlum, S, Fletcher, JLK, Kroon, EDMB, Jagodzinski, LL, Allen, IE, and Adams, CL
- Abstract
Objective To compare central nervous system (CNS) outcomes in participants treated during acute HIV infection with standard combination antiretroviral therapy (cART) vs. cART plus integrase inhibitor and CCR5 antagonist (cART+). Design 24-week randomized o
- Published
- 2015
3. The AG recombinant IbNG and novel strains of group M HIV-1 are common in Cameroon
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Carr, JK, Torimiro, JN, Wolfe, ND, Eitel, MN, Kim, B, Sanders-Buell, E, Jagodzinski, LL, Gotte, D, Burke, DS, Birx, DL, McCutchan, FE, Carr, JK, Torimiro, JN, Wolfe, ND, Eitel, MN, Kim, B, Sanders-Buell, E, Jagodzinski, LL, Gotte, D, Burke, DS, Birx, DL, and McCutchan, FE
- Abstract
The genetic diversity of group M HIV-1 is highest in west central Africa. Blood samples from four locations in Cameroon were collected to determine the molecular epidemiology of HIV-1. The C2-V5 region of envelope was sequenced from 39 of the 40 samples collected, and 7 samples were sequenced across the genome. All strains belonged to group M of HIV-1. The circulating recombinant form CRF02_AG (IbNG) was the most common strain (22/39, 56%). Two of these were confirmed by full genome analysis. Four samples (4/39, 10%) clustered with the sub-subtype F2 and one of these was confirmed by full genome sequencing. Recombinant forms, each different but containing subtype A, accounted for the next most common form (7/39, 18%). Among these recombinants, those combining subtypes A and G were the most common (4/7, 57%). Also found were 3 subtype A, 2 subtype G, and 1 subtype B strain. Many recombination break points were shared between IbNG and the other AG recombinants, though none of these other AG recombinants included IbNG as a parent. This suggests that there was an ancestral AG recombinant that gave rise to CRF02_AG (IbNG), the successful circulating recombinant form, and to others that were less successful and are now rare. © 2001 Academic Press.
- Published
- 2001
4. Antiviral effect and ex vivo CD4+ T cell proliferation in HIV-positive patients as a result of CD28 costimulation
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Levine, BL, Mosca, JD, Riley, JL, Carroll, RG, Vahey, MT, Jagodzinski, LL, Wagner, KF, Mayers, DL, Burke, DS, Weislow, OS, St. Louis, DC, June, CH, Levine, BL, Mosca, JD, Riley, JL, Carroll, RG, Vahey, MT, Jagodzinski, LL, Wagner, KF, Mayers, DL, Burke, DS, Weislow, OS, St. Louis, DC, and June, CH
- Abstract
Because stimulation of CD4+ lymphocytes leads to activation of human immunodeficiency virus-type 1 (HIV-1) replication, viral spread, and cell death, adoptive CD4+ T cell therapy has not been possible. When antigen and CD28 receptors on cultured T cells were stimulated by monoclonal antibodies (mAbs) to CD3 and CD28 that had been immobilized, there was an increase in the number of polyclonal CD4+ T cells from HIV-infected donors. Activated cells predominantly secreted cytokines associated with T helper cell type 1 function. The HIV-1 vital load declined in the absence of antiretroviral agents. Moreover, CD28 stimulation of CD4+ T cells from uninfected donors rendered these cells highly resistant to HIV-1 infection. Immobilization of CD28 mAb was crucial to the development of HIV resistance, as cells stimulated with soluble CD28 mAb were highly susceptible to HIV infection. The CD28-mediated antiviral effect occurred early in the viral life cycle, before HIV-1 DNA integration. These data may facilitate immune reconstitution and gene therapy approaches in persons with HIV infection.
- Published
- 1996
5. An investigation of bloodborne pathogen transmission due to multipatient sharing of insulin pens.
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Hakre S, Upshaw-Combs DR, Sanders-Buell EE, Scoville SL, Kuper JD, Jagodzinski LL, Bradfield AN, Davison DC, Callis WG, Owens AB, Michael NL, O'Connell RJ, Peel SA, Gardner JW, Thompson ND, Hu DJ, Kim JH, Tovanabutra S, Scott PT, and LaFon SG
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HEPATITIS B transmission , *HEPATITIS C transmission , *HIV infection transmission , *SUBCUTANEOUS injections , *DRUG delivery systems , *CROSS infection , *HEPATITIS B , *HEPATITIS C , *HIV infections , *HYPOGLYCEMIC agents , *INSULIN , *MILITARY hospitals , *RNA , *DISPOSABLE medical devices , *EQUIPMENT & supplies - Abstract
On January 30, 2009, nursing staff at a military hospital in Texas reported that single-patient use insulin pens were used on multiple patients. An investigation was initiated to determine if patient-to-patient bloodbome transmission occurred from the practice. Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) testing was offered to patients hospitalized from August 2007 to January 2009 and prescribed insulin pen injections. Virus from HCV-infected patients' sera was sequenced and compared for relatedness. An anonymous survey was administered to nurses. Of 2,113 patients prescribed insulin pen injections, 1,501 (71%) underwent testing; 6 (0.4%) were HIV positive, 6 (0.4%) were hepatitis B surface antigen positive, and 56 (3.7%) had HCV antibody. No viral sequences from 10 of 28 patients with newly diagnosed and 12 of 28 patients with preexisting HCV infection were closely related. Of 54 nurses surveyed, 74% reported being trained on insulin pen use, but 24% believed nurses used insulin pens on more than one patient. We found no clear evidence of bloodborne pathogen transmission. Training of hospital staff on correct use of insulin pens should be prioritized and their practices evaluated. Insulin pens should be more clearly labeled for single-patient use. [ABSTRACT FROM AUTHOR]
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- 2012
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6. Safety and Immunogenicity of an Accelerated Ebola Vaccination Schedule in People with and without Human Immunodeficiency Virus: A Randomized Clinical Trial.
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Ake JA, Paolino K, Hutter JN, Cicatelli SB, Eller LA, Eller MA, Costanzo MC, Paquin-Proulx D, Robb ML, Tran CL, Anova L, Jagodzinski LL, Ward LA, Kilgore N, Rusnak J, Bounds C, Badorrek CS, Hooper JW, Kwilas SA, Ilsbroux I, Anumendem DN, Gaddah A, Shukarev G, Bockstal V, Luhn K, Douoguih M, and Robinson C
- Abstract
The safety and immunogenicity of the two-dose Ebola vaccine regimen MVA-BN-Filo, Ad26.ZEBOV, 14 days apart, was evaluated in people without HIV (PWOH) and living with HIV (PLWH). In this observer-blind, placebo-controlled, phase 2 trial, healthy adults were randomized (4:1) to receive MVA-BN-Filo (dose 1) and Ad26.ZEBOV (dose 2), or two doses of saline/placebo, administered intramuscularly 14 days apart. The primary endpoints were safety (adverse events (AEs)) and immunogenicity (Ebola virus (EBOV) glycoprotein-specific binding antibody responses). Among 75 participants (n = 50 PWOH; n = 25 PLWH), 37% were female, the mean age was 44 years, and 56% were Black/African American. AEs were generally mild/moderate, with no vaccine-related serious AEs. At 21 days post-dose 2, EBOV glycoprotein-specific binding antibody responder rates were 100% among PWOH and 95% among PLWH; geometric mean antibody concentrations were 6286 EU/mL (n = 36) and 2005 EU/mL (n = 19), respectively. A total of 45 neutralizing and other functional antibody responses were frequently observed. Ebola-specific CD4+ and CD8+ T-cell responses were polyfunctional and durable to at least 12 months post-dose 2. The regimen was well tolerated and generated robust, durable immune responses in PWOH and PLWH. Findings support continued evaluation of accelerated vaccine schedules for rapid deployment in populations at immediate risk. Trial registration: NCT02598388 (submitted 14 November 2015).
- Published
- 2024
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7. Analytical validation of quantitative SARS-CoV-2 subgenomic and viral load laboratory developed tests conducted on the Panther Fusion® (Hologic) with preliminary application to clinical samples.
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Lakhal-Naouar I, Hack HR, Moradel E, Jarra A, Grove HL, Ismael RM, Padilla S, Coleman D, Ouellette J, Darden J, Storme C, Peachman KK, Hall TL, Huhtanen ME, Scott PT, Hakre S, Jagodzinski LL, and Peel SA
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- Humans, SARS-CoV-2 genetics, Subgenomic RNA, Viral Load, Biological Assay, RNA, COVID-19 diagnosis
- Abstract
Objective: Validate the performance characteristics of two analyte specific, laboratory developed tests (LDTs) for the quantification of SARS-CoV-2 subgenomic RNA (sgRNA) and viral load on the Hologic Panther Fusion® using the Open Access functionality., Methods: Custom-designed primers/probe sets targeting the SARS-CoV-2 Envelope gene (E) and subgenomic E were optimized. A 20-day performance validation following laboratory developed test requirements was conducted to assess assay precision, accuracy, analytical sensitivity/specificity, lower limit of detection and reportable range., Results: Quantitative SARS-CoV-2 sgRNA (LDT-Quant sgRNA) assay, which measures intermediates of replication, and viral load (LDT-Quant VLCoV) assay demonstrated acceptable performance. Both assays were linear with an R2 and slope equal to 0.99 and 1.00, respectively. Assay precision was evaluated between 4-6 Log10 with a maximum CV of 2.6% and 2.5% for LDT-Quant sgRNA and LDT-Quant VLCoV respectively. Using negative or positive SARS-CoV-2 human nasopharyngeal swab samples, both assays were accurate (kappa coefficient of 1.00 and 0.92). Common respiratory flora and other viral pathogens were not detected and did not interfere with the detection or quantification by either assay. Based on 95% detection, the assay LLODs were 729 and 1206 Copies/mL for the sgRNA and VL load LDTs, respectively., Conclusion: The LDT-Quant sgRNA and LDT-Quant VLCoV demonstrated good analytical performance. These assays could be further investigated as alternative monitoring assays for viral replication; and thus, medical management in clinical settings which could inform isolation/quarantine requirements., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
- Published
- 2023
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8. HIV-1 infected humanized DRAGA mice develop HIV-specific antibodies despite lack of canonical germinal centers in secondary lymphoid tissues.
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Ollerton MT, Folkvord JM, Peachman KK, Shashikumar S, Morrison EB, Jagodzinski LL, Peel SA, Khreiss M, D'Aquila RT, Casares S, Rao M, and Connick E
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- Mice, Animals, CD8-Positive T-Lymphocytes, Germinal Center, HIV Antibodies, HIV-1, HIV Infections
- Abstract
A major barrier in the use of humanized mice as models of HIV-1 (HIV) infection is the inadequate generation of virus-specific antibody responses. Humanized DRAGA (hDRAGA) mice generate antigen-specific class switched antibodies to several pathogens, but whether they do so in HIV infection and the extent to which their secondary lymphoid tissues (sLT) support germinal center responses is unknown. hDRAGA mice were evaluated for their ability to support HIV replication, generate virus-specific antibody responses, develop splenocyte subsets, and organize sLT architecture. hDRAGA mice supported persistent HIV replication and developed modest levels of gp41-specific human IgM and IgG. Spleens from uninfected and HIV infected hDRAGA mice contained differentiated B and CD4
+ T cell subsets including germinal center (GC) B cells and T follicular helper cells (TFH); relative expansions of TFH and CD8+ T cells, but not GC B cells, occurred in HIV-infected hDRAGA mice compared to uninfected animals. Immunofluorescent staining of spleen and mesenteric lymph node sections demonstrated atypical morphology. Most CD4+ and CD8+ T cells resided within CD20hi areas. CD20hi areas lacked canonical germinal centers, as defined by staining for IgD- Ki67+ cells. No human follicular dendritic cells (FDC) were detected. Mouse FDC were distributed broadly throughout both CD20hi and CD20lo regions of sLT. HIV RNA particles were detected by in situ hybridization within CD20+ areas and some co-localized with mouse FDC. Viral RNA+ cells were more concentrated within CD20hi compared to CD20lo areas of sLT, but differences were diminished in spleen and eliminated in mesenteric lymph nodes when adjusted for CD4+ cell frequency. Thus, hDRAGA mice recapitulated multiple aspects of HIV pathogenesis including HIV replication, relative expansions in TFH and CD8+ T cells, and modest HIV-specific antibody production. Nevertheless, classical germinal center morphology in sLT was not observed, which may account for the inefficient expansion of GC B cells and generation of low titer human antibody responses to HIV-1 in this model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ollerton, Folkvord, Peachman, Shashikumar, Morrison, Jagodzinski, Peel, Khreiss, D’Aquila, Casares, Rao and Connick.)- Published
- 2022
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9. Virological and Serological Assessment of US Army Trainees Isolated for Coronavirus Disease 2019.
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Hakre S, Lakhal-Naouar I, King DB, Burns JL, Jackson KN, Krauss SW, Chandrasekaran P, McCauley MD, Ober Shepherd BL, McHenry S, Bianchi EJ, Ouellette J, Darden JM, Sanborn AD, Daye SP, Kwon PO, Stubbs J, Brigantti CL, Hall TL, Beagle MH, Pieri JA, Frambes TR, O'Connell RJ, Modjarrad K, Murray CK, Jagodzinski LL, Scott PT, and Peel SA
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- Humans, SARS-CoV-2, COVID-19 Testing, Sensitivity and Specificity, RNA, RNA, Viral genetics, Reverse Transcriptase Polymerase Chain Reaction, COVID-19 diagnosis
- Abstract
Background: Laboratory screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key mitigation measure to avoid the spread of infection among recruits starting basic combat training in a congregate setting. Because viral nucleic acid can be detected persistently after recovery, we evaluated other laboratory markers to distinguish recruits who could proceed with training from those who were infected., Methods: Recruits isolated for coronavirus disease 2019 (COVID-19) were serially tested for SARS-CoV-2 subgenomic ribonucleic acid (sgRNA), and viral load (VL) by reverse-transcriptase polymerase chain reaction (RT-PCR), and for anti- SARS-CoV-2. Cluster and quadratic discriminant analyses of results were performed., Results: Among 229 recruits isolated for COVID-19, those with a RT-PCR cycle threshold >30.49 (sensitivity 95%, specificity 96%) or having sgRNA log10 RNA copies/mL <3.09 (sensitivity and specificity 96%) at entry into isolation were likely SARS-CoV-2 uninfected. Viral load >4.58 log10 RNA copies/mL or anti-SARS-CoV-2 signal-to-cutoff ratio <1.38 (VL: sensitivity and specificity 93%; anti-SARS-CoV-2: sensitivity 83%, specificity 79%) had comparatively lower sensitivity and specificity when used alone for discrimination of infected from uninfected., Conclusions: Orthogonal laboratory assays used in combination with RT-PCR may have utility in determining SARS-CoV-2 infection status for decisions regarding isolation., Competing Interests: Potential conflicts of interest . All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2022
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10. Validation of SARS-CoV-2 pooled testing for surveillance using the Panther Fusion® system: Impact of pool size, automation, and assay chemistry.
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Park R, Chandrasekaran P, Hernandez H, Lakhal-Naouar I, Peachman KK, Hack HR, Coleman D, Ouellette J, Darden JM, M'hamdi O, Sugiharto VA, Chen HW, Schilling MA, Simons MP, Collins ND, Johnson YS, Jagodzinski LL, and Peel SA
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- Humans, RNA, Viral genetics, Molecular Diagnostic Techniques methods, Automation, Sensitivity and Specificity, SARS-CoV-2 genetics, COVID-19 diagnosis
- Abstract
Combining diagnostic specimens into pools has been considered as a strategy to augment throughput, decrease turnaround time, and leverage resources. This study utilized a multi-parametric approach to assess optimum pool size, impact of automation, and effect of nucleic acid amplification chemistries on the detection of SARS-CoV-2 RNA in pooled samples for surveillance testing on the Hologic Panther Fusion® System. Dorfman pooled testing was conducted with previously tested SARS-CoV-2 nasopharyngeal samples using Hologic's Aptima® and Panther Fusion® SARS-CoV-2 Emergency Use Authorization assays. A manual workflow was used to generate pool sizes of 5:1 (five samples: one positive, four negative) and 10:1. An automated workflow was used to generate pool sizes of 3:1, 4:1, 5:1, 8:1 and 10:1. The impact of pool size, pooling method, and assay chemistry on sensitivity, specificity, and lower limit of detection (LLOD) was evaluated. Both the Hologic Aptima® and Panther Fusion® SARS-CoV-2 assays demonstrated >85% positive percent agreement between neat testing and pool sizes ≤5:1, satisfying FDA recommendation. Discordant results between neat and pooled testing were more frequent for positive samples with CT>35. Fusion® CT (cycle threshold) values for pooled samples increased as expected for pool sizes of 5:1 (CT increase of 1.92-2.41) and 10:1 (CT increase of 3.03-3.29). The Fusion® assay demonstrated lower LLOD than the Aptima® assay for pooled testing (956 vs 1503 cp/mL, pool size of 5:1). Lowering the cut-off threshold of the Aptima® assay from 560 kRLU (manufacturer's setting) to 350 kRLU improved the assay sensitivity to that of the Fusion® assay for pooled testing. Both Hologic's SARS-CoV-2 assays met the FDA recommended guidelines for percent positive agreement (>85%) for pool sizes ≤5:1. Automated pooling increased test throughput and enabled automated sample tracking while requiring less labor. The Fusion® SARS-CoV-2 assay, which demonstrated a lower LLOD, may be more appropriate for surveillance testing., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
- Published
- 2022
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11. A SARS-CoV-2 Spike Ferritin Nanoparticle Vaccine Is Protective and Promotes a Strong Immunological Response in the Cynomolgus Macaque Coronavirus Disease 2019 (COVID-19) Model.
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Johnston SC, Ricks KM, Lakhal-Naouar I, Jay A, Subra C, Raymond JL, King HAD, Rossi F, Clements TL, Fetterer D, Tostenson S, Cincotta CM, Hack HR, Kuklis C, Soman S, King J, Peachman KK, Kim D, Chen WH, Sankhala RS, Martinez EJ, Hajduczki A, Chang WC, Choe M, Thomas PV, Peterson CE, Anderson A, Swafford I, Currier JR, Paquin-Proulx D, Jagodzinski LL, Matyas GR, Rao M, Gromowski GD, Peel SA, White L, Smith JM, Hooper JW, Michael NL, Modjarrad K, Joyce MG, Nalca A, Bolton DL, and Pitt MLM
- Abstract
The COVID-19 pandemic has had a staggering impact on social, economic, and public health systems worldwide. Vaccine development and mobilization against SARS-CoV-2 (the etiologic agent of COVID-19) has been rapid. However, novel strategies are still necessary to slow the pandemic, and this includes new approaches to vaccine development and/or delivery that will improve vaccination compliance and demonstrate efficacy against emerging variants. Here, we report on the immunogenicity and efficacy of a SARS-CoV-2 vaccine comprising stabilized, pre-fusion spike protein trimers displayed on a ferritin nanoparticle (SpFN) adjuvanted with either conventional aluminum hydroxide or the Army Liposomal Formulation QS-21 (ALFQ) in a cynomolgus macaque COVID-19 model. Vaccination resulted in robust cell-mediated and humoral responses and a significant reduction in lung lesions following SARS-CoV-2 infection. The strength of the immune response suggests that dose sparing through reduced or single dosing in primates may be possible with this vaccine. Overall, the data support further evaluation of SpFN as a SARS-CoV-2 protein-based vaccine candidate with attention to fractional dosing and schedule optimization.
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- 2022
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12. A SARS-CoV-2 ferritin nanoparticle vaccine elicits protective immune responses in nonhuman primates.
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Joyce MG, King HAD, Elakhal-Naouar I, Ahmed A, Peachman KK, Macedo Cincotta C, Subra C, Chen RE, Thomas PV, Chen WH, Sankhala RS, Hajduczki A, Martinez EJ, Peterson CE, Chang WC, Choe M, Smith C, Lee PJ, Headley JA, Taddese MG, Elyard HA, Cook A, Anderson A, McGuckin Wuertz K, Dong M, Swafford I, Case JB, Currier JR, Lal KG, Molnar S, Nair MS, Dussupt V, Daye SP, Zeng X, Barkei EK, Staples HM, Alfson K, Carrion R, Krebs SJ, Paquin-Proulx D, Karasavva N, Polonis VR, Jagodzinski LL, Amare MF, Vasan S, Scott PT, Huang Y, Ho DD, de Val N, Diamond MS, Lewis MG, Rao M, Matyas GR, Gromowski GD, Peel SA, Michael NL, Bolton DL, and Modjarrad K
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- Animals, Antibodies, Neutralizing, Antibodies, Viral, COVID-19 Vaccines, Ferritins, Humans, Immunity, Macaca mulatta, SARS-CoV-2, Spike Glycoprotein, Coronavirus, COVID-19, Nanoparticles
- Abstract
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 spike ferritin nanoparticle (SpFN) vaccine in nonhuman primates. High-dose (50 μg) SpFN vaccine, given twice 28 days apart, induced a Th1-biased CD4 T cell helper response and elicited neutralizing antibodies against SARS-CoV-2 wild-type and variants of concern, as well as against SARS-CoV-1. These potent humoral and cell-mediated immune responses translated into rapid elimination of replicating virus in the upper and lower airways and lung parenchyma of nonhuman primates following high-dose SARS-CoV-2 respiratory challenge. The immune response elicited by SpFN vaccination and resulting efficacy in nonhuman primates supports the utility of SpFN as a vaccine candidate for SARS-causing betacoronaviruses.
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- 2022
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13. A SARS-CoV-2 spike ferritin nanoparticle vaccine protects hamsters against Alpha and Beta virus variant challenge.
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Wuertz KM, Barkei EK, Chen WH, Martinez EJ, Lakhal-Naouar I, Jagodzinski LL, Paquin-Proulx D, Gromowski GD, Swafford I, Ganesh A, Dong M, Zeng X, Thomas PV, Sankhala RS, Hajduczki A, Peterson CE, Kuklis C, Soman S, Wieczorek L, Zemil M, Anderson A, Darden J, Hernandez H, Grove H, Dussupt V, Hack H, de la Barrera R, Zarling S, Wood JF, Froude JW, Gagne M, Henry AR, Mokhtari EB, Mudvari P, Krebs SJ, Pekosz AS, Currier JR, Kar S, Porto M, Winn A, Radzyminski K, Lewis MG, Vasan S, Suthar M, Polonis VR, Matyas GR, Boritz EA, Douek DC, Seder RA, Daye SP, Rao M, Peel SA, Joyce MG, Bolton DL, Michael NL, and Modjarrad K
- Abstract
The emergence of SARS-CoV-2 variants of concern (VOC) requires adequate coverage of vaccine protection. We evaluated whether a SARS-CoV-2 spike ferritin nanoparticle vaccine (SpFN), adjuvanted with the Army Liposomal Formulation QS21 (ALFQ), conferred protection against the Alpha (B.1.1.7), and Beta (B.1.351) VOCs in Syrian golden hamsters. SpFN-ALFQ was administered as either single or double-vaccination (0 and 4 week) regimens, using a high (10 μg) or low (0.2 μg) dose. Animals were intranasally challenged at week 11. Binding antibody responses were comparable between high- and low-dose groups. Neutralizing antibody titers were equivalent against WA1, B.1.1.7, and B.1.351 variants following two high dose vaccinations. Dose-dependent SpFN-ALFQ vaccination protected against SARS-CoV-2-induced disease and viral replication following intranasal B.1.1.7 or B.1.351 challenge, as evidenced by reduced weight loss, lung pathology, and lung and nasal turbinate viral burden. These data support the development of SpFN-ALFQ as a broadly protective, next-generation SARS-CoV-2 vaccine., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)
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- 2021
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14. Pretreatment and Acquired Antiretroviral Drug Resistance Among Persons Living With HIV in Four African Countries.
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Crowell TA, Danboise B, Parikh A, Esber A, Dear N, Coakley P, Kasembeli A, Maswai J, Khamadi S, Bahemana E, Iroezindu M, Kiweewa F, Owuoth J, Freeman J, Jagodzinski LL, Malia JA, Eller LA, Tovanabutra S, Peel SA, Ake JA, and Polyak CS
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- Adult, Cohort Studies, Drug Resistance, Viral genetics, Humans, Mutation, Uganda, Viral Load, Anti-HIV Agents pharmacology, Anti-HIV Agents therapeutic use, HIV Infections drug therapy, HIV Infections epidemiology, HIV-1 genetics
- Abstract
Background: Emerging HIV drug resistance (HIVDR) could jeopardize the success of standardized HIV management protocols in resource-limited settings. We characterized HIVDR among antiretroviral therapy (ART)-naive and experienced participants in the African Cohort Study (AFRICOS)., Methods: From January 2013 to April 2019, adults with HIV-1 RNA >1000 copies/mL underwent ART history review and HIVDR testing upon enrollment at 12 clinics in Uganda, Kenya, Tanzania, and Nigeria. We calculated resistance scores for specific drugs and tallied major mutations to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) using Stanford HIVDB 8.8 and SmartGene IDNS software. For ART-naive participants, World Health Organization surveillance drug resistance mutations (SDRMs) were noted., Results: HIVDR testing was performed on 972 participants with median age 35.7 (interquartile range [IQR] 29.7-42.7) years and median CD4 295 (IQR 148-478) cells/mm3. Among 801 ART-naive participants, the prevalence of SDRMs was 11.0%, NNRTI mutations 8.2%, NRTI mutations 4.7%, and PI mutations 0.4%. Among 171 viremic ART-experienced participants, NNRTI mutation prevalence was 83.6%, NRTI 67.8%, and PI 1.8%. There were 90 ART-experienced participants with resistance to both efavirenz and lamivudine, 33 (36.7%) of whom were still prescribed these drugs. There were 10 with resistance to both tenofovir and lamivudine, 8 (80.0%) of whom were prescribed these drugs., Conclusions: Participants on failing ART regimens had a high burden of HIVDR that potentially limited the efficacy of standardized first- and second-line regimens. Management strategies that emphasize adherence counseling while delaying ART switch may promote drug resistance and should be reconsidered., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)
- Published
- 2021
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15. Central Nervous System Safety During Brief Analytic Treatment Interruption of Antiretroviral Therapy Within 4 Human Immunodeficiency Virus Remission Trials: An Observational Study in Acutely Treated People Living With Human Immunodeficiency Virus.
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Hellmuth J, Muccini C, Colby DJ, Kroon E, de Souza M, Crowell TA, Chan P, Sacdalan C, Intasan J, Benjapornpong K, Tipsuk S, Puttamaswin S, Chomchey N, Valcour V, Sarnecki M, Tomaka F, Krebs SJ, Slike BM, Jagodzinski LL, Dumrongpisutikul N, Sailasuta N, Samboju V, Michael NL, Robb ML, Vasan S, Ananworanich J, Phanuphak P, Phanuphak N, Paul R, and Spudich S
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- Adult, Anti-Retroviral Agents therapeutic use, Central Nervous System, Diffusion Tensor Imaging, HIV, Humans, Male, Viral Load, HIV Infections drug therapy
- Abstract
Background: The central nervous system (CNS) is a likely reservoir of human immunodeficiency virus (HIV), vulnerable to viral rebound, inflammation, and clinical changes upon stopping antiretroviral therapy (ART). It is critical to evaluate the CNS safety of studies using analytic treatment interruption (ATI) to assess HIV remission., Methods: Thirty participants who started ART during acute HIV infection underwent CNS assessments across 4 ATI remission trials. ART resumption occurred with plasma viral load >1000 copies/mL. CNS measures included paired pre- vs post-ATI measures of mood, cognitive performance, and neurologic examination, with elective cerebrospinal fluid (CSF) sampling, brain diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS)., Results: Median participant age was 30 years old and 29/30 were male. Participants' median time on ART before ATI was 3 years, and ATI lasted a median of 35 days. Post-ATI, there were no differences in median mood scores or neurologic findings and cognitive performance improved modestly. During ATI, a low level of CSF HIV-1 RNA was detectable in 6 of 20 participants with plasma viremia, with no group changes in CSF immune activation markers or brain DTI measures. Mild worsening was identified in post-ATI basal ganglia total choline MRS, suggesting an alteration in neuronal membranes., Conclusion: No adverse CNS effects were observed with brief, closely monitored ATI in participants with acutely treated HIV, except an MRS alteration in basal ganglia choline. Further studies are needed to assess CNS ATI safety in HIV remission trials, particularly for studies using higher thresholds to restart ART and longer ATI durations., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
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- 2021
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16. Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques.
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King HAD, Joyce MG, Lakhal-Naouar I, Ahmed A, Cincotta CM, Subra C, Peachman KK, Hack HR, Chen RE, Thomas PV, Chen WH, Sankhala RS, Hajduczki A, Martinez EJ, Peterson CE, Chang WC, Choe M, Smith C, Headley JA, Elyard HA, Cook A, Anderson A, Wuertz KM, Dong M, Swafford I, Case JB, Currier JR, Lal KG, Amare MF, Dussupt V, Molnar S, Daye SP, Zeng X, Barkei EK, Alfson K, Staples HM, Carrion R, Krebs SJ, Paquin-Proulx D, Karasavvas N, Polonis VR, Jagodzinski LL, Vasan S, Scott PT, Huang Y, Nair MS, Ho DD, de Val N, Diamond MS, Lewis MG, Rao M, Matyas GR, Gromowski GD, Peel SA, Michael NL, Modjarrad K, and Bolton DL
- Subjects
- Adjuvants, Immunologic administration & dosage, Animals, Antibodies, Neutralizing biosynthesis, Antibodies, Neutralizing immunology, Antibodies, Viral biosynthesis, Antibodies, Viral immunology, COVID-19 prevention & control, COVID-19 Vaccines immunology, Ferritins chemistry, SARS-CoV-2 metabolism, T-Lymphocytes immunology, COVID-19 virology, COVID-19 Vaccines administration & dosage, Macaca mulatta immunology, Nanoparticles chemistry, Receptors, Virus metabolism, SARS-CoV-2 immunology
- Abstract
Emergence of novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean serum neutralizing antibody titers of 14,000 to 21,000. Rapid control of viral replication was achieved in the upper and lower airways of animals after high-dose SARS-CoV-2 respiratory challenge, with undetectable replication within 4 d in seven of eight animals receiving 50 µg of RFN. Cross-neutralization activity against SARS-CoV-2 variant B.1.351 decreased only approximately twofold relative to WA1/2020. In addition, neutralizing, effector antibody and cellular responses targeted the heterotypic SARS-CoV-1, highlighting the broad immunogenicity of RFN-ALFQ for SARS-CoV-like Sarbecovirus vaccine development., Competing Interests: Competing interest statement: M.G.J. and K.M. are named as inventors on International Patent Application no. WO/2021/21405 entitled “Vaccines against SARS-CoV-2 and other coronaviruses.” M.G.J. is named as an inventor on International Patent Application no. WO/2018/081318 entitled “Prefusion Coronavirus Spike Proteins and Their Use.” M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech, and Carnival Corporation and is on the Scientific Advisory Boards of Moderna and Immunome. The M.S.D. laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions., (Copyright © 2021 the Author(s). Published by PNAS.)
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- 2021
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17. A SARS-CoV-2 spike ferritin nanoparticle vaccine protects against heterologous challenge with B.1.1.7 and B.1.351 virus variants in Syrian golden hamsters.
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Wuertz KM, Barkei EK, Chen WH, Martinez EJ, Lakhal-Naouar I, Jagodzinski LL, Paquin-Proulx D, Gromowski GD, Swafford I, Ganesh A, Dong M, Zeng X, Thomas PV, Sankhala RS, Hajduczki A, Peterson CE, Kuklis C, Soman S, Wieczorek L, Zemil M, Anderson A, Darden J, Hernandez H, Grove H, Dussupt V, Hack H, de la Barrera R, Zarling S, Wood JF, Froude JW, Gagne M, Henry AR, Mokhtari EB, Mudvari P, Krebs SJ, Pekosz AS, Currier JR, Kar S, Porto M, Winn A, Radzyminski K, Lewis MG, Vasan S, Suthar M, Polonis VR, Matyas GR, Boritz EA, Douek DC, Seder RA, Daye SP, Rao M, Peel SA, Joyce MG, Bolton DL, Michael NL, and Modjarrad K
- Abstract
The emergence of SARS-CoV-2 variants of concern (VOC) requires adequate coverage of vaccine protection. We evaluated whether a spike ferritin nanoparticle vaccine (SpFN), adjuvanted with the Army Liposomal Formulation QS21 (ALFQ), conferred protection against the B.1.1.7 and B.1.351 VOCs in Syrian golden hamsters. SpFN-ALFQ was administered as either single or double-vaccination (0 and 4 week) regimens, using a high (10 μg) or low (0.2 μg) immunogen dose. Animals were intranasally challenged at week 11. Binding antibody responses were comparable between high- and low-dose groups. Neutralizing antibody titers were equivalent against WA1, B.1.1.7, and B.1.351 variants following two high dose two vaccinations. SpFN-ALFQ vaccination protected against SARS-CoV-2-induced disease and viral replication following intranasal B.1.1.7 or B.1.351 challenge, as evidenced by reduced weight loss, lung pathology, and lung and nasal turbinate viral burden. These data support the development of SpFN-ALFQ as a broadly protective, next-generation SARS-CoV-2 vaccine.
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- 2021
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18. Efficacy of a Broadly Neutralizing SARS-CoV-2 Ferritin Nanoparticle Vaccine in Nonhuman Primates.
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Joyce MG, King HAD, Naouar IE, Ahmed A, Peachman KK, Cincotta CM, Subra C, Chen RE, Thomas PV, Chen WH, Sankhala RS, Hajduczki A, Martinez EJ, Peterson CE, Chang WC, Choe M, Smith C, Lee PJ, Headley JA, Taddese MG, Elyard HA, Cook A, Anderson A, McGuckin-Wuertz K, Dong M, Swafford I, Case JB, Currier JR, Lal KG, O'Connell RJ, Molnar S, Nair MS, Dussupt V, Daye SP, Zeng X, Barkei EK, Staples HM, Alfson K, Carrion R, Krebs SJ, Paquin-Proulx D, Karasavva N, Polonis VR, Jagodzinski LL, Amare MF, Vasan S, Scott PT, Huang Y, Ho DD, de Val N, Diamond MS, Lewis MG, Rao M, Matyas GR, Gromowski GD, Peel SA, Michael NL, Bolton DL, and Modjarrad K
- Abstract
The emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine in nonhuman primates (NHPs). High-dose (50 µ g) SpFN vaccine, given twice within a 28 day interval, induced a Th1-biased CD4 T cell helper response and a peak neutralizing antibody geometric mean titer of 52,773 against wild-type virus, with activity against SARS-CoV-1 and minimal decrement against variants of concern. Vaccinated animals mounted an anamnestic response upon high-dose SARS-CoV-2 respiratory challenge that translated into rapid elimination of replicating virus in their upper and lower airways and lung parenchyma. SpFN's potent and broad immunogenicity profile and resulting efficacy in NHPs supports its utility as a candidate platform for SARS-like betacoronaviruses., One-Sentence Summary: A SARS-CoV-2 Spike protein ferritin nanoparticle vaccine, co-formulated with a liposomal adjuvant, elicits broad neutralizing antibody responses that exceed those observed for other major vaccines and rapidly protects against respiratory infection and disease in the upper and lower airways and lung tissue of nonhuman primates.
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- 2021
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19. Hepatitis B seroprevalence in the U.S. military and its impact on potential screening strategies.
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Scott PT, Cohen RL, Brett-Major DM, Hakre S, Malia JA, Okulicz JF, Beckett CG, Blaylock JM, Forgione MA, Harrison SA, Murray CK, Rentas FJ, Fahie RL, Armstrong AW, Hayat AM, Pacha LA, Dawson P, Blackwell B, Eick-Cost AA, Maktabi HH, Michael NL, Jagodzinski LL, Cersovsky SB, and Peel SA
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- Adult, Afghanistan, Female, Humans, Iraq, Male, Mass Screening, Prevalence, Seroepidemiologic Studies, Hepatitis B diagnosis, Hepatitis B epidemiology, Military Personnel
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Introduction: Knowledge of the contemporary epidemiology of hepatitis B virus (HBV) infection among military personnel can inform potential Department of Defense (DoD) screening policy and infection and disease control strategies., Materials and Methods: HBV infection status at accession and following deployment was determined by evaluating reposed serum from 10,000 service members recently deployed to combat operations in Iraq and Afghanistan in the period from 2007 to 2010. A cost model was developed from the perspective of the Department of Defense for a program to integrate HBV infection screening of applicants for military service into the existing screening program of screening new accessions for vaccine-preventable infections., Results: The prevalence of chronic HBV infection at accession was 2.3/1,000 (95% CI: 1.4, 3.2); most cases (16/21, 76%) identified after deployment were present at accession. There were 110 military service-related HBV infections identified. Screening accessions who are identified as HBV susceptible with HBV surface antigen followed by HBV surface antigen neutralization for confirmation offered no cost advantage over not screening and resulted in a net annual increase in cost of $5.78 million. However, screening would exclude as many as 514 HBV cases each year from accession., Conclusions: Screening for HBV infection at service entry would potentially reduce chronic HBV infection in the force, decrease the threat of transfusion-transmitted HBV infection in the battlefield blood supply, and lead to earlier diagnosis and linkage to care; however, applicant screening is not cost saving. Service-related incident infections indicate a durable threat, the need for improved laboratory-based surveillance tools, and mandate review of immunization policy and practice., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States.)
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- 2020
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20. Performance evaluation of a laboratory developed PCR test for quantitation of HIV-2 viral RNA.
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Jagodzinski LL, Manak MM, Hack HR, Liu Y, and Peel SA
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- Case-Control Studies, HIV Infections blood, HIV Infections virology, HIV-1 isolation & purification, HIV-2 isolation & purification, Humans, RNA, Viral blood, Reagent Kits, Diagnostic, Viral Load, HIV Infections diagnosis, HIV-1 genetics, HIV-2 genetics, Laboratories standards, RNA, Viral genetics, Real-Time Polymerase Chain Reaction methods, Serologic Tests standards
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Management of Human Immunodeficiency Virus Type 2 (HIV-2) infections present unique challenges due to low viral titers, slow disease progression, and poor response to standard antiviral therapies. The need for a nucleic acid assay to detect and quantify HIV-2 virus has led to the development of a number of molecular-based assays for detection and/or quantification of HIV-2 viral RNA in plasma in order to provide laboratory evidence of HIV-2 infection and viral loads for use in treatment decisions. As HIV-2 is less pathogenic and transmissible than HIV-1 and has resistance to several of the antiretroviral drugs, delay of treatment is common. Cross sero-reactivity between HIV-1 and HIV-2 makes it difficult to distinguish between the two viruses based upon serological tests. As such we developed a quantitative reverse transcription PCR (qRT-PCR) assay targeting the 5' long terminal repeat of HIV-2 for detection and quantification of HIV-2 viral RNA in plasma to identify HIV-2 infection and for use in viral load monitoring. Serial dilutions of cultured HIV-2 virus demonstrated a wide dynamic range (10 to 100,000 copies/ml) with excellent reproducibility (standard deviation from 0.12-0.19), linearity (R2 = 0.9994), and a lower limit of detection at 79 copies/ml (NIH-Z). The assay is highly specific for HIV-2 Groups A and B and exhibits no cross reactivity to HIV-1, HBV or HCV. Precision of the assay was demonstrated for the High (Mean = 6.41; SD = 0.12) and Medium (Mean = 4.46; SD = 0.13) HIV-2 positive controls. Replicate testing of clinical specimens showed good reproducibility above 1,000 copies/ml, with higher variability under 1,000 copies/ml. Analysis of 220 plasma samples from HIV-2 infected West African individuals demonstrated significantly lower viral loads than those observed in HIV-1 infections, consistent with results of previous studies. Slightly more than seven percent of clinical samples (7.3%) demonstrated viral loads above 100,000 copies/ml, while 37.3% of samples were undetectable. The high sensitivity, specificity, precision, and linearity of the WRAIR qRT-PCR assay makes it well suited for detection and monitoring of HIV-2 RNA levels in plasma of infected individuals., Competing Interests: The authors have declared that no competing interests exist.
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- 2020
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21. Very Early Initiation of Antiretroviral Therapy During Acute HIV Infection Is Associated With Normalized Levels of Immune Activation Markers in Cerebrospinal Fluid but Not in Plasma.
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Hellmuth J, Slike BM, Sacdalan C, Best J, Kroon E, Phanuphak N, Fletcher JLK, Prueksakaew P, Jagodzinski LL, Valcour V, Robb M, Ananworanich J, Allen IE, Krebs SJ, and Spudich S
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- Acute Disease, Adult, Anti-Retroviral Agents therapeutic use, Antiretroviral Therapy, Highly Active, CD4 Lymphocyte Count, CD4-CD8 Ratio, Cohort Studies, Female, HIV Infections metabolism, Humans, Lymphocyte Activation, Male, RNA, Viral, Time-to-Treatment, Viral Load, Young Adult, Biomarkers blood, Biomarkers cerebrospinal fluid, HIV Infections drug therapy, HIV Infections immunology, HIV-1 immunology, Host-Pathogen Interactions immunology
- Abstract
Background: Chronic immune activation in the blood and central nervous system is a consequence of human immunodeficiency virus (HIV) infection that contributes to disease morbidity and can occur despite virally suppressive antiretroviral therapy (ART). The trajectory of HIV-related inflammation may vary with the timing of ART initiation. We examined immune activation markers in cerebrospinal fluid (CSF) and blood specimens collected over 96 weeks from participants who initiated ART during acute HIV infection (AHI)., Methods: RV254/SEARCH010 study participants with AHI underwent CSF (n = 89) and plasma (n = 146) sampling before initiating ART and at weeks 24 and 96 of treatment. A majority participants (64.4%) received a standard ART regimen (hereafter, "standard ART"), with some (34.7%) also receiving maraviroc and raltegravir for the first 24 weeks (hereafter, "ART plus"). We compared neopterin, CXCL10, CCL2, and interleukin 6 (IL-6) levels in the AHI group to those in 18 healthy, uninfected controls., Results: Following 24 and 96 weeks of treatment, levels of all CSF markers normalized while levels of several plasma markers remained elevated in the AHI group (P < .001). Participants receiving the ART-plus regimen had lower median plasma CCL2 levels at week 24 and lower plasma neopterin levels at week 96., Conclusions: ART initiation during AHI differentially impacts the brain compartment, with markers of inflammation returning to normal levels in the CSF, where they were sustained at week 96, but not in plasma., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2019
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22. Decreased Seroreactivity in Individuals Initiating Antiretroviral Therapy during Acute HIV Infection.
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Manak MM, Jagodzinski LL, Shutt A, Malia JA, Leos M, Ouellette J, Akapirat S, Colby DL, Phanuphak N, Eller LA, Robb ML, de Souza M, Ananworanich J, and Peel SA
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- Anti-HIV Agents administration & dosage, Anti-HIV Agents therapeutic use, Antiretroviral Therapy, Highly Active, Female, HIV Antibodies immunology, HIV Antigens immunology, HIV Infections drug therapy, HIV Infections immunology, HIV Seropositivity, Humans, Immunoassay, Male, RNA, Viral, Serologic Tests, Treatment Outcome, HIV genetics, HIV immunology, HIV Infections diagnosis, HIV Infections virology
- Abstract
Antiretroviral therapy (ART) during acute HIV infection (AHI) interrupts viral dynamics and may delay the emergence of serological markers targeted by current HIV screening and confirmatory assays, thus creating challenges for correctly classifying HIV infection status. The performance of three HIV antigen/antibody combination (HIV Ag/Ab Combo) assays (the Bio-Rad GS, Abbott Architect, and Bio-Rad BioPlex 2200 assays) was evaluated with samples collected from RV254/South East Asia Research Collaboration in HIV 010 (RV254/SEARCH010) study (Bangkok, Thailand) participants at weeks 12 and 24 following the initiation of ART at Fiebig stage I (FI) ( n = 23), FII ( n = 39), or FIII/IV ( n = 22). Supplemental, confirmatory testing was performed by the Geenius HIV 1/2 and HIV-1 Western blot assays (Bio-Rad). Samples from 30 untreated, HIV-1-infected individuals demonstrated robust HIV Ag/Ab Combo assay reactivity with well-developed HIV-1 Western blotting profiles by 24 weeks after infection. In contrast, 52.2% of samples from individuals initiating ART at FI, 7.7% of samples from individuals initiating ART at FII, and 4.5% of samples from individuals initiating ART at FIII/IV were nonreactive by the HIV Ag/Ab Combo assays, with 36.4 to 39.1% of samples having low signal-to-cutoff (S/CO) results by the Architect and BioPlex assays (S/CO < 10). Seroreversion from a reactive to a nonreactive status was observed in 10 individuals initiating ART at FII and 3 individuals initiating ART at FIII/IV. The Geenius and HIV-1 Western blot assay results were negative or indeterminate for 73.9% and 69.6% of individuals, respectively, treated at FI; 50.0% and 26.3% of individuals, respectively, treated at FII; and 54.5% and 40.9% of individuals, respectively, treated at FIII/IV. Virologic suppression of HIV-1 by ART during AHI impedes seroconversion to biomarkers of infection, limiting the utility of HIV Ag/Ab Combo and supplemental, confirmatory assays for infection status determination., (Copyright © 2019 American Society for Microbiology.)
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- 2019
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23. Deep Sequencing Reveals Central Nervous System Compartmentalization in Multiple Transmitted/Founder Virus Acute HIV-1 Infection.
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Tovanabutra S, Sirijatuphat R, Pham PT, Bonar L, Harbolick EA, Bose M, Song H, Chang D, Oropeza C, O'Sullivan AM, Balinang J, Kroon E, Colby DJ, Sacdalan C, Hellmuth J, Chan P, Prueksakaew P, Pinyakorn S, Jagodzinski LL, Sutthichom D, Pattamaswin S, de Souza M, Gramzinski RA, Kim JH, Michael NL, Robb ML, Phanuphak N, Ananworanich J, Valcour V, Kijak GH, Sanders-Buell E, and Spudich S
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- Adult, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Sequence Analysis, RNA, Virus Replication, Young Adult, Genes, env genetics, Genes, pol genetics, HIV Infections blood, HIV Infections cerebrospinal fluid, HIV-1 genetics, HIV-1 physiology, RNA, Viral blood
- Abstract
HIV-1 disseminates to a broad range of tissue compartments during acute HIV-1 infection (AHI). The central nervous system (CNS) can serve as an early and persistent site of viral replication, which poses a potential challenge for HIV-1 remission strategies that target the HIV reservoir. CNS compartmentalization is a key feature of HIV-1 neuropathogenesis. Thus far, the timing of how early CNS compartmentalization develops after infection is unknown. We examined whether HIV-1 transmitted/founder (T/F) viruses differ between CNS and blood during AHI using single-genome sequencing of envelope gene and further examined subregions in pol and env using next-generation sequencing in paired plasma and cerebrospinal fluid (CSF) from 18 individuals. Different proportions of mostly minor variants were found in six of the eight multiple T/F-infected individuals, indicating enrichment of some variants in CSF that may lead to significant compartmentalization in the later stages of infection. This study provides evidence for the first time that HIV-1 compartmentalization in the CNS can occur within days of HIV-1 exposure in multiple T/F infections. Further understanding of factors that determine enrichment of T/F variants in the CNS, as well as potential long-term implications of these findings for persistence of HIV-1 reservoirs and neurological impairment in HIV, is needed.
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- 2019
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24. Asymptomatic Visceral Leishmania infantum Infection in US Soldiers Deployed to Iraq.
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Mody RM, Lakhal-Naouar I, Sherwood JE, Koles NL, Shaw D, Bigley DP, Co EA, Copeland NK, Jagodzinski LL, Mukbel RM, Smiley RA, Duncan RC, Kamhawi S, Jeronimo SMB, DeFraites RF, and Aronson NE
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- Adult, Female, Geography, Humans, Iraq epidemiology, Leishmaniasis, Visceral diagnosis, Male, Middle Aged, Public Health Surveillance, United States epidemiology, Young Adult, Asymptomatic Infections, Leishmania infantum, Leishmaniasis, Visceral epidemiology, Leishmaniasis, Visceral parasitology, Military Personnel
- Abstract
Background: Visceral leishmaniasis (VL), due to Leishmania infantum, is a persistent intracellular parasitic infection transmitted by the bite of infected sand flies. Symptomatic VL has been reported in U.S. soldiers with Iraq deployment. Untreated symptomatic VL can be fatal; asymptomatic VL (AVL) may establish a lifelong risk of reactivation. We report prevalence and AVL risk factors in Operation Iraqi Freedom (OIF) deployers during 2002-11., Methods: Healthy soldiers exposed to VL endemic areas in Iraq and 50 controls who never traveled to endemic regions were recruited through military healthcare facilities (2015-17). Responses to a risk factor survey and blood samples were obtained. Leishmania research diagnostics utilized included enzyme-linked immunosorbent assay (ELISA), rk39 test strips, quantitative polymerase chain reaction (PCR), and interferon gamma release (IGRA) assays. Statistical analyses included Fisher exact test, Pearson χ2 test, Mann-Whitney U test, and logistic regression., Results: 200 deployed subjects were enrolled, mostly males (84.0%), of white ethnicity (79.0%), and median age 41 (range 24-61) years. 64% were seropositive for Phlebotomus alexandri saliva antibodies. Prevalence of AVL (any positive test result) was 39/200 (19.5%, 95% confidence interval 14.4%-25.8%). Two (1.0%) PCR, 10 (5%) ELISA, and 28 (14%) IGRA samples were positive. Travel to Ninewa governorate increased risk for AVL (P = .01)., Conclusion: AVL was identified in 19.5% of OIF deployers; travel to northwest Iraq correlated with infection. Further studies are needed to inform risk for reactivation VL in US veterans and to target additional blood safety and surveillance measures., (Published by Oxford University Press for the Infectious Diseases Society of America 2018.)
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- 2019
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25. Impact of Early Antiretroviral Therapy on Detection of Cell-Associated HIV-1 Nucleic Acid in Blood by the Roche Cobas TaqMan Test.
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Jagodzinski LL, Manak MM, Hack HR, Liu Y, Malia JA, Freeman J, Phanuphak N, de Souza M, Kroon ED, Colby DJ, Chomchey N, Lally MA, Michael NL, Ananworanich J, and Peel SA
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- Adolescent, Adult, HIV Infections blood, HIV-1, Humans, Male, Middle Aged, Prospective Studies, Reagent Kits, Diagnostic, Sensitivity and Specificity, Specimen Handling, Viral Load, Young Adult, Anti-Retroviral Agents therapeutic use, HIV Infections drug therapy, Leukocytes, Mononuclear virology, RNA, Viral blood
- Abstract
The Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test, v2.0 (the CAP/CTM assay), was used to quantify cell-associated HIV-1 (CAH) nucleic acid in peripheral blood mononuclear cells (PBMC) from well-characterized clinical specimens from HIV-1-infected individuals on antiretroviral therapy (ART). Chronically infected individuals on ART with no detectable plasma HIV-1 RNA demonstrated average CAH burdens of 3.2 HIV-1 log
10 copies/million cells. Assay sensitivity and specificity were 98.9% and 100%, respectively, with the positive and negative predictive values being 100% and 98.6%, respectively. The CAH burden was also measured at weeks 0, 1, 2, 8, and 60 in 37 participants (RV254/SEARCH010, Bangkok, Thailand) stratified by Fiebig stage (Fiebig stage I [FI] to FVI) at ART initiation. Prior to ART initiation, the average CAH burden was 1.4, 4.1, and 3.6 log10 copies/million PBMCs for individuals who initiated ART at FI, FII, and FIII to FVI, respectively. Initiation of ART resulted in a rapid decline of CAH in all individuals, with the greatest decrease being observed in individuals who initiated ART at FI to FIII. By week 60, 100% (FI), 71.8% (FII/FIII), and 20.5% (FIV to FVI) of samples from individuals initiating treatment were at or near the limit of quantitation. Residual CAH was detectable at 60 weeks in most individuals who initiated ART at later stages (FIV to FVI) and averaged 1.9 ± 0.7 log10 copies/million PBMCs. The modified Roche CAP/CTM assay provides a convenient, standardized approach to measure residual HIV in blood and may be useful for monitoring patients under therapy or those participating in HIV remission studies.- Published
- 2019
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26. Stability of Human Immunodeficiency Virus Serological Markers in Samples Collected as HemaSpot and Whatman 903 Dried Blood Spots.
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Manak MM, Hack HR, Shutt AL, Danboise BA, Jagodzinski LL, and Peel SA
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- AIDS Serodiagnosis, HIV immunology, HIV Antibodies blood, HIV Antibodies chemistry, HIV Antigens blood, HIV Antigens chemistry, HIV Infections blood, HIV Seropositivity blood, Humans, Immunoenzyme Techniques standards, Protein Stability, Reproducibility of Results, Sensitivity and Specificity, Temperature, Time Factors, Dried Blood Spot Testing instrumentation, HIV isolation & purification, HIV Infections diagnosis, Specimen Handling instrumentation
- Abstract
Dried blood spots (DBS) are frequently used in clinical testing for biosurveillance, infectious disease and confirmatory testing, and clinical trials, particularly for populations in remote areas. The HemaSpot-HF blood collection device (HS) provides an alternative format to the Whatman 903 cards (903) to simplify sample collection and processing. In this study, the performance of the HS was compared to that of the 903 using previously characterized clinical specimens and HIV seroconversion panels known to exhibit markers of early human immunodeficiency virus (HIV) infection. HS and 903 samples were prepared and tested by Bio-Rad GS HIV Combo Ag/Ab enzyme immunoassay (EIA), GS HIV-1/-2 Plus O EIA, GS HIV-1 Western blot, and HIV-1 Geenius assays. Both HS and 903 performed well for up to 6 months at room temperature, but a marked loss of Western blot and low titer antibody signals from early infection samples was observed in samples stored for 180 days at elevated (37 to 45°C) temperatures and high humidity (95%). HemaSpot samples placed in sealed bags with additional desiccant were protected from degradation and showed improved signal recovery relative to that of the 903. HS was easier to use than the 903 and showed higher sensitivity and reproducibility for early infection samples and improved stability.
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- 2018
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27. Acute Retroviral Syndrome Is Associated With High Viral Burden, CD4 Depletion, and Immune Activation in Systemic and Tissue Compartments.
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Crowell TA, Colby DJ, Pinyakorn S, Fletcher JLK, Kroon E, Schuetz A, Krebs SJ, Slike BM, Leyre L, Chomont N, Jagodzinski LL, Sereti I, Utay NS, Dewar R, Rerknimitr R, Chomchey N, Trichavaroj R, Valcour VG, Spudich S, Michael NL, Robb ML, Phanuphak N, and Ananworanich J
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- Acute Retroviral Syndrome epidemiology, Acute Retroviral Syndrome immunology, Adult, Anti-Retroviral Agents therapeutic use, Biomarkers, Central Nervous System Diseases etiology, Central Nervous System Diseases pathology, Central Nervous System Diseases virology, DNA, Viral isolation & purification, Female, Gastrointestinal Diseases immunology, Gastrointestinal Diseases pathology, Gastrointestinal Diseases virology, HIV-1, Humans, Inflammation metabolism, Inflammation pathology, Male, RNA, Viral, Thailand epidemiology, Young Adult, Acute Retroviral Syndrome pathology, Acute Retroviral Syndrome virology, CD4 Lymphocyte Count, Immune System Phenomena physiology, Immunity, Cellular physiology, Viral Load
- Abstract
Background: Many individuals with acute human immunodeficiency virus infection (AHI) experience acute retroviral syndrome (ARS), which is associated with adverse long-term clinical outcomes., Methods: Participants presenting for voluntary human immunodeficiency virus (HIV) testing were enrolled during AHI in Bangkok, Thailand. ARS was defined by ≥3 qualifying signs/symptoms. HIV burden, immunophenotypes, and biomarkers were stratified by ARS diagnosis at enrollment and after up to 96 weeks of antiretroviral therapy (ART)., Results: From 212382 samples screened, 430 participants were enrolled during AHI, including 335 (78%) with ARS. Median age was 26 years and 416 (97%) were men. Sixty (14%) underwent sigmoid biopsy and 105 (24%) underwent lumbar puncture during AHI. Common symptoms included fever (93%), fatigue (79%), pharyngitis (67%), and headache (64%). Compared to those without ARS, participants with ARS were in later Fiebig stages with higher HIV RNA in blood, colon, and cerebrospinal fluid; higher total HIV DNA in blood; CD4 depletion in blood and colon; and elevated plasma tumor necrosis factor alpha (TNF-α), C-reactive protein, and D-dimer (all P < .05). Subgroup analyses of Fiebig I/II participants (95 with ARS, 69 without) demonstrated similar findings. After 96 weeks of ART, TNF-α and interleukin 6 were elevated in the ARS group (P < .05) but other biomarkers equilibrated., Conclusions: ARS was associated with high viral burden, CD4 depletion, and immune activation across multiple body compartments during AHI and prior to ART. Persistent inflammation despite suppressive ART could contribute to increased morbidity in individuals who experience ARS.
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- 2018
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28. Depression and Anxiety are Common in Acute HIV Infection and Associate with Plasma Immune Activation.
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Hellmuth J, Colby D, Valcour V, Suttichom D, Spudich S, Ananworanich J, Prueksakaew P, Sailasuta N, Allen I, Jagodzinski LL, Slike B, Ochi D, and Paul R
- Subjects
- Adult, Anxiety epidemiology, Biomarkers blood, CD4 Lymphocyte Count, Depression epidemiology, Depression psychology, Female, HIV Infections blood, HIV Infections immunology, Humans, Male, Thailand, Viral Load, Young Adult, Anxiety complications, Anxiety immunology, Depression complications, Depression immunology, HIV Infections complications, HIV Infections physiopathology, Lymphocyte Activation immunology, RNA, Viral blood
- Abstract
This observational study of 123 Thai participants sought to determine the rate and severity of affective symptoms during acute HIV infection (AHI) and possible associations to disease mechanisms. At diagnosis, just prior to starting combination antiretroviral therapy (cART), AHI participants completed assessments of depression and anxiety symptoms that were repeated at 4, 12, and 24 weeks. Blood markers of HIV infection and immune activation were measured at study entry, with optional cerebrospinal fluid measures. A high frequency of participants reported symptoms that exceeded published thresholds supportive of depression (55.0%) and anxiety (65.8%) at diagnosis, with significant reductions after starting cART. Meeting a threshold for clinically relevant depressive symptoms at study entry was associated with higher baseline plasma HIV RNA (5.98 vs. 5.50, t = 2.46, p = 0.015), lower CD4 counts (328 vs. 436 cells/mm
3 , t = 3.46, p = 0.001), and higher plasma neopterin, a marker of macrophage activation (2694 vs. 1730 pg/mL, Mann-Whitney U = 152.5, p = 0.011). Controlling for plasma HIV RNA and CD4 count, higher baseline plasma neopterin correlated with worse initial depression and anxiety scores. Depression and anxiety symptoms are frequent in acute HIV infection, associate with plasma immune activation, and can improve concurrent with cART.- Published
- 2017
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29. Characteristics of HIV-infected U.S. Army soldiers linked in molecular transmission clusters, 2001-2012.
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Hakre S, Jagodzinski LL, Liu Y, Pham PT, Kijak GH, Tovanabutra S, McCutchan FE, Scoville SL, Cersovsky SB, Michael NL, Scott PT, and Peel SA
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- Adolescent, Adult, Female, HIV Infections transmission, Humans, Male, Middle Aged, United States, HIV Infections epidemiology, Military Personnel statistics & numerical data
- Abstract
Objective: Recent surveillance data suggests the United States (U.S.) Army HIV epidemic is concentrated among men who have sex with men. To identify potential targets for HIV prevention strategies, the relationship between demographic and clinical factors and membership within transmission clusters based on baseline pol sequences of HIV-infected Soldiers from 2001 through 2012 were analyzed., Methods: We conducted a retrospective analysis of baseline partial pol sequences, demographic and clinical characteristics available for all Soldiers in active service and newly-diagnosed with HIV-1 infection from January 1, 2001 through December 31, 2012. HIV-1 subtype designations and transmission clusters were identified from phylogenetic analysis of sequences. Univariate and multivariate logistic regression models were used to evaluate and adjust for the association between characteristics and cluster membership., Results: Among 518 of 995 HIV-infected Soldiers with available partial pol sequences, 29% were members of a transmission cluster. Assignment to a southern U.S. region at diagnosis and year of diagnosis were independently associated with cluster membership after adjustment for other significant characteristics (p<0.10) of age, race, year of diagnosis, region of duty assignment, sexually transmitted infections, last negative HIV test, antiretroviral therapy, and transmitted drug resistance. Subtyping of the pol fragment indicated HIV-1 subtype B infection predominated (94%) among HIV-infected Soldiers., Conclusion: These findings identify areas to explore as HIV prevention targets in the U.S. Army. An increased frequency of current force testing may be justified, especially among Soldiers assigned to duty in installations with high local HIV prevalence such as southern U.S. states.
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- 2017
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30. Identification of Acute HIV-1 Infection by Hologic Aptima HIV-1 RNA Qualitative Assay.
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Manak MM, Eller LA, Malia J, Jagodzinski LL, Trichavaroj R, Oundo J, Lueer C, Cham F, de Souza M, Michael NL, Robb ML, and Peel SA
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- Africa, Early Diagnosis, HIV-1 genetics, Humans, Predictive Value of Tests, RNA, Viral genetics, Sensitivity and Specificity, Thailand, HIV Infections diagnosis, HIV-1 isolation & purification, Molecular Diagnostic Techniques methods, RNA, Viral blood
- Abstract
The Hologic Aptima HIV-1 Qualitative RNA assay was used in a rigorous screening approach designed to identify individuals at the earliest stage of HIV-1 infection for enrollment into subsequent studies of cellular and viral events in early infection (RV 217/Early Capture HIV Cohort [ECHO] study). Volunteers at high risk for HIV-1 infection were recruited from study sites in Thailand, Tanzania, Uganda, and Kenya with high HIV-1 prevalence rates among the populations examined. Small-volume blood samples were collected by finger stick at twice-weekly intervals and tested with the Aptima assay. Participants with reactive Aptima test results were contacted immediately for entry into a more comprehensive follow-up schedule with frequent blood draws. Evaluation of the Aptima test prior to use in this study showed a detection sensitivity of 5.5 copies/ml (50%), with all major HIV-1 subtypes detected. A total of 54,306 specimens from 1,112 volunteers were examined during the initial study period (August 2009 to November 2010); 27 individuals were identified as converting from uninfected to infected status. A sporadic reactive Aptima signal was observed in HIV-1-infected individuals under antiretroviral therapy. Occasional false-reactive Aptima results in uninfected individuals, or nonreactive results in HIV-1-infected individuals not on therapy, were observed and used to calculate assay sensitivity and specificity. The sensitivity and specificity of the Aptima assay were 99.03% and 99.23%, respectively; positive and negative predictive values were 92.01% and 99.91%, respectively. Conversion from HIV-1-uninfected to -infected status was rapid, with no evidence of a prolonged period of intermittent low-level viremia., (Copyright © 2017 Manak et al.)
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- 2017
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31. A Recombinant Vesicular Stomatitis Virus Ebola Vaccine.
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Regules JA, Beigel JH, Paolino KM, Voell J, Castellano AR, Hu Z, Muñoz P, Moon JE, Ruck RC, Bennett JW, Twomey PS, Gutiérrez RL, Remich SA, Hack HR, Wisniewski ML, Josleyn MD, Kwilas SA, Van Deusen N, Mbaya OT, Zhou Y, Stanley DA, Jing W, Smith KS, Shi M, Ledgerwood JE, Graham BS, Sullivan NJ, Jagodzinski LL, Peel SA, Alimonti JB, Hooper JW, Silvera PM, Martin BK, Monath TP, Ramsey WJ, Link CJ, Lane HC, Michael NL, Davey RT Jr, and Thomas SJ
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- Adult, Antibodies, Viral blood, Double-Blind Method, Ebola Vaccines administration & dosage, Ebola Vaccines adverse effects, Ebolavirus genetics, Ebolavirus isolation & purification, Enzyme-Linked Immunosorbent Assay, Female, Hemorrhagic Fever, Ebola immunology, Humans, Male, Middle Aged, Recombinant Proteins, Seroconversion, Vaccines, Attenuated immunology, Vesicular stomatitis Indiana virus, Viral Envelope Proteins isolation & purification, Viremia, Ebola Vaccines immunology, Ebolavirus immunology, Hemorrhagic Fever, Ebola prevention & control
- Abstract
Background: The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD., Methods: We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed., Results: The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months., Conclusions: This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses. (Funded by the National Institutes of Health and others; rVSV∆G-ZEBOV-GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408 .).
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- 2017
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32. Evaluation of Hologic Aptima HIV-1 Quant Dx Assay on the Panther System on HIV Subtypes.
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Manak MM, Hack HR, Nair SV, Worlock A, Malia JA, Peel SA, and Jagodzinski LL
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- Genotype, HIV classification, HIV genetics, Humans, Molecular Diagnostic Techniques methods, HIV isolation & purification, HIV Infections virology, Viral Load methods
- Abstract
Quantitation of the HIV-1 viral load in plasma is the current standard of care for clinical monitoring of HIV-infected individuals undergoing antiretroviral therapy. This study evaluated the analytical and clinical performances of the Aptima HIV-1 Quant Dx assay (Hologic, San Diego, CA) for monitoring viral load by using 277 well-characterized subtype samples, including 171 cultured virus isolates and 106 plasma samples from 35 countries, representing all major HIV subtypes, recombinants, and circulating recombinant forms (CRFs) currently in circulation worldwide. Linearity of the Aptima assay was tested on each of 6 major HIV-1 subtypes (A, B, C, D, CRF01_AE, and CRF02_AG) and demonstrated an R(2) value of ≥0.996. The performance of the Aptima assay was also compared to those of the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 v.2 (CAP/CTM) and Abbott m2000 RealTime HIV-1 (RealTime) assays on all subtype samples. The Aptima assay values averaged 0.21 log higher than the CAP/CTM values and 0.30 log higher than the RealTime values, and the values were >0.4 log higher than CAP/CTM values for subtypes F and G and than RealTime values for subtypes C, F, and G and CRF02_AG. Two samples demonstrated results with >1-log differences from RealTime results. When the data were adjusted by the average difference, 94.9% and 87.0% of Aptima results fell within 0.5 log of the CAP/CTM and RealTime results, respectively. The linearity and accuracy of the Aptima assay in correctly quantitating all major HIV-1 subtypes, coupled with the completely automated format and high throughput of the Panther system, make this system well suited for reliable measurement of viral load in the clinical laboratory., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
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- 2016
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33. Neurologic signs and symptoms frequently manifest in acute HIV infection.
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Hellmuth J, Fletcher JL, Valcour V, Kroon E, Ananworanich J, Intasan J, Lerdlum S, Narvid J, Pothisri M, Allen I, Krebs SJ, Slike B, Prueksakaew P, Jagodzinski LL, Puttamaswin S, Phanuphak N, and Spudich S
- Subjects
- Acute Disease, Adult, Anti-Retroviral Agents therapeutic use, Biomarkers blood, Biomarkers cerebrospinal fluid, Brain diagnostic imaging, Cognition, Cohort Studies, Female, Follow-Up Studies, HIV Infections drug therapy, HIV Infections epidemiology, Humans, Incidence, Magnetic Resonance Imaging, Male, Motor Activity, Severity of Illness Index, Time Factors, HIV Infections physiopathology, HIV Infections psychology
- Abstract
Objective: To determine the incidence, timing, and severity of neurologic findings in acute HIV infection (pre-antibody seroconversion), as well as persistence with combination antiretroviral therapy (cART)., Methods: Participants identified with acute HIV were enrolled, underwent structured neurologic evaluations, immediately initiated cART, and were followed with neurologic evaluations at 4 and 12 weeks. Concurrent brain MRIs and both viral and inflammatory markers in plasma and CSF were obtained., Results: Median estimated HIV infection duration was 19 days (range 3-56) at study entry for the 139 participants evaluated. Seventy-three participants (53%) experienced one or more neurologic findings in the 12 weeks after diagnosis, with one developing a fulminant neurologic manifestation (Guillain-Barré syndrome). A total of 245 neurologic findings were noted, reflecting cognitive symptoms (33%), motor findings (34%), and neuropathy (11%). Nearly half of the neurologic findings (n = 121, 49%) occurred at diagnosis, prior to cART initiation, and most of these (n = 110, 90%) remitted concurrent with 1 month on treatment. Only 9% of neurologic findings (n = 22) persisted at 24 weeks on cART. Nearly all neurologic findings (n = 236, 96%) were categorized as mild in severity. No structural neuroimaging abnormalities were observed. Participants with neurologic findings had a higher mean plasma log10 HIV RNA at diagnosis compared to those without neurologic findings (5.9 vs 5.4; p = 0.006)., Conclusions: Acute HIV infection is commonly associated with mild neurologic findings that largely remit while on treatment, and may be mediated by direct viral factors. Severe neurologic manifestations are infrequent in treated acute HIV., (© 2016 American Academy of Neurology.)
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- 2016
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34. Drug resistance mutations after the first 12 months on antiretroviral therapy and determinants of virological failure in Rwanda.
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Ndahimana Jd, Riedel DJ, Mwumvaneza M, Sebuhoro D, Uwimbabazi JC, Kubwimana M, Mugabo J, Mulindabigwi A, Kirk C, Kanters S, Forrest JI, Jagodzinski LL, Peel SA, Ribakare M, Redfield RR, and Nsanzimana S
- Subjects
- Adult, CD4 Lymphocyte Count, Female, Genotype, Humans, Logistic Models, Male, Middle Aged, Odds Ratio, Retrospective Studies, Rwanda, Tenofovir therapeutic use, Treatment Failure, Young Adult, Anti-HIV Agents therapeutic use, Antiretroviral Therapy, Highly Active, Drug Resistance, Viral genetics, HIV Infections drug therapy, HIV-1 genetics, Mutation, Viral Load
- Abstract
Objective: To evaluate HIV drug resistance (HIVDR) and determinants of virological failure in a large cohort of patients receiving first-line tenofovir-based antiretroviral therapy (ART) regimens., Methods: A nationwide retrospective cohort from 42 health facilities was assessed for virological failure and development of HIVDR mutations. Data were collected at ART initiation and at 12 months of ART on patients with available HIV-1 viral load (VL) and ART adherence measurements. HIV resistance genotyping was performed on patients with VL ≥1000 copies/ml. Multiple logistic regression was used to determine factors associated with treatment failure., Results: Of 828 patients, 66% were women, and the median age was 37 years. Of the 597 patients from whom blood samples were collected, 86.9% were virologically suppressed, while 11.9% were not. Virological failure was strongly associated with age <25 years (adjusted odds ratio [aOR]: 6.4; 95% confidence interval [CI]: 3.2-12.9), low adherence (aOR: 2.87; 95% CI: 1.5-5.0) and baseline CD4 counts <200 cells/μl (aOR 3.4; 95% CI: 1.9-6.2). Overall, 9.1% of all patients on ART had drug resistance mutations after 1 year of ART; 27% of the patients who failed treatment had no evidence of HIVDR mutations. HIVDR mutations were not observed in patients on the recommended second-line ART regimen in Rwanda., Conclusions: The last step of the UNAIDS 90-90-90 target appears within grasp, with some viral failures still due to non-adherence. Nonetheless, youth and late initiators are at higher risk of virological failure. Youth-focused programmes could help prevent further drug HIVDR development., (© 2016 John Wiley & Sons Ltd.)
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- 2016
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35. Safety and Immunogenicity of a Randomized Phase 1 Prime-Boost Trial With ALVAC-HIV (vCP205) and Oligomeric Glycoprotein 160 From HIV-1 Strains MN and LAI-2 Adjuvanted in Alum or Polyphosphazene.
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O'Connell RJ, Excler JL, Polonis VR, Ratto-Kim S, Cox J, Jagodzinski LL, Liu M, Wieczorek L, McNeil JG, El-Habib R, Michael NL, Gilliam BL, Paris R, VanCott TC, Tomaras GD, Birx DL, Robb ML, and Kim JH
- Subjects
- AIDS Vaccines administration & dosage, Adolescent, Adult, Alum Compounds administration & dosage, Antibodies, Neutralizing, Female, HIV Antibodies immunology, HIV Antigens administration & dosage, HIV Antigens immunology, HIV Envelope Protein gp160 administration & dosage, HIV Infections immunology, HIV Infections virology, Humans, Immunization, Leukocytes, Mononuclear immunology, Male, Middle Aged, Organophosphorus Compounds administration & dosage, Polymers administration & dosage, Young Adult, AIDS Vaccines immunology, Adjuvants, Immunologic administration & dosage, HIV Antibodies blood, HIV Envelope Protein gp160 immunology, HIV Infections prevention & control, HIV-1 immunology
- Abstract
Background: Prime-boost regimens comprising ALVAC-HIV (prime) and human immunodeficiency virus type 1 (HIV) Env (boost) induce HIV-specific neutralizing antibody and cell-mediated immune responses, but the impact of boost schedule and adjuvant requires further definition., Methods: A phase 1 trial was conducted. In part A (open label), 19 volunteers received oligomeric glycoprotein 160 from HIV strains MN and LAI-2 (ogp160 MN/LAI-2) with dose escalation (25, 50, 100 μg) and either polyphosphazene (pP) or alum adjuvant. In part B, 72 volunteers received either placebo (n=12) or recombinant canarypox virus expressing HIV antigens (ALVAC-HIV [vCP205]) with different doses and schedules of ogp160 MN/LAI-2 in pP or alum (n = 60)., Results: The vaccines were safe and well tolerated, with no vaccine-related serious adverse events. Anti-gp70 V1V2 antibody responses were detected in 17 of 19 part A volunteers (89%) and 10%-100% of part B volunteers. Use of a peripheral blood mononuclear cell-based assay revealed that US-1 primary isolate neutralization was induced in 2 of 19 recipients of ogp160 protein alone (10.5%) and 5 of 49 prime-boost volunteers (10.2%). Among ogp160 recipients, those who received pP were more likely than those who received alum to have serum that neutralized tier 2 viruses (12% vs 0%; P = .015)., Conclusions: Administration of ogp160 with pP induces primary isolate tier 2 neutralizing antibody responses in a small percentage of volunteers, demonstrating proof of concept and underscoring the importance of further optimization of prime-boost strategies for HIV infection prevention., Clinical Trials Registration: NCT00004579., (Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
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- 2016
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36. Prospective Study of Acute HIV-1 Infection in Adults in East Africa and Thailand.
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Robb ML, Eller LA, Kibuuka H, Rono K, Maganga L, Nitayaphan S, Kroon E, Sawe FK, Sinei S, Sriplienchan S, Jagodzinski LL, Malia J, Manak M, de Souza MS, Tovanabutra S, Sanders-Buell E, Rolland M, Dorsey-Spitz J, Eller MA, Milazzo M, Li Q, Lewandowski A, Wu H, Swann E, O'Connell RJ, Peel S, Dawson P, Kim JH, and Michael NL
- Subjects
- Adolescent, Adult, Africa, Eastern, Antibodies, Viral blood, CD4 Lymphocyte Count, Disease Progression, Female, HIV Infections virology, Humans, Male, Middle Aged, Prospective Studies, RNA, Viral blood, Thailand, Viral Load, HIV Infections diagnosis, HIV-1 genetics, HIV-1 immunology, HIV-1 isolation & purification, Viremia diagnosis
- Abstract
Background: Acute human immunodeficiency virus type 1 (HIV-1) infection is a major contributor to transmission of HIV-1. An understanding of acute HIV-1 infection may be important in the development of treatment strategies to eradicate HIV-1 or achieve a functional cure., Methods: We performed twice-weekly qualitative plasma HIV-1 RNA nucleic acid testing in 2276 volunteers who were at high risk for HIV-1 infection. For participants in whom acute HIV-1 infection was detected, clinical observations, quantitative measurements of plasma HIV-1 RNA levels (to assess viremia) and HIV antibodies, and results of immunophenotyping of lymphocytes were obtained twice weekly., Results: Fifty of 112 volunteers with acute HIV-1 infection had two or more blood samples collected before HIV-1 antibodies were detected. The median peak viremia (6.7 log10 copies per milliliter) occurred 13 days after the first sample showed reactivity on nucleic acid testing. Reactivity on an enzyme immunoassay occurred at a median of 14 days. The nadir of viremia (4.3 log10 copies per milliliter) occurred at a median of 31 days and was nearly equivalent to the viral-load set point, the steady-state viremia that persists durably after resolution of acute viremia (median plasma HIV-1 RNA level, 4.4 log10 copies per milliliter). The peak viremia and downslope were correlated with the viral-load set point. Clinical manifestations of acute HIV-1 infection were most common just before and at the time of peak viremia. A median of one symptom of acute HIV-1 infection was recorded at a median of two study visits, and a median of one sign of acute HIV-1 infection was recorded at a median of three visits., Conclusions: The viral-load set point occurred at a median of 31 days after the first detection of plasma viremia and correlated with peak viremia. Few symptoms and signs were observed during acute HIV-1 infection, and they were most common before peak viremia. (Funded by the Department of Defense and the National Institute of Allergy and Infectious Diseases.)., Competing Interests: No potential conflict of interest relevant to this article was reported.
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- 2016
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37. HIV drug resistance mutations among patients failing second-line antiretroviral therapy in Rwanda.
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Ndahimana Jd, Riedel DJ, Muhayimpundu R, Nsanzimana S, Niyibizi G, Mutaganzwa E, Mulindabigwi A, Baribwira C, Kiromera A, Jagodzinski LL, Peel SA, and Redfield RR
- Subjects
- Adult, Anti-HIV Agents administration & dosage, Female, HIV Infections epidemiology, HIV-1 genetics, Humans, Male, Medication Adherence, Middle Aged, Mutation, Rwanda epidemiology, Anti-HIV Agents therapeutic use, Drug Resistance, Viral genetics, HIV Infections drug therapy, HIV Infections virology, HIV-1 drug effects
- Abstract
Background: Studies of patients failing second-line antiretroviral therapy (ART) in resource-limited settings (RLS) are few. Evidence suggests most patients who appear to be virologically failing do so not due to drug resistance but to poor adherence, which, if properly addressed, could allow continued use of less expensive first- and second-line regimens. Drug resistant mutations (DRMs) were characterized among patients virologically failing second-line ART in Rwanda., Methods: A total of 128 adult patients receiving second-line ART for at least 6 months were invited to participate; 74 agreed and had HIV-1 viral load (VL) measured. Resistance genotypes were conducted in patients with virological failure (VF; that is, VL ≥1,000 copies/ml)., Results: In total, 35 patients met the criteria for VF. The median time on lopinavir/ritonavir-based second-line ART was 2.7 years. Of 30 successful resistance genotype analyses, 13 (43%) had ≥1 nucleoside reverse transcriptase inhibitor (NRTI) mutation, 18 (60%) had at least 1 non-NRTI mutation and 5 (17%) had at least 1 major protease inhibitor mutation. Eleven (37%) had virus without significant mutations that would be fully sensitive to first-line ART; 12 (40%) had DRM to first-line ART but sensitive to second-line ART. Only 7 patients (23%) demonstrated a DRM profile requiring third-line ART., Conclusions: Among 30 genotyped samples of patients with VF on second-line ART, more than one-third had no significant DRMs, implicating poor adherence as the primary cause of VF. The majority of patients (77%) would not have required third-line ART. These findings reinforce the need for intensive adherence assessment and counselling for patients who appear to be failing second-line ART in RLS.
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- 2016
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38. Neurological Response to cART vs. cART plus Integrase Inhibitor and CCR5 Antagonist Initiated during Acute HIV.
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Valcour VG, Spudich SS, Sailasuta N, Phanuphak N, Lerdlum S, Fletcher JL, Kroon ED, Jagodzinski LL, Allen IE, Adams CL, Prueksakaew P, Slike BM, Hellmuth JM, Kim JH, and Ananworanich J
- Subjects
- Adolescent, Adult, Anti-HIV Agents administration & dosage, Drug Therapy, Combination, Female, HIV Integrase Inhibitors administration & dosage, Humans, Male, Middle Aged, Young Adult, Anti-HIV Agents therapeutic use, HIV Infections drug therapy, HIV Integrase Inhibitors therapeutic use, Receptors, CCR5 drug effects
- Abstract
Objective: To compare central nervous system (CNS) outcomes in participants treated during acute HIV infection with standard combination antiretroviral therapy (cART) vs. cART plus integrase inhibitor and CCR5 antagonist (cART+)., Design: 24-week randomized open-label prospective evaluation., Method: Participants were evaluated then randomized to initiate cART (efavirenz, tenofovir, and either emtricitabine or lamivudine) vs. cART+ (cART plus raltegravir and maraviroc) during acute HIV and re-evaluated at 4, 12 and 24 weeks. We examined plasma and CSF cytokines, HIV RNA levels, neurological and neuropsychological findings, and brain MRS across groups and compared to healthy controls., Results: At baseline, 62 participants were in Fiebig stages I-V. Randomized groups were similar for mean age (27 vs. 25, p = 0.137), gender (each 94% male), plasma log10 HIV RNA (5.4 vs. 5.6, p = 0.382), CSF log10 HIV RNA (2.35 vs. 3.31, p = 0.561), and estimated duration of HIV (18 vs. 17 days, p = 0.546). Randomized arms did not differ at 24 weeks by any CNS outcome. Combining arms, all measures concurrent with antiretroviral treatment improved, for example, neuropsychological testing (mean NPZ-4 of -0.408 vs. 0.245, p<0.001) and inflammatory markers by MRS (e.g. mean frontal white matter (FWM) choline of 2.92 vs. 2.84, p = 0.045) at baseline and week 24, respectively. Plasma neopterin (p<0.001) and interferon gamma-induced protein 10 (IP-10) (p = 0.007) remained elevated in participants compared to controls but no statistically significant differences were seen in CSF cytokines compared to controls, despite individual variability among the HIV-infected group., Conclusions: A 24-week course of cART+ improved CNS related outcomes, but was not associated with measurable differences compared to standard cART.
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- 2015
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39. Evaluation of Performance of Two Rapid Tests for Detection of HIV-1 and -2 in High- and Low-Prevalence Populations in Nigeria.
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Manak MM, Njoku OS, Shutt A, Malia J, Jagodzinski LL, Milazzo M, Suleiman A, Ogundeji AA, Nelson R, Ayemoba OR, O'Connell RJ, Singer DE, Michael NL, and Peel SA
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- AIDS Vaccines therapeutic use, False Negative Reactions, False Positive Reactions, Female, HIV Antibodies, HIV-1 genetics, HIV-2 genetics, Humans, Nigeria epidemiology, RNA, Viral analysis, RNA, Viral genetics, Sensitivity and Specificity, Diagnostic Tests, Routine methods, HIV Infections diagnosis, HIV Infections epidemiology, HIV-1 immunology, HIV-2 immunology, Immunoassay methods
- Abstract
The availability of reliable human immunodeficiency virus types 1 and 2 (HIV-1/2) rapid tests in resource-limited settings represents an important advancement in the accurate diagnosis of HIV infection and presents opportunities for implementation of effective prevention and treatment interventions among vulnerable populations. A study of the potential target populations for future HIV vaccine studies examined the prevalence of HIV infections at six selected sites in Nigeria and evaluated the use of two rapid diagnostic tests (RDTs) for HIV. The populations included market workers at sites adjacent to military installations and workers at highway settlements (truck stops) who may have a heightened risk of HIV exposure. Samples from 3,187 individuals who provided informed consent were tested in parallel using the Determine (DT) and Stat-Pak (SP) RDTs; discordant results were subjected to the Uni-Gold (UG) RDT as a tiebreaker. The results were compared to those of a third-generation enzyme immunoassay screen with confirmation of repeat reactive samples by HIV-1 Western blotting. One participant was HIV-2 infected, yielding positive results on both RDTs. Using the laboratory algorithm as a gold standard, we calculated sensitivities of 98.5% (confidence interval [CI], 97.1 to 99.8%) for DT and 98.1% (CI, 96.7 to 99.6%) for SP and specificities of 98.7% (CI, 98.3 -99.1%) for DT and 99.8% (CI, 99.6 to 100%) for SP. Similar results were obtained when the sites were stratified into those of higher HIV prevalence (9.4% to 22.8%) versus those of lower prevalence (3.2% to 7.3%). A parallel two-test algorithm requiring both DT and SP to be positive resulted in the highest sensitivity (98.1%; CI, 96.7 to 99.6%) and specificity (99.97%; CI, 99.9 to 100%) relative to those for the reference laboratory algorithm., (Copyright © 2015, Manak et al.)
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- 2015
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40. Centralized HIV Program Oversight: An Investigation of a Case Series of New HIV Infections among US Army Soldiers, 2012 to 2013.
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Pacha LA, Hakre S, Myles O, Sanders-Buell EE, Scoville SL, Kijak GH, Price MW, Mody RM, Liu Y, Miller SL, Pham PT, Michael NL, Kim JH, Peel SA, Tovanabutra S, Jagodzinski LL, Cersovsky SB, and Scott PT
- Subjects
- Adult, HIV Infections diagnosis, HIV Infections prevention & control, HIV Infections transmission, Humans, Interviews as Topic, Male, United States epidemiology, HIV Infections epidemiology, Military Personnel statistics & numerical data, Public Health Surveillance
- Abstract
Centralized HIV program oversight and repeal of the Department of Defense policy "Don't Ask Don't Tell" permitted characterization of HIV transmission among soldiers assigned to a large US Army base continental United States from 2012 to 2013. An investigation of a greater than expected number of new HIV infections among soldiers was initiated to characterize transmission and identify opportunities to disrupt transmission and deliver services.All soldiers who were assigned to the base at the time of their first positive HIV test and who had their first positive HIV test in 2012 or in the first 6 months of 2013 and who had a clinical genotype available for analysis were eligible for inclusion in the investigation.All patients (n = 19) were men; most were black (52%) and less than 30 years old (64%). Fifteen of the 19 patients participated in in-depth interviews. Eighty percent were men who have sex with men who reported multiple sex partners having met through social and electronic networks. All were subtype B infections. Significant knowledge gaps and barriers to accessing testing and care in the military healthcare system were identified. Most (58%) belonged to transmission networks involving other soldiers.This investigation represents an important step forward in on-going efforts to develop a comprehensive understanding of transmission networks in the Army that can inform delivery of best practices combination prevention services. The Army is developing plans to directly engage individuals in key affected populations most at risk for HIV infection to identify and address unmet needs and expand delivery and uptake of prevention services. Further investigation is underway and will determine whether these findings are generalizable to the Army.
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- 2015
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41. HIV outcomes in Hepatitis B virus coinfected individuals on HAART.
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Chun HM, Mesner O, Thio CL, Bebu I, Macalino G, Agan BK, Bradley WP, Malia J, Peel SA, Jagodzinski LL, Weintrob AC, Ganesan A, Bavaro M, Maguire JD, and Landrum ML
- Subjects
- Adult, CD4 Lymphocyte Count, Coinfection virology, Female, Follow-Up Studies, HIV Infections complications, Hepatitis B complications, Hepatitis B Core Antigens metabolism, Humans, Logistic Models, Male, Prospective Studies, Young Adult, Antiretroviral Therapy, Highly Active, Coinfection drug therapy, HIV Infections drug therapy, Hepatitis B drug therapy
- Abstract
Background: Understanding the impact of hepatitis B virus (HBV) coinfection on HIV outcomes in the highly active antiretroviral therapy (HAART) era continues to be a critical priority given the high prevalence of coinfection and the potential for impaired immunologic, virologic, and clinical recovery., Methods: Participants from the US Military HIV Natural History Study with an HIV diagnosis on HAART and serologically confirmed HBV infection status at HAART initiation (HI) were classified into 4 HBV infection (HB) groups. HIV virologic, immunologic, and clinical outcomes were evaluated by HB status., Results: Of 2536 HIV-positive HAART recipients, with HBV testing results available to determine HB status in the HI window, HB status at HI was classified as HB negative (n = 1505; 66%), resolved HB (n = 518; 23%), isolated hepatitis B core antigen (n = 139; 6%), or chronic HB (n = 131; 6%). HIV virologic suppression and failure at 6 months or 1 year were not significantly different by HB status. A significantly faster rate of increase in CD4 cell count during the period between 4 and 12 years was observed for chronic HB relative to HB negative. Chronic and resolved HB were associated with an increased risk of AIDS/death compared with HB-negative individuals (chronic HB-hazard ratio = 1.68, 95% confidence interval: 1.05 to 2.68; resolved HB-hazard ratio = 1.61, 95% confidence interval: 1.15 to 2.25)., Conclusions: HB status did not have a significant impact on HIV virologic outcomes, however, CD4 cell count reconstitution after HI and the risk of an AIDS event or death after HI may be associated with HB status.
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- 2014
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42. Discrepant amplification results during the development of an assay leads to reclassification of two AIDS reagent repository HIV-2 isolates as HIV-1.
- Author
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Jagodzinski LL, Liu Y, Hack HR, Kibirige C, Peel SA, and Manak MM
- Subjects
- DNA Primers, Databases, Genetic, HIV-1 classification, HIV-1 isolation & purification, HIV-2 classification, HIV-2 isolation & purification, Humans, National Institute of Allergy and Infectious Diseases (U.S.), Nucleic Acid Amplification Techniques, Phylogeny, RNA, Viral genetics, United States, HIV-1 genetics, HIV-2 genetics
- Abstract
The development and verification of HIV-2 assays depends in part on the availability of well-characterized samples, including those from reagent repositories. During the development of an HIV-2 RNA quantification assay, two HIV-2 viral isolates (CDC 301340 and CDC 301342) obtained from the NIAID AIDS Reagent and Reference Repository were not detected leading to an investigation. Two HIV-2 primers/probe sets of known performance in real-time viral RNA quantification assays, targeting different regions of the virus, also failed to generate RT-PCR products for these two isolates. These isolates were tested in the HIV-1 specific COBAS AmpliPrep/COBAS TaqMan HIV-1 Test v2.0 (Roche Molecular Diagnostics) and were quantified at high copy number. Other HIV-2 isolates tested were not amplified in the COBAS HIV-1 TaqMan assay. Furthermore, the discrepant isolates were highly reactive in an HIV-1 p24 antigen test while the other HIV-2 isolates showed very weak, if any, cross-reactivity with the HIV-1 p24 assay. Phylogenetic tree analysis of sequences from the protease-reverse transcriptase regions of the discrepant HIV-2 isolates mapped with HIV-1 Group M, Subtype CRF02_AG confirming these isolates were of HIV-1 origin and had been misclassified as HIV-2. The use of misclassified isolates in the verification of molecular and immunological assays can lead to misinterpretation of test results, misdirection of efforts into assay redesign and increased development costs. The results of this study were shared with the NIAID AIDS Reagent Program, leading to the reclassification of the two discrepant isolates as HIV-1.
- Published
- 2014
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43. Platelets and erythrocyte-bound platelets bind infectious HIV-1 in plasma of chronically infected patients.
- Author
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Beck Z, Jagodzinski LL, Eller MA, Thelian D, Matyas GR, Kunz AN, and Alving CR
- Subjects
- HIV Infections virology, HIV-1 pathogenicity, Host-Pathogen Interactions, Humans, Blood Platelets virology, Erythrocytes virology, HIV Infections blood, HIV-1 physiology, Membrane Fusion
- Abstract
Chronic HIV-1 infection is associated with persistent viremia in most patients, but it remains unclear how free virus may survive the potential hostile effects of plasma. We investigated whether sites might exist on the surfaces of circulating blood cells for protection of infectious HIV-1 particles. Red blood cells (RBC) either from blood of uninfected normal individuals, or from blood obtained without EDTA from chronically infected HIV-1 patients, invariably contained a small number of RBC having attached platelets as determined by flow cytometry, light microscopy, and immunofluorescence microscopy. After mixing normal RBC with platelet-rich plasma, discrete populations of RBC, platelets, and complexes of platelets attached to RBC were purified by fluorescence-activated cell sorting. Upon incubation of purified cells or platelets with HIV-1 followed by washing and co-incubation with CD4-positive peripheral blood mononuclear cells (PBMC), platelets, and platelet-RBC complexes, but not platelet-free RBC, caused infection of PBMC. Infection was prevented by pre-treating the platelet-RBC complexes with EDTA. Plasma and RBC (comprising a RBC/platelet-RBC mixture) from chronically infected patients with low viral loads were also co-incubated with PBMC ex vivo to determine the presence of infectious HIV-1. All freshly isolated plasmas from the HIV-1-infected donors, obtained in the absence of anticoagulant, were noninfectious. Interestingly, the RBC from most of the patients caused cell-cell infection of PBMC that was prevented by stripping the RBC with EDTA. A monoclonal antibody to DC-SIGN partially inhibited cell-cell HIV-1 infection of PBMC by normal RBC pre-incubated with platelets and HIV-1. We conclude: (a) platelet-free EDTA-free plasma from chronically infected HIV-1 patients, although containing viral RNA, is an environment that lacks detectable infectious HIV-1; (b) platelets and platelet-RBC complexes, but not purified RBC, bind infectious HIV-1; (c) DC-SIGN, and possibly other C-type lectins, may represent binding sites for infectious HIV-1 on platelets and platelet-RBC complexes.
- Published
- 2013
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44. Transfusion-transmitted human T-lymphotropic virus Type I infection in a United States military emergency whole blood transfusion recipient in Afghanistan, 2010.
- Author
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Hakre S, Manak MM, Murray CK, Davis KW, Bose M, Harding AJ, Maas PR, Jagodzinski LL, Kim JH, Michael NL, Rentas FJ, Peel SA, Scott PT, and Tovanabutra S
- Subjects
- Adult, Emergencies, Human T-lymphotropic virus 1 classification, Human T-lymphotropic virus 1 genetics, Humans, Male, Military Personnel, Phylogeny, HTLV-I Infections transmission, Transfusion Reaction
- Abstract
Background: The United States introduced human T-lymphotropic virus Type I (HTLV-I) screening of blood donors in 1988. The US military uses freshly collected blood products for life-threatening injuries when available stored blood components in theater have been exhausted or when these components are unsuccessful for resuscitation. These donors are screened after donation by the Department of Defense (DoD) retrospective testing program. All recipients of blood collected in combat are tested according to policy soon after and at 3, 6, and 12 months after transfusion., Case Report: A 31-year-old US Army soldier tested positive for HTLV-I 44 days after receipt of emergency blood transfusions for severe improvised explosive device blast injuries. One donor's unit tested HTLV-I positive on the DoD-mandated retrospective testing. Both the donor and the recipient tested reactive with enzyme immunoassay and supplemental confirmation by HTLV-I Western blot. The donor and recipient reported no major risk factors for HTLV-I. Phylogenetic analysis of HTLV-I sequences indicated Cosmopolitan subtype, Subgroup B infections. Comparison of long terminal repeat and env sequences revealed molecular genetic linkage of the viruses from the donor and recipient., Conclusion: This case is the first report of transfusion transmission of HTLV-I in the US military during combat operations. The emergency fresh whole blood policy enabled both the donor and the recipient to be notified of their HTLV-I infection. While difficult in combat, predonation screening of potential emergency blood donors with Food and Drug Administration-mandated infectious disease testing as stated by the DoD Health Affairs policy should be the goal of every facility engaged with emergency blood collection in theater., (© 2013 Henry M. Jackson Foundation. Transfusion © 2013 American Association of Blood Banks.)
- Published
- 2013
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45. Molecular epidemiology of early and acute HIV type 1 infections in the United States Navy and Marine Corps, 2005-2010.
- Author
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Heipertz RA Jr, Sanders-Buell E, Kijak G, Howell S, Lazzaro M, Jagodzinski LL, Eggleston J, Peel S, Malia J, Armstrong A, Michael NL, Kim JH, O'Connell RJ, Scott PT, Brett-Major DM, and Tovanabutra S
- Subjects
- Cluster Analysis, HIV-1 isolation & purification, Humans, Molecular Epidemiology, Molecular Sequence Data, Phylogeny, RNA, Viral genetics, Sequence Analysis, DNA, United States epidemiology, Viral Proteins genetics, HIV Infections epidemiology, HIV Infections virology, HIV-1 classification, HIV-1 genetics, Military Personnel
- Abstract
The U.S. military represents a unique population within the human immunodeficiency virus 1 (HIV-1) pandemic. The last comprehensive study of HIV-1 in members of the U.S. Navy and Marine Corps (Sea Services) was completed in 2000, before large-scale combat operations were taking place. Here, we present molecular characterization of HIV-1 from 40 Sea Services personnel who were identified during their seroconversion window and initially classified as HIV-1 negative during screening. Protease/reverse transcriptase (pro/rt) and envelope (env) sequences were obtained from each member of the cohort. Phylogenetic analyses were carried out on these regions to determine relatedness within the cohort and calculate the most recent common ancestor for the related sequences. We identified 39 individuals infected with subtype B and one infected with CRF01_AE. Comparison of the pairwise genetic distance of Sea Service sequences and reference sequences in the env and pro/rt regions showed that five samples were part of molecular clusters, a group of two and a group of three, confirmed by single genome amplification. Real-time molecular monitoring of new HIV-1 acquisitions in the Sea Services may have a role in facilitating public health interventions at sites where related HIV-1 infections are identified.
- Published
- 2013
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46. Cross-sectional assessment of prevalence and correlates of blood-borne and sexually-transmitted infections among Afghan National Army recruits.
- Author
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Todd CS, Nasir A, Mansoor GF, Sahibzada SM, Jagodzinski LL, Salimi F, Khateri MN, Hale BR, Barthel RV, and Scott PT
- Subjects
- Adolescent, Afghanistan, Cross-Sectional Studies, Female, Humans, Male, Military Personnel, Prevalence, Random Allocation, Risk Factors, Surveys and Questionnaires, Young Adult, HIV Infections epidemiology, Hepatitis C epidemiology, Herpes Genitalis epidemiology, Syphilis epidemiology
- Abstract
Background: Few data are available in Afghanistan to shape national military force health practices, particularly with regard to sexually-transmitted infections (STIs). We measured prevalence and correlates of HIV, syphilis, herpes simplex 2 virus (HSV-2), and hepatitis C virus (HCV) among Afghan National Army (ANA) recruits., Methods: A cross-sectional sample of male ANA recruits aged 18-35 years were randomly selected at the Kabul Military Training Center between February 2010 and January 2011. Participants completed an interviewer-administered questionnaire and serum-based rapid testing for syphilis and hepatitis C virus antibody on-site; HIV and HSV-2 screening, and confirmatory testing were performed off-site. Prevalence of each infection was calculated and logistic regression analysis performed to identify correlates., Results: Of 5313 recruits approached, 4750 consented to participation. Participants had a mean age of 21.8 years (SD±3.8), 65.5% had lived outside Afghanistan, and 44.3% had no formal education. Few reported prior marijuana (16.3%), alcohol (5.3%), or opiate (3.4%) use. Of sexually active recruits (58.7%, N = 2786), 21.3% reported paying women for sex and 21.3% reported sex with males. Prevalence of HIV (0.063%, 95% CI: 0.013- 0.19), syphilis (0.65%, 95% CI: 0.44 - 0.93), and HCV (0.82%, 95% CI: 0.58 - 1.12) were quite low. Prevalence of HSV-2 was 3.03% (95% CI: 2.56 - 3.57), which was independently associated with age (Adjusted Odds Ratio (AOR) = 1.04, 95% CI: 1.00 - 1.09) and having a television (socioeconomic marker) (AOR = 1.46, 95% CI: 1.03 - 2.05)., Conclusion: Though prevalence of HIV, HCV, syphilis, and HSV-2 was low, sexual risk behaviors and intoxicant use were present among a substantial minority, indicating need for prevention programming. Formative work is needed to determine a culturally appropriate approach for prevention programming to reduce STI risk among Afghan National Army troops.
- Published
- 2012
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47. Efficient quantification of HIV-1 in heparin plasma spiked with cultured HIV-1 by the Roche Cobas TaqMan and Abbott RealTime HIV-1 tests.
- Author
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Jagodzinski LL, Weston HR, Liu Y, O'Connell RJ, and Peel SA
- Subjects
- Anticoagulants metabolism, Automation methods, Heparin metabolism, Humans, HIV-1 isolation & purification, Plasma virology, Real-Time Polymerase Chain Reaction methods, Specimen Handling methods, Viral Load methods
- Abstract
The current automated real-time HIV-1 viral load assays, the Roche Cobas AmpliPrep/Cobas TaqMan test and the Abbott RealTime test, are FDA cleared for use with EDTA plasma. We show that both real-time reverse transcription-PCR (RT-PCR) tests reliably quantify HIV-1 RNA in heparin plasma specimens spiked with HIV-1 isolate MN.
- Published
- 2012
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48. Inclusion of a CRF01_AE HIV envelope protein boost with a DNA/MVA prime-boost vaccine: Impact on humoral and cellular immunogenicity and viral load reduction after SHIV-E challenge.
- Author
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Cox JH, Ferrari MG, Earl P, Lane JR, Jagodzinski LL, Polonis VR, Kuta EG, Boyer JD, Ratto-Kim S, Eller LA, Pham DT, Hart L, Montefiori D, Ferrari G, Parrish S, Weiner DB, Moss B, Kim JH, Birx D, and VanCott TC
- Subjects
- AIDS Vaccines administration & dosage, AIDS Vaccines genetics, Animals, Antibodies, Neutralizing blood, CD8-Positive T-Lymphocytes immunology, Female, Gene Products, gag immunology, Gene Products, pol immunology, HIV Antibodies blood, HIV-1 immunology, Immunization, Secondary, Immunoglobulin G blood, Macaca mulatta, Male, Simian Immunodeficiency Virus immunology, Vaccines, DNA administration & dosage, Vaccines, DNA genetics, Viral Vaccines administration & dosage, Viral Vaccines immunology, AIDS Vaccines immunology, Immunity, Cellular, Immunity, Humoral, Vaccines, DNA immunology, Viral Load, env Gene Products, Human Immunodeficiency Virus immunology
- Abstract
The current study assessed the immunogenicity and protective efficacy of various prime-boost vaccine regimens in rhesus macaques using combinations of recombinant DNA (rDNA), recombinant MVA (rMVA), and subunit gp140 protein. The rDNA and rMVA vectors were constructed to express Env from HIV-1 subtype CRF01_AE and Gag-Pol from CRF01_AE or SIVmac 239. One of the rMVAs, MVA/CMDR, has been recently tested in humans. Immunizations were administered at months 0 and 1 (prime) and months 3 and 6 (boost). After priming, HIV env-specific serum IgG was detected in monkeys receiving gp140 alone or rMVA but not in those receiving rDNA. Titers were enhanced in these groups after boosting either with gp140 alone or with rMVA plus gp140. The groups that received the rDNA prime developed env-specific IgG after boosting with rMVA with or without gp140. HIV Env-specific serum IgG binding antibodies were elicited more frequently and of higher titer, and breadth of neutralizing antibodies was increased with the inclusion of the subunit Env boost. T cell responses were measured by tetramer binding to Gag p11c in Mamu-A*01 macaques, and by IFN-γ ELISPOT assay to SIV-Gag. T cell responses were induced after vaccination with the highest responses seen in macaques immunized with rDNA and rMVA. Macaques were challenged intravenously with a novel SHIV-E virus (SIVmac239 Gag-Pol with an HIV-1 subtype E-Env CAR402). Post challenge with SHIV-E, antibody titers were boosted in all groups and peaked at 4 weeks. Robust T cell responses were seen in all groups post challenge and in macaques immunized with rDNA and rMVA a clear boosting of responses was seen. A greater than two-log drop in RNA copies/ml at peak viremia and earlier set point was achieved in macaques primed with rDNA, and boosted with rMVA/SHIV-AE plus gp140. Post challenge viremia in macaques immunized with other regimens was not significantly different to that of controls. These results demonstrate that a gp140 subunit and inclusion of SIV Gag-Pol may be critical for control of SHIV post challenge., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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49. Hepatitis B virus coinfection negatively impacts HIV outcomes in HIV seroconverters.
- Author
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Chun HM, Roediger MP, Hullsiek KH, Thio CL, Agan BK, Bradley WP, Peel SA, Jagodzinski LL, Weintrob AC, Ganesan A, Wortmann G, Crum-Cianflone NF, Maguire JD, and Landrum ML
- Subjects
- Acquired Immunodeficiency Syndrome complications, Adult, Antiretroviral Therapy, Highly Active, CD4 Lymphocyte Count, Female, HIV Seropositivity complications, Hepatitis B Core Antigens blood, Hepatitis B Surface Antigens blood, Hepatitis B, Chronic blood, Humans, Kaplan-Meier Estimate, Male, Multivariate Analysis, Proportional Hazards Models, Risk Factors, Young Adult, Acquired Immunodeficiency Syndrome epidemiology, Coinfection virology, Disease Progression, HIV Seropositivity virology, Hepatitis B, Chronic complications, Hepatitis B, Chronic virology
- Abstract
Background: Understanding the impact of hepatitis B virus (HBV) in human immunodeficiency virus (HIV) coinfection has been limited by heterogeneity of HIV disease. We evaluated HBV coinfection and HIV-related disease progression in a cohort of HIV seroconverters., Methods: Participants with HIV diagnosis seroconversion window of ≤ 3 years and serologically confirmed HBV infection (HB) status were classified at baseline into 4 HB groups. The risk of clinical AIDS/death in HIV seroconverters was calculated by HB status., Results: Of 2352 HIV seroconverters, 474 (20%) had resolved HB, 82 (3%) had isolated total antibody to hepatitis B core antigen (HBcAb), and 64 (3%) had chronic HB. Unadjusted rates (95% confidence intervals [CIs]) of clinical AIDS/death for the HB-negative, resolved HB, isolated HBcAb, and chronic HB groups were 2.43 (2.15-2.71); 3.27 (2.71-3.84); 3.75 (2.25-5.25); and 5.41 (3.41-7.42), respectively. The multivariable risk of clinical AIDS/death was significantly higher in the chronic HB group compared to the HB-negative group (hazard ratio [HR], 1.80; 95% CI, 1.20-2.69); while the HRs were increased but nonsignificant for those with resolved HB (HR, 1.17; 95% CI, .94-1.46) and isolated HBcAb (HR, 1.14; 95% CI, .75-1.75)., Conclusions: HBV coinfection has a significant impact on HIV outcomes. The hazard for an AIDS or death event is almost double for those with chronic HB compared, with HIV-monoinfected persons.
- Published
- 2012
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- View/download PDF
50. Transfusion-transmissible viral infections among US military recipients of whole blood and platelets during Operation Enduring Freedom and Operation Iraqi Freedom.
- Author
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Hakre S, Peel SA, O'Connell RJ, Sanders-Buell EE, Jagodzinski LL, Eggleston JC, Myles O, Waterman PE, McBride RH, Eader SA, Davis KW, Rentas FJ, Sateren WB, Naito NA, Tobler SK, Tovanabutra S, Petruccelli BP, McCutchan FE, Michael NL, Cersovsky SB, and Scott PT
- Subjects
- Adult, Aged, Base Sequence, Female, HIV Infections epidemiology, HIV Infections transmission, Hepatitis B epidemiology, Hepatitis B transmission, Hepatitis C epidemiology, Hepatitis C transmission, Humans, Iraq epidemiology, Male, Middle Aged, Molecular Sequence Data, Virus Diseases epidemiology, Iraq War, 2003-2011, Military Personnel, Platelet Transfusion adverse effects, Transfusion Reaction, Virus Diseases transmission
- Abstract
Background: Current US military clinical practice guidelines permit emergency transfusions of non-Food and Drug Administration (FDA)-compliant freshly collected blood products in theaters of war. This investigation aimed to characterize the risks of transfusion-transmitted infections (TTIs) associated with battlefield transfusions of non-FDA-compliant blood products., Study Design and Methods: US Service members who received emergency transfusion products in Iraq and Afghanistan (March 1, 2002-September 30, 2007) were tested for hepatitis C virus (HCV), human immunodeficiency virus (HIV), and hepatitis B virus (HBV) infections using reposed pre- and posttransfusion sera. Selected regions of viral genomes from epidemiologically linked infected recipients and their donors were sequenced and compared., Results: Of 761 US Service members who received emergency transfusion products, 475 were tested for HCV, 472 for HIV, and 469 for HBV. One transfusion-transmitted HCV infection (incidence rate of 2.1/1000 persons) was identified. The pretransfusion numbers (prevalence per 1000 persons) were HCV-four (8/1000), HIV-zero (0/1000), chronic HBV-two (4 /1000), and naturally immune (antibody to HBV core antigen)-nine (19/1000)., Conclusion: One HCV TTI was determined to be associated with emergency blood product use. The pretransfusion HCV and HBV prevalence in transfusion recipients, themselves members of the potential donor population, indicates better characterization of the deployed force's actual donor population, and further investigations of the TTI prevalence in these donors are needed. These data will inform countermeasure development and clinical decision making., (© 2010 American Association of Blood Banks.)
- Published
- 2011
- Full Text
- View/download PDF
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