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Prakoeswa FRS, Maharani F, Bestari RS, Aisyah R, Ichsan B, Nursanto D, Listiansyah R, Tuanaya MRN. Aging and HIV: Recent Findings in Contributing Factors. AIDS Res Treat 2025; 2025:8814760. [PMID: 40255985 PMCID: PMC12008487 DOI: 10.1155/arat/8814760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 01/20/2025] [Indexed: 04/22/2025] Open
Abstract
Background: Aging among people living with HIV (PLWH) presents multifaceted challenges influenced by antiretroviral therapy (ART), chronic inflammation, viral coinfections, stigma, multimorbidity, and immunosuppression. Methods: This review synthesizes recent research findings to outline factors contributing to aging with HIV. A comprehensive literature search was done using electronic databases including PubMed, Web of Science, Google Scholar, and CINAHL with keywords "HIV," "Aging," "Elderly," "Geriatrics," "Older Adults," "HIV Infections," and "HIV/AIDS. Results: Addressing age-related comorbidities, cognitive impairment, and non-AIDS events is imperative as older PLWH face increased morbidity and mortality rates compounded by coinfections such as HCV, HPV, TB, HSV, and bacterial infections. While ART is vital for viral suppression, it introduces challenges such as mitochondrial toxicity, metabolic disorders, and decreased CD4 cell counts, accelerating the aging process. Lifestyle factors, including smoking, substance abuse, malnutrition, sedentary behavior, and mental health conditions, further exacerbate aging in PLWH. Conclusions: This study emphasizes the necessity of holistic approaches to meet the unique healthcare needs of older PLWH, with insights into immunosenescence, coinfections, disease progression, ART exposure, and lifestyle factors. Understanding these dynamics is crucial for improving health outcomes and quality of life in aging PLWH.
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Affiliation(s)
- Flora Ramona Sigit Prakoeswa
- Department of Dermatovenereology, Faculty of Medicine, Universitas Muhammadiyah Surakarta, Surakarta, Central Java, Indonesia
- Department of Dermatovenereology, PKU Muhammadiyah Hospital, Surakarta, Indonesia
| | - Faradiba Maharani
- Department of Dermatology, Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Central Java, Indonesia
| | - Rochmadina Suci Bestari
- Department of Parasitology, Faculty of Medicine, Universitas Muhammadiyah Surakarta, Surakarta, Central Java, Indonesia
| | - Riandini Aisyah
- Department of Molecular Biology, Faculty of Medicine, Universitas Muhammadiyah Surakarta, Surakarta, Central Java, Indonesia
| | - Burhannudin Ichsan
- Department of Public Health, Faculty of Medicine, Universitas Muhammadiyah Surakarta, Surakarta, Central Java, Indonesia
| | - Dodik Nursanto
- Department of Anatomy and Embryology, Faculty of Medicine, Universitas Muhammadiyah Surakarta, Surakarta, Central Java, Indonesia
| | - Rizki Listiansyah
- Department of Medical Education, Faculty of Medicine, Universitas Muhammadiyah Surakarta, Surakarta, Central Java, Indonesia
| | - Muhammad Rizqy Noer Tuanaya
- Department of Medical Education, Faculty of Medicine, Universitas Muhammadiyah Surakarta, Surakarta, Central Java, Indonesia
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Henrich TJ, Bosch RJ, Godfrey C, Mar H, Nair A, Keefer M, Fichtenbaum C, Moisi D, Clagett B, Buck AM, Deitchman AN, Aweeka F, Li JZ, Kuritzkes DR, Lederman MM, Hsue PY, Deeks SG. Sirolimus reduces T cell cycling, immune checkpoint marker expression, and HIV-1 DNA in people with HIV. Cell Rep Med 2024; 5:101745. [PMID: 39321793 PMCID: PMC11513808 DOI: 10.1016/j.xcrm.2024.101745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 04/10/2024] [Accepted: 08/28/2024] [Indexed: 09/27/2024]
Abstract
Key HIV cure strategies involve reversing immune dysfunction and limiting the proliferation of infected T cells. We evaluate the safety of sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in people with HIV (PWH) and study the impact of sirolimus on HIV-1 reservoir size and HIV-1-specific immunity in a single-arm study of 20 weeks of treatment in PWH on antiretroviral therapy (ART). Sirolimus treatment does not impact HIV-1-specific CD8 T cell responses but leads to a significant decrease in CD4+ T cell-associated HIV-1 DNA levels at 20 weeks of therapy in the primary efficacy population (n = 16; 31% decline, p = 0.008). This decline persists for at least 12 weeks following cessation of the study drug. Sirolimus treatment also leads to a significant reduction in CD4+ T cell cycling and PD-1 expression on CD8+ lymphocytes. These data suggest that homeostatic proliferation of infected cells, an important mechanism for HIV persistence, is an intriguing therapeutic target.
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Affiliation(s)
- Timothy J Henrich
- Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA.
| | - Ronald J Bosch
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Catherine Godfrey
- Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
| | - Hanna Mar
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Apsara Nair
- Frontier Science and Technology Research Foundation, Amherst, NY 14226, USA
| | - Michael Keefer
- Department of Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA
| | - Carl Fichtenbaum
- Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Daniela Moisi
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Brian Clagett
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Amanda M Buck
- Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA; San Francisco State University, San Francisco, CA 94132, USA
| | - Amelia N Deitchman
- Department of Clinical Pharmacology, University of California San Francisco, San Francisco, CA 94110, USA
| | - Francesca Aweeka
- Department of Clinical Pharmacology, University of California San Francisco, San Francisco, CA 94110, USA
| | - Jonathan Z Li
- Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Daniel R Kuritzkes
- Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Michael M Lederman
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Priscilla Y Hsue
- Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA
| | - Steven G Deeks
- Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA
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Gatarayiha A, Brookes Z, Rulisa S, Andegiorgish AK, Mutesa L. Association between Periodontitis and Hypertension among Adult Population in Rwanda. J Clin Med 2024; 13:4722. [PMID: 39200864 PMCID: PMC11355554 DOI: 10.3390/jcm13164722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/31/2024] [Accepted: 08/01/2024] [Indexed: 09/02/2024] Open
Abstract
Background/Objectives: Mortality due to various non-communicable diseases, including hypertension, is increasing globally. Studies have reported that periodontitis, a chronic inflammatory disorder caused by oral pathogens, is a potential risk factor for hypertension. These pathogens can invade arterial walls, leading to vascular inflammation and endothelial dysfunction, which then increases the likelihood of developing hypertension. However, evidence of the association between periodontitis and hypertension remains limited. Therefore, the aim of this study is to determine whether periodontitis is associated with hypertension among adults in Rwanda. Methods: A cross-sectional study was carried out among 420 participants (hypertensive and non-hypertensive) at the University Teaching Hospital of Kigali (CHUK) and Ruhengeri Hospital in Rwanda. Periodontitis was assessed using clinical parameters: clinical attachment loss (CAL), bleeding on probing (BoP), and periodontal pocket depth (PDD). Hypertension was defined as a patient with a systolic or diastolic blood pressure (SBP/DBP) of ≥140/90 mmHg. Descriptive statistics, the Chi-square test, and logistical regression were performed using SPSS version 29 for statistical data analysis. Results: The prevalence of periodontitis was found to be 69.5% among hypertensive patients and 52.4% among non-hypertensive patients. Clinical attachment loss was 6.24 times (AOR = 6.24, 95% CI: 1.99-19.56) higher among hypertensive patients and the difference was significant (p = 0.001). Other periodontal parameters such as periodontal pocket depth and bleeding on probing showed a more significant association among hypertensive than non-hypertensive patients. Conclusions: Our study found a significant association between periodontitis and hypertension in Rwandan adults. However, further intervention studies are needed to explore causality and potential interventions.
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Affiliation(s)
- Agnes Gatarayiha
- School of Dentistry, College of Medicine and Health Sciences, University of Rwanda, Kigali P.O. Box 3286, Rwanda
| | - Zoe Brookes
- Peninsula Dental School, Plymouth University, Plymouth PL4 8AA, UK
| | - Stephen Rulisa
- School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali P.O. Box 3286, Rwanda
| | - Amanuel Kidane Andegiorgish
- School of Public Health, College of Medicine and Health Sciences, University of Rwanda, Kigali P.O. Box 3286, Rwanda
| | - Léon Mutesa
- Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali P.O. Box 3286, Rwanda
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Wang R, Underwood M, Llibre JM, Bernal Morell E, Brinson C, Sanz Moreno J, Scholten S, Moore R, Saggu P, Oyee J, Moodley R, Wynne B, Kisare M, Jones B, Ait-Khaled M. Very-Low-Level Viremia, Inflammatory Biomarkers, and Associated Baseline Variables: Three-Year Results of the Randomized TANGO Study. Open Forum Infect Dis 2024; 11:ofad626. [PMID: 38213637 PMCID: PMC10783236 DOI: 10.1093/ofid/ofad626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Indexed: 01/13/2024] Open
Abstract
Background We compared proportions of participants with target detected, target not detected (TND), and elevated viral load (VL) and assessed baseline variables associated with week 144 inflammatory biomarker levels between dolutegravir-lamivudine (DTG/3TC) and tenofovir alafenamide-based regimens (TBRs) in the TANGO study (post hoc). Methods TANGO is an open-label, multicenter, phase 3 study that randomized adults with VL <50 copies/mL to switch to once-daily fixed-dose DTG/3TC or continue TBR. At baseline and each study visit, the VL was measured. Elevated VL event frequencies were assessed, including "blips." Interleukin 6, D-dimer, high-sensitivity C-reactive protein, soluble CD14, and soluble CD163 were measured at baseline and at week 144. Loge-transformed week 144 biomarker levels were compared between treatment groups using an analysis of covariance model adjusting for baseline variables. Results High, comparable proportions of participants had VL <40 copies/mL and TND at week 144 (DTG/3TC, 279 of 369 [76%]; TBR, 267 of 372 [72%], intention-to-treat exposed Snapshot analysis; adjusted difference, 3.9% [95% confidence interval, -2.5% to 10.2%]), with similar TND proportions at all postbaseline visits (123 of 369 [33%] vs 101 of 372 [27%], respectively). Similar proportions of DTG/3TC participants had ≥1 postbaseline VL ≥50 copies/mL (28 of 369 [8%] vs 42 of 372 [11%] for TBR), primarily blips (18 of 369 [5%] and 26 of 372 [7%], respectively). Week 144 inflammatory biomarker levels were low and comparable between groups and associated with multiple demographic and baseline characteristics, including baseline biomarker levels, indicating a multifactorial inflammatory response. Conclusions Week 144 biomarker levels were low and generally comparable between treatment groups, reflecting similar, robust, and durable viral suppression observed using the stringent TND end point. Trial registration: ClinicalTrials.gov, NCT03446573.
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Affiliation(s)
- Ruolan Wang
- ViiV Healthcare, Durham, North Carolina, USA
| | | | - Josep M Llibre
- Infectious Diseases Division and Fight Infections Foundation, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain
| | - Enrique Bernal Morell
- Department of Infectious Diseases, Hospital General Universitario Reina Sofía, Murcia, Spain
| | | | - José Sanz Moreno
- Departamento de Medicina Interna, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain
| | | | | | | | | | | | - Brian Wynne
- ViiV Healthcare, Durham, North Carolina, USA
| | | | - Bryn Jones
- ViiV Healthcare, Brentford, United Kingdom
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González-Cordón A, Assoumou L, Moyle G, Waters L, Johnson M, Domingo P, Fox J, Stellbrink HJ, Guaraldi G, Masiá M, Gompels M, De Wit S, Florence E, Esser S, Raffi F, Behrens G, Pozniak A, Gatell JM, Martínez E. Long-term effects on subclinical cardiovascular disease of switching from boosted protease inhibitors to dolutegravir. J Antimicrob Chemother 2023; 78:2361-2365. [PMID: 37539492 PMCID: PMC7617418 DOI: 10.1093/jac/dkad247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 07/19/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND In the NEAT022 trial, switching from boosted PIs (PI/r) to dolutegravir in people with HIV (PWH) with high cardiovascular risk decreased plasma lipids, soluble CD14 and adiponectin, and showed consistent favourable, although non-significant, effects on carotid intima-media thickness (CIMT) progression at 48 weeks. We hereby communicate planned final 96 week results on biomarker changes and CIMT progression. METHODS PWH on a PI/r-based triple therapy regimen were randomly assigned (1:1) to switch the PI/r component to dolutegravir either immediately (DTG-I group) or after 48 weeks (DTG-D group) and were followed up to 96 weeks. We assessed changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury and glomerular and tubular kidney injury, and right and left CIMT progression at 48 and 96 weeks. RESULTS Of 415 PWH randomized, 287 (69%) and 143 (34%) contributed to the biomarker and CIMT substudies respectively. There were significant 96 week changes in biomarkers associated with inflammation, immune activation, oxidation, insulin resistance and myocardial injury. Most changes were favourable, except for adiponectin reduction, which may suggest higher insulin resistance. We were unable to detect significant changes in the progression of CIMT between arms or within arms at 96 weeks. DISCUSSION After 96 weeks, switching from PI/r to dolutegravir in PWH with high cardiovascular risk led to significant changes in several biomarkers associated with cardiovascular disease. Although most changes were favourable, adiponectin reduction was not. There were non-significant changes in CIMT progression.
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Affiliation(s)
- Ana González-Cordón
- Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Lambert Assoumou
- INSERM, Institut Pierre Louis d’Épidémiologie et de Santé Publique, Sorbonne Université, Paris, France
| | - Graeme Moyle
- Consultant Physician in HIV Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
| | - Laura Waters
- Mortimer Market Centre, Central and North West London NHS Foundation Trust, London, UK
| | - Margaret Johnson
- Senior Consultant Physician in Thoracic Medicine, Royal Free London NHS Foundation Trust, London, UK
| | - Pere Domingo
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Senior Consultant at Infectious Diseases Unit, Hospital de Sant Pau, Barcelona, Spain
| | - Julie Fox
- HIV Research Lead, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
| | | | - Giovanni Guaraldi
- Professor of Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Mar Masiá
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Professor of Medicine, Hospital General Universitario de Elche, Elche, Spain
| | - Mark Gompels
- Clinical Lead for Allergy, Immunology and HIV, North Bristol NHS Trust, Bristol, UK
| | - Stephane De Wit
- Professor of Medicine, Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium
| | - Eric Florence
- Head of the HIV Clinic, Universitair Ziekenhuis Antwerpen, Antwerp, Belgium
| | - Stefan Esser
- Academic Director, Universitätsklinikum, Essen, Germany
| | - François Raffi
- Professor of Infectious Diseases, Centre Hospitalier Universitaire, Nantes, France
| | - Georg Behrens
- Profesor of Immunology, Medizinische Hochschule, Hannover, Germany
| | - Anton Pozniak
- Consultant Physician in HIV Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
| | | | - Esteban Martínez
- Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain
- CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
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Haddaji A, Ouladlahsen A, Lkhider M, Bensghir R, Jebbar S, Hilmi S, Abbadi I, Sodqi M, Marih L, Pineau P, El Filali KM, Ezzikouri S. Impact of the first-line antiretroviral therapy on soluble markers of inflammation in cohort of human immunodeficiency virus type 1 in Moroccan patients: a prospective study. Arch Microbiol 2023; 205:223. [PMID: 37154966 DOI: 10.1007/s00203-023-03574-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 04/04/2023] [Accepted: 05/01/2023] [Indexed: 05/10/2023]
Abstract
Chronic inflammation and immune activation are a hallmark of HIV-1 infection. In this study, we assessed inflammation biomarkers in a cohort of people living with HIV-1 (PLWH) before and after long-term suppressive combined antiretroviral therapy (cART). A single-center prospective cohort study was conducted to assess inflammatory biomarkers in 86 cART-naive PLWH and after receiving suppressive cART and 50 uninfected controls. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and soluble CD14 (sCD14) were measured using enzyme-linked immunosorbent assay (ELISA). No significant difference was found in IL-6 levels between cART-naïve PLWH and controls (p = 0.753). In contrast, TNF-α level showed a significant difference between cART naïve-PLWH and controls (p = 0.019). Interestingly, IL-6 and TNF-α levels were significantly decreased in PLWH after cART (p < 0.0001). The sCD14 showed no significant difference between cART-naïve patients and controls (p = 0.839) and similar levels were observed in pre- and post-treatment (p = 0.719). Our results highlight the critical importance of early treatment to reduce inflammation and its consequences during HIV infection.
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Affiliation(s)
- Asmaa Haddaji
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, 1, Place Louis Pasteur, 20360, Casablanca, Morocco
- Laboratory of Virology, Oncology, Biosciences, Environment and New Energies, Faculty of Sciences and Techniques of Mohammedia, Hassan II University of Casablanca, Mohammedia, Morocco
| | - Ahd Ouladlahsen
- Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca, Morocco
- Service Des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Mustapha Lkhider
- Laboratory of Virology, Oncology, Biosciences, Environment and New Energies, Faculty of Sciences and Techniques of Mohammedia, Hassan II University of Casablanca, Mohammedia, Morocco
| | - Rajaa Bensghir
- Service Des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Sanaa Jebbar
- Service Des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Soufiane Hilmi
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, 1, Place Louis Pasteur, 20360, Casablanca, Morocco
| | - Islam Abbadi
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, 1, Place Louis Pasteur, 20360, Casablanca, Morocco
- Laboratory of Virology, Oncology, Biosciences, Environment and New Energies, Faculty of Sciences and Techniques of Mohammedia, Hassan II University of Casablanca, Mohammedia, Morocco
| | - Mustapha Sodqi
- Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca, Morocco
- Service Des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Latifa Marih
- Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca, Morocco
- Service Des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Pascal Pineau
- Unité "Organisation Nucléaire et Oncogenèse", INSERM U993, Institut Pasteur, Paris, France
| | - Kamal Marhoum El Filali
- Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca, Morocco
- Service Des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, 1, Place Louis Pasteur, 20360, Casablanca, Morocco.
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MacDonald DM, Samorodnitsky S, Wendt CH, Baker JV, Collins G, Kruk M, Lock EF, Paredes R, Poongulali S, Weise DO, Winston A, Wood R, Kunisaki KM. Pneumoproteins and biomarkers of inflammation and coagulation do not predict rapid lung function decline in people living with HIV. Sci Rep 2023; 13:4749. [PMID: 36959289 PMCID: PMC10036615 DOI: 10.1038/s41598-023-29739-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 02/09/2023] [Indexed: 03/25/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is among the leading causes of death worldwide and HIV is an independent risk factor for the development of COPD. However, the etiology of this increased risk and means to identify persons with HIV (PWH) at highest risk for COPD have remained elusive. Biomarkers may reveal etiologic pathways and allow better COPD risk stratification. We performed a matched case:control study of PWH in the Strategic Timing of Antiretoviral Treatment (START) pulmonary substudy. Cases had rapid lung function decline (> 40 mL/year FEV1 decline) and controls had stable lung function (+ 20 to - 20 mL/year). The analysis was performed in two distinct groups: (1) those who were virally suppressed for at least 6 months and (2) those with untreated HIV (from the START deferred treatment arm). We used linear mixed effects models to test the relationship between case:control status and blood concentrations of pneumoproteins (surfactant protein-D and club cell secretory protein), and biomarkers of inflammation (IL-6 and hsCRP) and coagulation (d-dimer and fibrinogen); concentrations were measured within ± 6 months of first included spirometry. We included an interaction with treatment group (untreated HIV vs viral suppression) to test if associations varied by treatment group. This analysis included 77 matched case:control pairs in the virally suppressed batch, and 42 matched case:control pairs in the untreated HIV batch (n = 238 total) who were followed for a median of 3 years. Median (IQR) CD4 + count was lowest in the controls with untreated HIV at 674 (580, 838). We found no significant associations between case:control status and pneumoprotein or biomarker concentrations in either virally suppressed or untreated PWH. In this cohort of relatively young, recently diagnosed PWH, concentrations of pneumoproteins and biomarkers of inflammation and coagulation were not associated with subsequent rapid lung function decline.Trial registration: NCT00867048 and NCT01797367.
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Affiliation(s)
- David M MacDonald
- Minneapolis Veterans Affairs Health Care System, Pulmonary, Critical Care, and Sleep Apnea (111N), One Veterans Drive, Minneapolis, MN, 55417, USA.
- University of Minnesota, Minneapolis, USA.
| | | | - Chris H Wendt
- Minneapolis Veterans Affairs Health Care System, Pulmonary, Critical Care, and Sleep Apnea (111N), One Veterans Drive, Minneapolis, MN, 55417, USA
- University of Minnesota, Minneapolis, USA
| | - Jason V Baker
- University of Minnesota, Minneapolis, USA
- Hennepin Healthcare Research Institute, Minneapolis, USA
| | | | | | | | | | - Selvamuthu Poongulali
- Chennai Antiviral Research and Treatment Centre Clinical Research Site, CART-CRS-Infectious Diseases Medical Centre, VHS Chennai, Chennai, India
| | | | - Alan Winston
- Imperial College London, London, UK
- St. Mary's Hospital, London, UK
| | - Robin Wood
- Desmond Tutu Health Foundation, Cape Town, South Africa
| | - Ken M Kunisaki
- Minneapolis Veterans Affairs Health Care System, Pulmonary, Critical Care, and Sleep Apnea (111N), One Veterans Drive, Minneapolis, MN, 55417, USA
- University of Minnesota, Minneapolis, USA
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8
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Manto C, Castro-Gordon A, Goujard C, Meyer L, Lambotte O, Essat A, Shaiykova A, Boufassa F, Noël N. Non-AIDS-Defining Events in Human Immunodeficiency Virus Controllers Versus Antiretroviral Therapy-Controlled Patients: A Cohort Collaboration From the French National Agency for Research on AIDS CO21 (CODEX) and CO06 (PRIMO) Cohorts. Open Forum Infect Dis 2023; 10:ofad067. [PMID: 36846610 PMCID: PMC9945930 DOI: 10.1093/ofid/ofad067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 02/04/2023] [Indexed: 02/10/2023] Open
Abstract
Background Low-grade chronic inflammation may persist in spontaneous human immunodeficiency virus controllers (HICs), leading to non-AIDS-defining events (nADEs). Methods Two hundred twenty-seven antiretroviral therapy (ART)-naive HICs (known human immunodeficiency virus type 1 [HIV-1] infection ≥5 years and at least 5 consecutive viral loads [VLs] <400 HIV RNA copies/mL) were compared with 328 patients who initiated ART ≤1 month after primary HIV infection diagnosis and had undetectable VL within 12 months following ART initiation for at least 5 years. Incidence rates of first nADEs were compared between HICs and ART-treated patients. Determinants of nADEs were assessed by using Cox regression models. Results All-cause nADEs incidence rates were 7.8 (95% confidence interval [CI], 5.9-9.6) and 5.2 (95% CI, 3.9-6.4) per 100 person-months among HICs and ART patients, respectively (incidence rate ratio [IRR], 1.5 [95% CI, 1.1-2.2]; adjusted IRR, 1.93 [95% CI, 1.16-3.20]). After adjustment for the cohort, demographic, and immunological characteristics, the only other factor associated with all-cause nADE occurrence was age ≥43 (vs <43) years at the beginning of viral control (IRR, 1.69 [95% CI, 1.11-2.56]). The most frequent events observed in the 2 cohorts were non-AIDS-related benign infections (54.6% and 32.9% of all nADEs, respectively, for HICs and ART patients). No differences in cardiovascular or psychiatric events were observed. Conclusions HICs experienced 2 times more nADEs than virologically suppressed patients on ART, mainly non-AIDS-related benign infections. Older age was associated with nADE occurrence, independent of immune or virologic parameters. These results do not argue in favor of expanding the ART indication for HICs but rather a case-by-case approach considering clinical outcomes such as nADEs besides immune activation.
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Affiliation(s)
- Carmelite Manto
- INSERM U1018, Université Paris Saclay, Centre de recherche en Epidémiologie et Santé des Populations (CESP), Le Kremlin Bicêtre, France,Clinical Research Education, Networking & Consultancy (CRENC), Douala, Cameroon
| | - Alicia Castro-Gordon
- Assistance Publique-Hôpitaux de Paris.Université Paris-Saclay, Service de Médecine Interne et Immunologie Clinique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Cécile Goujard
- INSERM U1018, Université Paris Saclay, Centre de recherche en Epidémiologie et Santé des Populations (CESP), Le Kremlin Bicêtre, France,Assistance Publique-Hôpitaux de Paris.Université Paris-Saclay, Service de Médecine Interne et Immunologie Clinique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Laurence Meyer
- INSERM U1018, Université Paris Saclay, Centre de recherche en Epidémiologie et Santé des Populations (CESP), Le Kremlin Bicêtre, France,Assistance Publique-Hôpitaux de Paris.Université Paris-Saclay, Service de Santé Publique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Olivier Lambotte
- Assistance Publique-Hôpitaux de Paris.Université Paris-Saclay, Service de Médecine Interne et Immunologie Clinique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France,Unité mixte de recherche (UMR) INSERM/CEA/Université Paris Saclay U1184, Centre de recherche en Immunologie des infections virales et des maladies auto-immunes (ImVA), Le Kremlin Bicêtre, France
| | - Asma Essat
- INSERM U1018, Université Paris Saclay, Centre de recherche en Epidémiologie et Santé des Populations (CESP), Le Kremlin Bicêtre, France,Assistance Publique-Hôpitaux de Paris.Université Paris-Saclay, Service de Santé Publique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Arnoo Shaiykova
- INSERM U1018, Université Paris Saclay, Centre de recherche en Epidémiologie et Santé des Populations (CESP), Le Kremlin Bicêtre, France
| | | | - Nicolas Noël
- Correspondence: Nicolas Noël, MD, PhD, Service de Médecine Interne et Immunologie Clinique, Hôpital Bicêtre, 63 rue Gabriel Peri, 94275 Le Kremlin-Bicêtre Cedex, France ()
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9
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Zerangian N, Erabi G, Poudineh M, Monajjem K, Diyanati M, Khanlari M, Khalaji A, Allafi D, Faridzadeh A, Amali A, Alizadeh N, Salimi Y, Ghane Ezabadi S, Abdi A, Hasanabadi Z, ShojaeiBaghini M, Deravi N. Venous thromboembolism in viral diseases: A comprehensive literature review. Health Sci Rep 2023; 6:e1085. [PMID: 36778773 PMCID: PMC9900357 DOI: 10.1002/hsr2.1085] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 12/25/2022] [Accepted: 01/19/2023] [Indexed: 02/09/2023] Open
Abstract
Venous thromboembolism (VTE) is known to be a common respiratory and/or cardiovascular complication in hospitalized patients with viral infections. Numerous studies have proven human immunodeficiency virus infection to be a prothrombotic condition. An elevated VTE risk has been observed in critically ill H1N1 influenza patients. VTE risk is remarkably higher in patients infected with the Hepatitis C virus in contrast to uninfected subjects. The elevation of D-dimer levels supported the association between Chikungunya and the Zika virus and the rise of clinical VTE risk. Varicella-zoster virus is a risk factor for both cellulitis and the consequent invasive bacterial disease which may take part in thrombotic initiation. Eventually, hospitalized patients infected with the coronavirus disease of 2019 (COVID-19), the cause of the ongoing worldwide pandemic, could mainly suffer from an anomalous risk of coagulation activation with enhanced venous thrombosis events and poor quality clinical course. Although the risk of VTE in nonhospitalized COVID-19 patients is not known yet, there are a large number of guidelines and studies on thromboprophylaxis administration for COVID-19 cases. This study aims to take a detailed look at the effect of viral diseases on VTE, the epidemiology of VTE in viral diseases, and the diagnosis and treatment of VTE.
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Affiliation(s)
- Nasibeh Zerangian
- Health Education and Health Promotion, Department of Health Education and Health Promotion, School of HealthMashhad University of Medical SciencesMashhadIran
| | - Gisou Erabi
- Student Research CommitteeUrmia University of Medical SciencesUrmiaIran
| | | | - Kosar Monajjem
- Student Research CommitteeTabriz University of Medical SciencesTabrizIran
| | - Maryam Diyanati
- Student Research CommitteeRafsanjan University of Medical SciencesRafsanjanIran
| | - Maryam Khanlari
- Student Research CommitteeTabriz University of Medical SciencesTabrizIran
| | | | - Diba Allafi
- Student Research CommitteeUrmia University of Medical SciencesUrmiaIran
| | - Arezoo Faridzadeh
- Department of Immunology and Allergy, School of MedicineMashhad University of Medical SciencesMashhadIran
- Immunology Research CenterMashhad University of Medical SciencesMashhadIran
| | - Arian Amali
- Student Research Committee, Paramedical DepartmentIslamic Azad University, Mashhad BranchMashhadIran
| | - Nilufar Alizadeh
- Doctor of Medicine (MD), School of MedicineIran University of Medical SciencesTehranIran
| | - Yasaman Salimi
- Student Research CommitteeKermanshah University of Medical SciencesKermanshahIran
| | - Sajjad Ghane Ezabadi
- Student's Scientific Research Center, School of MedicineTehran University of Medical SciencesTehranIran
| | - Amir Abdi
- Student Research Committee, School of Medicine, Tehran Medical SciencesIslamic Azad UniversityTehranIran
| | - Zahra Hasanabadi
- Doctor of Medicine (MD), School of MedicineQazvin University of Medical ScienceQazvinIran
| | - Mahdie ShojaeiBaghini
- Medical Informatics Research Center, Institute for Futures Studies in HealthKerman University of Medical SciencesKermanIran
| | - Niloofar Deravi
- Student Research Committee, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
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10
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Perkins MV, Joseph S, Dittmer DP, Mackman N. Cardiovascular Disease and Thrombosis in HIV Infection. Arterioscler Thromb Vasc Biol 2023; 43:175-191. [PMID: 36453273 PMCID: PMC10165851 DOI: 10.1161/atvbaha.122.318232] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 11/18/2022] [Indexed: 12/03/2022]
Abstract
HIV infection has transitioned from an acute, fatal disease to a chronic one managed by antiretroviral therapy. Thus, the aging population of people living with HIV (PLWH) continues to expand. HIV infection results in a dysregulated immune system, wherein CD4+ T cells are depleted, particularly in the gastrointestinal tract, disrupting the gut epithelial barrier. Long-term HIV infection is associated with chronic inflammation through potentially direct mechanisms caused by viral replication or exposure to viral proteins and indirect mechanisms resulting from increased translocation of microbial products from the intestine or exposure to antiretroviral therapy. Chronic inflammation (as marked by IL [interleukin]-6 and CRP [C-reactive protein]) in PLWH promotes endothelial cell dysfunction and atherosclerosis. PLWH show significantly increased rates of cardiovascular disease, such as myocardial infarction (risk ratio, 1.79 [95% CI, 1.54-2.08]) and stroke (risk ratio, 2.56 [95% CI, 1.43-4.61]). In addition, PLWH have increased levels of the coagulation biomarker D-dimer and have a two to ten-fold increased risk of venous thromboembolism compared with the general population. Several small clinical trials analyzed the effect of different antithrombotic agents on platelet activation, coagulation, inflammation, and immune cell activation. Although some markers for coagulation were reduced, most agents failed to reduce inflammatory markers in PLWH. More studies are needed to understand the underlying mechanisms driving inflammation in PLWH to create better therapies for lowering chronic inflammation in PLWH. Such therapies can potentially reduce atherosclerosis, cardiovascular disease, and thrombosis rates in PLWH and thus overall mortality in this population.
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Affiliation(s)
- Megan V. Perkins
- UNC Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Sarah Joseph
- UNC Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Dirk P. Dittmer
- UNC Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Nigel Mackman
- UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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11
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Wang NC, Chen HW, Lin TY. Association of protein disulfide isomerase family A, member 4, and inflammation in people living with HIV. Int J Infect Dis 2023; 126:79-86. [PMID: 36375691 DOI: 10.1016/j.ijid.2022.11.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 10/25/2022] [Accepted: 11/08/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Protein disulfide isomerase (PDI) family members are specific endoplasmic reticulum proteins associated with inflammation, obesity, and cancer. In HIV infection, the role of PDI family A, member 4 (PDIA4), is unclear. This study aimed to clarify the association between plasma PDIA4 levels and inflammation in people living with HIV (PLWH). METHODS In this study, 287 PLWH and 74 healthy participants were enrolled. The plasma PDIA4 values, demographic data, laboratory data, and other inflammatory markers were recorded. The association between PDIA4 level and inflammatory extent was analyzed using logistic regression and Spearman rank-order correlations. Other results were analyzed using Student's t-test or chi-square test. RESULTS In PLWH, the PDIA4 levels were positively associated with the inflammatory markers, interleukin 6 (r = 0.209, p = 0.001), and tumor necrosis factor-α (r = 0.162, p = 0.01) levels, but not with high-sensitivity C-reactive protein levels. Moreover, the plasma PDIA4 level of PLWH decreased after anti-viral treatment (p = 0.0001). CONCLUSION Plasma PDIA4 levels are closely associated with inflammation in PLWH and have a positive correlation with the viral load during anti-viral therapy.
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Affiliation(s)
- Ning-Chi Wang
- Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Hsuan-Wei Chen
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Te-Yu Lin
- Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
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12
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Gilada T, Schnittman SR, White E, Mercader J, Wang Y, Dasgupta S, Valdez R, Pinto-Santini D, Pasalar S, Sanchez J, Gonzales P, Lama JR, Bender Ignacio R, Duerr A. Immune Activation in Primary Human Immunodeficiency Virus: Influence of Duration of Infection, Treatment, and Substance Use. Open Forum Infect Dis 2022; 9:ofac155. [PMID: 35611350 PMCID: PMC9124591 DOI: 10.1093/ofid/ofac155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 03/23/2022] [Indexed: 11/12/2022] Open
Abstract
Background Primary human immunodeficiency virus (HIV) is characterized by dynamic changes in viral load and innate and adaptive immune responses; it is unclear the extent to which time from acquisition to antiretroviral therapy (ART) initiation and substance use impact these immunologic changes. Methods We studied plasma immune activation biomarkers, viral load, and CD4+ and CD8+ cell counts in participants from the Sabes primary infection study in Peru, who had been randomized to begin ART immediately after diagnosis vs 24 weeks later. We modeled influence of substance use and duration of HIV infection on biomarkers at baseline and over 24 weeks. Results Compared to participants enrolled >30 days after HIV acquisition, participants enrolled during acute infection (≤30 days) had higher mean interferon (IFN)-γ and IFN-α2a (1.7-fold and 3.8-fold interquartile range [IQR] higher, respectively). Participants enrolled >30 days after HIV acquisition had higher mean baseline CD8+ cell count (2.7 times the IQR). Alcohol use (positive phosphatidylethanol level) was associated with elevated IFN-γ, tumor necrosis factor alpha (TNF-α), and interleukin 12p70 (IL-12p70), and smoking was associated with higher macrophage inflammatory protein 1α, TNF-α, and IL-12p70. Most biomarkers declined more quickly in participants who initiated ART immediately; however, substance use and duration of HIV infection at enrollment had little influence on rate of decline. Conclusions IFN-γ and other biomarkers are elevated during early primary infection, when exposure to HIV antigens is high. Immune activation decreased most quickly in those who started ART during acute/early primary infection. Higher CD8+ cell counts and a trend toward higher soluble CD163 levels during the 30 days after acquisition suggest the onset of compensatory responses and immune exhaustion.
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Affiliation(s)
| | - Samuel R Schnittman
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Edward White
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Jacqueline Mercader
- Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA
| | - Yixin Wang
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Sayan Dasgupta
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Rogelio Valdez
- Case Western Reserve School of Medicine, Cleveland, Ohio, USA
| | - Delia Pinto-Santini
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Siavash Pasalar
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Jorge Sanchez
- Centro de Investigaciones Tecnológicas, Biomédicas y Medioambientales, Universidad Nacional Mayor de San Marcos, Lima, Peru
| | | | - Javier R Lama
- Asociacion Civil Impacta Salud y Educacion, Lima, Peru
| | - Rachel Bender Ignacio
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Ann Duerr
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
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13
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Coordination of inflammatory responses in children with perinatally-acquired HIV infection. AIDS 2022; 36:1117-1127. [PMID: 35442223 DOI: 10.1097/qad.0000000000003229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE We investigated dynamics of inflammatory biomarkers in children with perinatally-acquired HIV (PHIV) who started antiretrovirals at age <3 years and achieved sustained virologic control (HIV plasma RNA<400 copies/mL). DESIGN This was a retrospective analysis of inflammatory biomarkers in children enrolled in a randomized trial of early (<3 years of age) PI-based versus NNRTI-based regimens (P1060), who achieved sustained virologic control and participated in a neurodevelopmental follow-up study (P1104 s) between ages 5-11 years. METHODS We measured 20 inflammatory biomarkers using ELISA or chemiluminescence at onset of sustained virologic control (Tc) and at P1104 s entry (Te). RESULTS The 213 participants had median ages of 1.2, 1.9, and 7.0 years at antiretroviral initiation, Tc, and Te, respectively, with 138 on PI-based and 74 on NNRTI-based regimens at Tc. Eighteen markers decreased and two increased from Tc to Te (Te-Tc). Biomarker subsets, particularly cytokines, the chemokine IP-10, and adhesion molecules sICAM-1 and sVCAM-1, correlated at Tc, Te, and Te-Tc. At Tc, higher biomarker levels were associated with younger age, female sex, HIV plasma RNA ≥750,000 copies/mL, lower nadir CD4+%, lower nadir weight z-scores, and NNRTI-based treatment. Greater Te-Tc biomarker declines were associated with younger age, male sex, higher Tc biomarker levels, lower nadir CD4+%, and NNRTI-based treatment. Duration of controlled viremia and nadir height Z-scores showed mixed associations. CONCLUSIONS Biomarker expression showed substantial coordination. Most markers decreased after virologic control. Demographic and clinical variables associated with biomarker patterns were identified. Mechanistic studies of these biomarker patterns are needed to inform interventions to control inflammation.
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14
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Kovacs L, Kress TC, Belin de Chantemèle EJ. HIV, Combination Antiretroviral Therapy, and Vascular Diseases in Men and Women. JACC Basic Transl Sci 2022; 7:410-421. [PMID: 35540101 PMCID: PMC9079796 DOI: 10.1016/j.jacbts.2021.10.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 12/01/2022]
Abstract
Thanks to the advent of combination antiretroviral therapy (cART), people living with human immunodeficiency virus (HIV) (PLWH) experienced a marked increase in life expectancy but are now at higher risk for cardiovascular disease (CVD), the current leading cause of death in PLWH on cART. Although HIV preponderantly affects men over women, manifestations of HIV-related CVD differ by sex with women experiencing greater risks than men. Despite extensive investigation, the etiopathology of CVD, notably the respective contribution of viral infection and cART, remain ill-defined. However, both viral infection and cART have been reported to contribute to endothelial dysfunction, the precursor and major cause of atherosclerosis-associated CVD, through mechanisms involving endothelial cell activation, inflammation, and oxidative stress, all leading to reduced nitric oxide bioavailability. Therefore, preserving endothelial function in PLWH on cART should be a main target to reduce CVD morbidity and mortality, notably in females.
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Key Words
- CVD, cardiovascular disease
- FMD, flow-mediated dilatation
- HF, heart failure
- HIV
- HIV, human immunodeficiency virus
- MI, myocardial infarction
- NO, nitric oxide
- PAD, peripheral artery disease
- PH, pulmonary hypertension
- PLWH, people living with HIV
- cART, combination antiretroviral therapy
- cIMT, carotid intima-media thickness
- combination antiretroviral therapy
- endothelial dysfunction
- sex differences
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Affiliation(s)
- Laszlo Kovacs
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - Taylor C Kress
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
| | - Eric J Belin de Chantemèle
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.,Division of Cardiology, Department of Medicine, Medical College of Georgia at Augusta University, Augusta Georgia, USA
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15
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Chen S, Xu Q, Wang J, Tan X. Effects of Artesunate Tablet on Immune Activation and Reconstitution Among Highly Active Antiretroviral Therapy-Treated Patients with Incomplete Immune Responses. AIDS Res Hum Retroviruses 2022; 38:100-110. [PMID: 33913736 DOI: 10.1089/aid.2020.0254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The level of T cell activation is a better predictor of CD4+ T cell depletion in highly active antiretroviral therapy (HAART) patients than viral load. Artesunate is an artemisinin derivative that has an immunomodulatory effect. This study investigated whether artesunate tablet reduces T cell activation and improves immune reconstitution among patients with suboptimal immune recovery despite receiving long-term effective HAART. This was a randomized prospective parallel open-label trial consisting of 45 participants whose plasma HIV load was effectively suppressed by HAART for >18 months and who had CD4+ T cell counts of <300 cells/μL or an increase of <20% from baseline. The patients were randomized 2:1 into the artesunate group or the control group and received artesunate tablets (orally, 50 mg two times daily) combined with HAART or HAART alone, respectively. T cell subsets, activation markers, clinical symptoms, viral load, and side effects were assessed. By 48 weeks, artesunate tablet did not improve CD4+ T cell recovery or reduce the activation of T cell subsets but induced in a smaller decline in the expression of T cell activation markers among HAART patients with incomplete immune responses. However, artesunate tablet did appear to reduce the level of T cell apoptosis. One subject developed moderate anemia. Long-term use of artesunate tablet is unlikely to produce substantial clinical benefits in patients receiving HAART who exhibit an incomplete immune response.
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Affiliation(s)
- Siyan Chen
- Artemisia annua Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qihua Xu
- Artemisia annua Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jian Wang
- Chinese Medicine Research Center for AIDS Prevention and Treatment, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xinghua Tan
- Hepatology Department of Integrated Traditional Chinese and Western Medicine, Guangzhou Eighth People's Hospital, Guangzhou, China
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16
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Jianu C, Itu-Mureşan C, Drugan C, Filipescu I, Topan AV, Jianu ME, Morar II, Bolboacă SD. Evaluation of several serum interleukins as markers for treatment effectiveness in naïve HIV infected patients: A pilot study. PLoS One 2021; 16:e0260007. [PMID: 34784398 PMCID: PMC8594820 DOI: 10.1371/journal.pone.0260007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 11/01/2021] [Indexed: 11/20/2022] Open
Abstract
In this observational pilot study, we investigated the impact of Dolutegravir, Raltegravir, Elvitegravir (Integrase Strand Transfer Inhibitors, INSTIs), or boosted Darunavir (a Protease Inhibitor, PI) in combination with two nucleoside reverstranscriptase inhibitors (Emtricitabine/Tenofovir disoproxil or Lamivudine/Tenofovir disoproxil, NRTI) on four interleukins (IL-4, IL-10, IL-13, and IL-21) as immune activation markers in naïve HIV(Human Immunodeficiency Virus)-infected patients during the first six months of combined standard-of-care antiretroviral therapy (cART). Newly diagnosed with HIV-infected subjects and without any disease that could affect the immune activation markers were evaluated. The patients’ physicians recommended the cART as standard-of-care and the ILs were measured before cART and six months of cART. The levels of CD4+ T-cells count and CD4+/CD8+ ratio significantly increased at six months (P-value<0.02) regardless of the drugs, INSTIs or PI. However, a CD4+/CD8+ >1 was observed in 25% of patients treated with Raltegravir and half of those treated with Dolutegravir. At six months of cART, viral load was detectable in only 6/31 individuals. IL-21 had an undetectable level in 30/31 patients after six months of cART. Our results suggest the potency in restoring immune markers in HIV-infected patients with all investigated drugs. Dolutegravir showed a tendency to statistically significant changes in IL-4 and IL-10. A clinical trial with random allocation of medication and an extensive follow-up is needed to replicate this research and validate the usefulness of evaluated ILs as markers of cART effectiveness.
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Affiliation(s)
- Cristian Jianu
- Department of Medical Informatics and Biostatistics, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Immunosuppressed, Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania
| | - Corina Itu-Mureşan
- Department of Immunosuppressed, Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania
| | - Cristina Drugan
- Department of Biochemistry, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Irina Filipescu
- Department of Immunosuppressed, Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania
| | - Adriana Violeta Topan
- Department of Immunosuppressed, Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania
- Department of Infectious Diseases, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Mihaela Elena Jianu
- Department of Histology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- * E-mail: (MEJ); (SDB)
| | - Ioana Iulia Morar
- Department of Pathophysiology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Sorana D. Bolboacă
- Department of Medical Informatics and Biostatistics, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- * E-mail: (MEJ); (SDB)
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17
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Ashuro AA, Fan YG, Fu YS, Di DS, Sam NB, Pan HF, Ye DQ. The Effect of Rosuvastatin on Plasma/Serum Levels of High-Sensitivity C-Reactive Protein, Interleukin-6, and D-Dimer in People Living with Human Immunodeficiency Virus: A Systematic Review and Meta-Analysis. AIDS Res Hum Retroviruses 2021; 37:821-833. [PMID: 33913752 DOI: 10.1089/aid.2020.0273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Rosuvastatin therapy might have an effect on the inflammatory and coagulation biomarkers. However, the evidence about the effect of rosuvastatin therapy on the high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer levels among people living with human immunodeficiency virus (PLHIV) is still unclear. Therefore, this study investigated the relational effect of rosuvastatin therapy on serum/plasma hsCRP, IL-6 and D-dimer levels in PLHIV. The literature search was done from Embase, PubMed, and Web of Science databases. The review and meta-analysis included studies written in English language up to January 4, 2020. Random effects model was used to evaluate the pooled standard mean difference with 95% confidence interval. A meta-analysis was performed using nine articles with 392 PLHIV. The result revealed that the plasma/serum levels of IL-6 were significantly reduced after the intervention. However, hsCRP and D-dimer levels showed no significant difference (p > .05) between before and after the intervention. The subgroup analysis showed that there was significant association between PLHIV ages <45 years and cohort studies with IL-6 levels. The current CD4+ counts ≥350 cells/mm3 correlated with hsCRP as well as IL-6. Similarly, nadir CD4+ counts ≥200 cells/mm3 and duration of HIV diagnosis <10 years also showed significant association with IL-6 and D-dimer levels. It was also indicated that participants who were under antiretroviral drug for <7 years were significantly associated with hsCRP levels. This study established that IL-6 levels were significantly reduced after the intervention while hsCRP and D-dimer levels showed no significant difference between before and after the intervention.
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Affiliation(s)
- Akililu Alemu Ashuro
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Yin-Guang Fan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China
| | - Yuan-Sheng Fu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Dong-Sheng Di
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China
| | - Napoleon Bellua Sam
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China
| | - Dong-Qing Ye
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China
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18
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Freiberg MS, Duncan MS, Alcorn C, Chang CH, Kundu S, Mumpuni A, Smith EK, Loch S, Bedigian A, Vittinghoff E, So‐Armah K, Hsue PY, Justice AC, Tseng ZH. HIV Infection and the Risk of World Health Organization-Defined Sudden Cardiac Death. J Am Heart Assoc 2021; 10:e021268. [PMID: 34493058 PMCID: PMC8649505 DOI: 10.1161/jaha.121.021268] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 07/09/2021] [Indexed: 12/04/2022]
Abstract
Background People living with HIV have higher sudden cardiac death (SCD) rates compared with the general population. Whether HIV infection is an independent SCD risk factor is unclear. Methods and Results This study evaluated participants from the Veterans Aging Cohort Study, an observational, longitudinal cohort of veterans with and without HIV infection matched 1:2 on age, sex, race/ethnicity, and clinical site. Baseline for this study was a participant's first clinical visit on or after April 1, 2003. Participants were followed through December 31, 2014. Using Cox proportional hazards regression, we assessed whether HIV infection, CD4 cell counts, and/or HIV viral load were associated with World Health Organization (WHO)-defined SCD risk. Among 144 336 participants (30% people living with HIV), the mean (SD) baseline age was 50.0 years (10.6 years), 97% were men, and 47% were of Black race. During follow-up (median, 9.0 years), 3035 SCDs occurred. HIV infection was associated with increased SCD risk (hazard ratio [HR], 1.14; 95% CI, 1.04-1.25), adjusting for possible confounders. In analyses with time-varying CD4 and HIV viral load, people living with HIV with CD4 counts <200 cells/mm3 (HR, 1.57; 95% CI, 1.28-1.92) or viral load >500 copies/mL (HR, 1.70; 95% CI, 1.46-1.98) had increased SCD risk versus veterans without HIV. In contrast, people living with HIV who had CD4 cell counts >500 cells/mm3 (HR, 1.03; 95% CI, 0.90-1.18) or HIV viral load <500 copies/mL (HR, 0.97; 95% CI, 0.87-1.09) were not at increased SCD risk. Conclusions HIV infection is associated with increased risk of WHO-defined SCD among those with elevated HIV viral load or low CD4 cell counts.
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Affiliation(s)
- Matthew S. Freiberg
- Division of Cardiovascular MedicineVanderbilt University Medical CenterNashvilleTN
- Geriatric Research Education and Clinical Centers (GRECC)Veterans Affairs Tennessee Valley Healthcare SystemNashvilleTN
- Department of MedicineVanderbilt University Medical CenterNashvilleTN
- Yale School of Public HealthNew HavenCT
| | - Meredith S. Duncan
- Division of Cardiovascular MedicineVanderbilt University Medical CenterNashvilleTN
- Department of BiostatisticsUniversity of KentuckyLexingtonKY
| | - Charles Alcorn
- Department of BiostatisticsGraduate School of Public HealthUniversity of PittsburghPA
| | - Chung‐Chou H. Chang
- Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghPA
| | - Suman Kundu
- Division of Cardiovascular MedicineVanderbilt University Medical CenterNashvilleTN
| | - Asri Mumpuni
- Division of Cardiovascular MedicineVanderbilt University Medical CenterNashvilleTN
- Vanderbilt Institute for Clinical and Translational ResearchVanderbilt University Medical CenterNashvilleTN
| | - Emily K. Smith
- Division of Cardiovascular MedicineVanderbilt University Medical CenterNashvilleTN
| | - Sarah Loch
- Division of Cardiovascular MedicineVanderbilt University Medical CenterNashvilleTN
- Vanderbilt Center for Child Health PolicyVanderbilt University Medical CenterNashvilleTN
| | | | - Eric Vittinghoff
- Department of Epidemiology and BiostatisticsUniversity of California at San FranciscoCA
| | - Kaku So‐Armah
- Division of General Internal MedicineBoston UniversityBostonMA
| | - Priscilla Y. Hsue
- Division of CardiologyUniversity of California San FranciscoSan FranciscoCA
| | - Amy C. Justice
- Veterans Affairs Connecticut Health Care SystemWest Haven Veterans Administration Medical CenterWest HavenCT
- Department of MedicineYale School of MedicineNew HavenCT
| | - Zian H. Tseng
- Cardiac Electrophysiology Section, Division of CardiologyUniversity of California San FranciscoSan FranciscoCA
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19
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Plasmatic Coagulation Capacity Correlates With Inflammation and Abacavir Use During Chronic HIV Infection. J Acquir Immune Defic Syndr 2021; 87:711-719. [PMID: 33492017 DOI: 10.1097/qai.0000000000002633] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 12/21/2020] [Indexed: 11/26/2022]
Abstract
BACKGROUND D-dimer concentrations in people living with HIV (PLHIV) on combination antiretroviral therapy (cART) are increased and have been linked to mortality. D-dimer is a biomarker of in vivo coagulation. In contrast to reports on D-dimer, data on coagulation capacity in PLHIV are conflicting. In this study, we assessed the effect of cART and inflammation on coagulation capacity. SETTING We explored coagulation capacity using calibrated thrombin generation (TG) and linked this to persistent inflammation and cART in a cross-sectional study including PLHIV with viral suppression and uninfected controls. METHODS We used multivariate analyses to identify independent factors influencing in vivo coagulation (D-dimer) and ex vivo coagulation capacity (TG). RESULTS Among 208 PLHIV, 94 (45%) were on an abacavir-containing regimen. D-dimer levels (219.1 vs 170.5 ng/mL, P = 0.001) and inflammatory makers (sCD14, sCD163, and high-sensitive C-reactive protein) were increased in PLHIV compared with those in controls (n = 56). PLHIV experienced lower TG (reflected by endogenous thrombin potential [ETP]) when compared with controls, after correction for age, sex, and antiretroviral therapy. Abacavir use was independently associated with increased ETP. Prothrombin concentrations were strongly associated with ETP and lower in PLHIV on a non-abacavir-containing regimen compared with those in controls, suggesting consumption as a possible mechanism for HIV-associated reduction in TG. D-dimer concentrations were associated with inflammation, but not TG. CONCLUSIONS Abacavir use was associated with increased TG and could serve as an additional factor in the reported increase in thrombotic events during abacavir use. Increased exposure to triggers that propagate coagulation, such as inflammation, likely underlie increased D-dimer concentrations found in most PLHIV.
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20
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Nozza S, Ferrarese R, Poli A, Galli L, Sampaolo M, Bigoloni A, Galli A, Muccini C, Spagnuolo V, Lazzarin A, Clementi M, Mancini N, Castagna A. Analysis of the faecal microbiome during analytical treatment interruption in people with chronic HIV infection and long-lasting virological suppression (APACHE study). J Antimicrob Chemother 2021; 75:2700-2702. [PMID: 32542322 DOI: 10.1093/jac/dkaa231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- S Nozza
- San Raffaele Scientific Institute, Milan, Italy
| | - R Ferrarese
- San Raffaele Scientific Institute, Milan, Italy
| | - A Poli
- San Raffaele Scientific Institute, Milan, Italy
| | - L Galli
- San Raffaele Scientific Institute, Milan, Italy
| | - M Sampaolo
- San Raffaele Scientific Institute, Milan, Italy
| | - A Bigoloni
- San Raffaele Scientific Institute, Milan, Italy
| | - A Galli
- San Raffaele Scientific Institute, Milan, Italy
| | - C Muccini
- University Vita-Salute San Raffaele, Milan, Italy
| | - V Spagnuolo
- University Vita-Salute San Raffaele, Milan, Italy
| | - A Lazzarin
- San Raffaele Scientific Institute, Milan, Italy.,University Vita-Salute San Raffaele, Milan, Italy
| | - M Clementi
- San Raffaele Scientific Institute, Milan, Italy.,University Vita-Salute San Raffaele, Milan, Italy
| | - N Mancini
- San Raffaele Scientific Institute, Milan, Italy.,University Vita-Salute San Raffaele, Milan, Italy
| | - A Castagna
- San Raffaele Scientific Institute, Milan, Italy.,University Vita-Salute San Raffaele, Milan, Italy
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21
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González-Cordón A, Assoumou L, Moyle G, Waters L, Johnson M, Domingo P, Fox J, Stellbrink HJ, Guaraldi G, Masiá M, Gompels M, De Wit S, Florence E, Esser S, Raffi F, Behrens G, Pozniak A, Gatell JM, Martínez E. Switching from boosted PIs to dolutegravir decreases soluble CD14 and adiponectin in high cardiovascular risk people living with HIV. J Antimicrob Chemother 2021; 76:2380-2393. [PMID: 34120186 DOI: 10.1093/jac/dkab158] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 04/23/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Switching from boosted PIs to dolutegravir in people living with HIV (PLWH) with high cardiovascular risk improved plasma lipids at 48 weeks in the NEAT022 trial. Whether this strategy may have an impact on cardiovascular biomarkers is unknown. METHODS We assessed 48 week changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury, and glomerular and tubular kidney injury. RESULTS Of 415 PLWH randomized in the NEAT022 study, 313 (75.4%) remained on allocated therapy and had paired samples available. Soluble CD14 (-11%, P < 0.001) and adiponectin (-11%, P < 0.001) significantly declined and high-sensitive C-reactive protein (-13%, P = 0.069) and oxidized LDL (-13%, P = 0.084) tended to decrease with dolutegravir. Switching to dolutegravir remained significantly associated with soluble CD14 and adiponectin reductions after adjustment for baseline variables. There were inverse correlations between soluble CD14 and CD4 count changes (P = 0.05), and between adiponectin and BMI changes (P < 0.001). CONCLUSIONS Switching from boosted PIs to dolutegravir in PLWH with high cardiovascular risk led to soluble CD14 and adiponectin reductions at 48 weeks. While decreasing soluble CD14 may entail favourable health effects in PLWH, adiponectin reduction may reflect less insulin sensitivity associated with weight gain.
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Affiliation(s)
| | - Lambert Assoumou
- Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Paris, France
| | - Graeme Moyle
- Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
| | - Laura Waters
- Mortimer Market Centre, Central & North West London NHS Foundation Trust, London, UK
| | | | | | - Julie Fox
- Guy's & St Thomas' NHS Foundation Trust, London, UK
| | | | | | - Mar Masiá
- Hospital General Universitario de Elche, Elche, Spain
| | | | - Stephane De Wit
- Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium
| | | | | | | | | | - Anton Pozniak
- Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
| | - José M Gatell
- Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain.,ViiV Healthcare, Brentford, UK
| | - Esteban Martínez
- Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain
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22
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Zhu Z, Li T, Chen J, Kumar J, Kumar P, Qin J, Hadigan C, Sereti I, Baker JV, Catalfamo M. The Role of Inflammation and Immune Activation on Circulating Endothelial Progenitor Cells in Chronic HIV Infection. Front Immunol 2021; 12:663412. [PMID: 34079548 PMCID: PMC8165313 DOI: 10.3389/fimmu.2021.663412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/20/2021] [Indexed: 11/13/2022] Open
Abstract
Endothelial inflammation and damage are the main drivers of cardiovascular risk/disease. Endothelial repair is mediated in part by recruitment of bone marrow endothelial progenitor/endothelial colony forming cells (EPC/ECFC). People with HIV (PWH) have increased cardiovascular risk and the impact of infection in endothelial repair is not well defined. The low frequencies and challenges to in vitro isolation and differentiation of EPC/ECFC from PBMCs had made it difficult to study their role in this context. We hypothesized that HIV driven inflammation induces phenotypic changes that reflects the impact of infection. To test this hypothesis, we evaluated expression of markers of trafficking, endothelial differentiation, and angiogenesis, and study their association with biomarkers of inflammation in a cohort of PWH. In addition, we investigated the relationship of circulating endothelial progenitors and angiogenic T cells, a T cell subset with angiogenic function. Using a flow cytometry approach, we identified two subsets of circulating progenitors LIN4-CD45-CD34+ and LIN4-CD45dimCD34+ in PWH. We found that the phenotype but not frequencies were associated with biomarkers of inflammation. In addition, the percentage of LIN4-CD45dimCD34+ was associated with serum levels of lipids. This data may provide a new tool to better address the impact of HIV infection in endothelial inflammation and repair.
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Affiliation(s)
- Ziang Zhu
- Department of Microbiology and Immunology. Georgetown University School of Medicine, Washington, DC, United States
| | - Tong Li
- Department of Microbiology and Immunology. Georgetown University School of Medicine, Washington, DC, United States
| | - Jinya Chen
- Department of Microbiology and Immunology. Georgetown University School of Medicine, Washington, DC, United States
| | - Jai Kumar
- Division of Infectious Diseases and Tropical Medicine, Georgetown University School of Medicine, Washington, DC, United States
| | - Princy Kumar
- Division of Infectious Diseases and Tropical Medicine, Georgetown University School of Medicine, Washington, DC, United States
| | - Jing Qin
- Biostatistics Research Branch, Division of Clinical Research (DCR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Colleen Hadigan
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Irini Sereti
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Jason V Baker
- Hennepin Healthcare Research Institute, University of Minnesota, Minneapolis, MN, United States
| | - Marta Catalfamo
- Department of Microbiology and Immunology. Georgetown University School of Medicine, Washington, DC, United States
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23
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Gisslen M, Keating SM, Spudich S, Arechiga V, Stephenson S, Zetterberg H, Di Germanio C, Blennow K, Fuchs D, Hagberg L, Norris PJ, Peterson J, Shacklett BL, Yiannoutsos CT, Price RW. Compartmentalization of cerebrospinal fluid inflammation across the spectrum of untreated HIV-1 infection, central nervous system injury and viral suppression. PLoS One 2021; 16:e0250987. [PMID: 33983973 PMCID: PMC8118251 DOI: 10.1371/journal.pone.0250987] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 04/16/2021] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE To characterize the evolution of central nervous system (CNS) inflammation in HIV-1 infection applying a panel of cerebrospinal fluid (CSF) inflammatory biomarkers to grouped subjects representing a broad spectrum of systemic HIV-1 immune suppression, CNS injury and viral control. METHODS This is a cross-sectional analysis of archived CSF and blood samples, assessing concentrations of 10 functionally diverse soluble inflammatory biomarkers by immunoassays in 143 HIV-1-infected subjects divided into 8 groups: untreated primary HIV-1 infection (PHI); four untreated groups defined by their blood CD4+ T lymphocyte counts; untreated patients presenting with subacute HIV-associated dementia (HAD); antiretroviral-treated subjects with ≥1 years of plasma viral suppression; and untreated elite controllers. Twenty HIV-1-uninfected controls were included for comparison. Background biomarkers included blood CD4+ and CD8+ T lymphocytes, CSF and blood HIV-1 RNA, CSF white blood cell (WBC) count, CSF/blood albumin ratio, CSF neurofilament light chain (NfL), and CSF t-tau. FINDINGS HIV-1 infection was associated with a broad compartmentalized CSF inflammatory response that developed early in its course and changed with systemic disease progression, development of neurological injury, and viral suppression. CSF inflammation in untreated individuals without overt HAD exhibited at least two overall patterns of inflammation as blood CD4+ T lymphocytes decreased: one that peaked at 200-350 blood CD4+ T cells/μL and associated with lymphocytic CSF inflammation and HIV-1 RNA concentrations; and a second that steadily increased through the full range of CD4+ T cell decline and associated with macrophage responses and increasing CNS injury. Subacute HAD was distinguished by a third inflammatory profile with increased blood-brain barrier permeability and robust combined lymphocytic and macrophage CSF inflammation. Suppression of CSF and blood HIV-1 infections by antiretroviral treatment and elite viral control were associated with reduced CSF inflammation, though not fully to levels found in HIV-1 seronegative controls.
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Affiliation(s)
- Magnus Gisslen
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Sheila M. Keating
- Vitalant Research Institute (formerly Blood Systems Research Institute), San Francisco, CA, United States of America
| | - Serena Spudich
- Department of Neurology, Yale University School of Medicine, New Haven, CT, United States of America
| | - Victor Arechiga
- Department of Neurology, University of California San Francisco, San Francisco, CA, United States of America
| | - Sophie Stephenson
- Department of Neurology, University of California San Francisco, San Francisco, CA, United States of America
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
- UK Dementia Research Institute at UCL, London, United Kingdom
| | - Clara Di Germanio
- Vitalant Research Institute (formerly Blood Systems Research Institute), San Francisco, CA, United States of America
| | - Kaj Blennow
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Dietmar Fuchs
- Institute of Biological Chemistry, Innsbruck Medical University, Innsbruck, Austria
| | - Lars Hagberg
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Philip J. Norris
- Vitalant Research Institute (formerly Blood Systems Research Institute), San Francisco, CA, United States of America
| | - Julia Peterson
- Department of Neurology, University of California San Francisco, San Francisco, CA, United States of America
| | - Barbara L. Shacklett
- Department of Medical Microbiology and Immunology, University of California Davis, Davis CA, United States of America
| | - Constantin T. Yiannoutsos
- Department of Biostatistics, Indiana University R.M. Fairbanks School of Public Health, Indianapolis, IN, United States of America
| | - Richard W. Price
- Department of Neurology, University of California San Francisco, San Francisco, CA, United States of America
- * E-mail:
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24
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Knudsen AD, Krebs-Demmer L, Bjørge NID, Elming MB, Gelpi M, Sigvardsen PE, Lebech AM, Fuchs A, Kühl JT, Køber L, Lundgren J, Nordestgaard BG, Kofoed KF, Nielsen SD. Pericardial Adipose Tissue Volume Is Independently Associated With Human Immunodeficiency Virus Status and Prior Use of Stavudine, Didanosine, or Indinavir. J Infect Dis 2021; 222:54-61. [PMID: 32027374 DOI: 10.1093/infdis/jiaa057] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 02/04/2020] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Increased pericardial adipose tissue is associated with higher risk of cardiovascular disease. We aimed to determine whether human immunodeficiency virus (HIV) status was independently associated with larger pericardial adipose tissue volume and to explore possible HIV-specific risk factors. METHODS Persons with HIV (PWH) were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study and matched 1:1 on age and sex to uninfected controls. Pericardial adipose tissue volume was measured using cardiac computed tomography. RESULTS A total of 587 PWH and 587 controls were included. Median age was 52 years, and 88% were male. Human immunodeficiency virus status was independently associated with 17 mL (95% confidence interval [CI], 10-23; P < .001) larger pericardial adipose tissue volume. Larger pericardial adipose tissue volume was associated with low CD4+ nadir and prior use of stavudine, didanosine, and indinavir. Among PWH without thymidine analogue or didanosine exposure, time since initiating combination antiretroviral treatment (per 5-year use) was associated with l6 mL (95% CI, -6 to -25; P = .002) lower pericardial adipose tissue volume. CONCLUSIONS Human immunodeficiency virus status was independently associated with larger pericardial adipose tissue volume. Severe immunodeficiency, stavudine, didanosine, and indinavir were associated with larger pericardial adipose tissue volume. Persons with HIV with prior exposure to these drugs may constitute a distinct cardiovascular risk population.
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Affiliation(s)
- Andreas D Knudsen
- Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.,Department of Cardiology, The Heart Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Lisanne Krebs-Demmer
- Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Natascha I D Bjørge
- Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Marie B Elming
- Department of Cardiology, The Heart Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Marco Gelpi
- Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Per E Sigvardsen
- Department of Cardiology, The Heart Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Anne-Mette Lebech
- Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Andreas Fuchs
- Department of Cardiology, The Heart Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jørgen T Kühl
- Department of Cardiology, The Heart Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Lars Køber
- Department of Cardiology, The Heart Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jens Lundgren
- CHIP Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Børge G Nordestgaard
- The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Klaus F Kofoed
- Department of Cardiology, The Heart Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.,Department of Radiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Susanne D Nielsen
- Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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25
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van Welzen BJ, Oomen PGA, Hoepelman AIM. Dual Antiretroviral Therapy-All Quiet Beneath the Surface? Front Immunol 2021; 12:637910. [PMID: 33643320 PMCID: PMC7906996 DOI: 10.3389/fimmu.2021.637910] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/22/2021] [Indexed: 11/13/2022] Open
Abstract
Infection with the human immunodeficiency virus (HIV) is characterized by progressive depletion of CD4+ lymphocytes cells as a result of chronic immune activation. Next to the decreases in the number of CD4+ cells which leads to opportunistic infections, HIV-related immune activation is associated with several prevalent comorbidities in the HIV-positive population such as cardiovascular and bone disease. Traditionally, combination antiretroviral therapy (cART) consists of three drugs with activity against HIV and is highly effective in diminishing the degree of immune activation. Over the years, questions were raised whether virological suppression could also be achieved with fewer antiretroviral drugs, i.e., dual- or even monotherapy. This is an intriguing question considering the fact that antiretroviral drugs should be used lifelong and their use could also induce cardiovascular and bone disease. Therefore, the equilibrium between drug-induced toxicity and immune activation related comorbidity is delicate. Recently, two large clinical trials evaluating two-drug cART showed non-inferiority with respect to virological outcomes when compared to triple-drug regimens. This led to adoption of dual antiretroviral therapy in current HIV treatment guidelines. However, it is largely unknown whether dual therapy is also able to suppress immune activation to the same degree as triple therapy. This poses a risk for an imbalance in the delicate equilibrium. This mini review gives an overview of the current available evidence concerning immune activation in the setting of cART with less than three antiretroviral drugs.
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Affiliation(s)
- Berend J van Welzen
- Department of Internal Medicine and Infectious Diseases, University Medical Centre Utrecht, Utrecht, Netherlands
| | - Patrick G A Oomen
- Department of Internal Medicine and Infectious Diseases, University Medical Centre Utrecht, Utrecht, Netherlands
| | - Andy I M Hoepelman
- Department of Internal Medicine and Infectious Diseases, University Medical Centre Utrecht, Utrecht, Netherlands
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26
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Hoenigl M, Little SJ. Salvage Antiretroviral Therapy: Time for "DeNUKElearization"? J Infect Dis 2021; 221:1390-1393. [PMID: 31136663 DOI: 10.1093/infdis/jiz283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 05/24/2019] [Indexed: 01/08/2023] Open
Affiliation(s)
- Martin Hoenigl
- Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego
| | - Susan J Little
- Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego
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27
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Tindle HA, Freiberg MS, Gnatienko N, Blokhina E, Cheng DM, Yaroslavtseva T, Bendiks S, Winter M, Krupitsky E, Samet JH. Design of a randomized controlled trial of smoking cessation medications for alcohol reduction among HIV-positive heavy drinkers and daily smokers in St. Petersburg, Russia. Contemp Clin Trials Commun 2020; 19:100625. [PMID: 33659761 PMCID: PMC7889999 DOI: 10.1016/j.conctc.2020.100625] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 07/08/2020] [Accepted: 07/13/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND HIV, heavy drinking, and smoking are all pro-inflammatory and increase risk for coronary heart disease (CHD). Interventions that reduce alcohol use, smoking, or both in HIV-positive people could lower inflammation, CHD and death risk. Varenicline and cytisine are proven therapies for smoking cessation and may also reduce alcohol consumption. The comparative efficacy of varenicline and cytisine to reduce alcohol consumption has not been tested, nor has their comparative effectiveness been reported for smoking. OBJECTIVE This paper describes the protocol of the Studying Partial agonists for Ethanol and Tobacco Elimination in Russians with HIV (St PETER HIV), a four-arm parallel-group randomized controlled trial comparing effects of varenicline, cytisine, and nicotine replacement therapy (NRT). METHODS The study is recruiting four hundred HIV-positive heavy drinking smokers interested in cutting down on alcohol and/or tobacco in St. Petersburg, Russia. Participants are randomly assigned to receive either active varenicline + NRT placebo, varenicline placebo + active NRT, active cytisine + NRT placebo, cytisine placebo + active NRT. All participants receive evidence-based counseling for alcohol and tobacco use, one active medication, and one placebo. Outcomes are: 1) % heavy drinking days in the past month (primary study outcome at three months) and alcohol craving; 2) cigarettes per day (primary smoking outcome at 3 months) and 7-day point prevalence abstinence and; 3) inflammation, CHD risk, and mortality risk. CONCLUSION St PETER HIV addresses the paucity of randomized controlled trial data to guide treatment of alcohol consumption and smoking in HIV-positive heavy drinking smokers.
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Affiliation(s)
- Hilary A. Tindle
- Vanderbilt Center for Tobacco, Addiction and Lifestyle (ViTAL), Vanderbilt University Medical Center, Division of General Internal Medicine & Public Health and Vanderbilt Ingram Cancer Center, 2525 West End, Suite 450, Nashville, TN, 37203, United States
- Veterans Health Administration-Tennessee Valley Healthcare System Geriatric Research Education Clinical Center (GRECC), Nashville, TN, United States
| | - Matthew S. Freiberg
- Veterans Health Administration-Tennessee Valley Healthcare System Geriatric Research Education Clinical Center (GRECC), Nashville, TN, United States
- Vanderbilt Center for Clinical Cardiovascular Trials Evaluation (V-C3REATE), Vanderbilt University Medical Center, Division of Cardiovascular Medicine, 2525 West End, Suite 300-A, Nashville, TN, 37203, United States
| | - Natalia Gnatienko
- Department of Medicine, Section of General Internal Medicine, Boston Medical Center, Clinical Addiction Research and Education (CARE) Unit, 801 Massachusetts Avenue, 2nd Floor, Boston, MA, 02118, United States
| | - Elena Blokhina
- Pavlov University, Lev Tolstoy St. 6-8, St. Petersburg, 197022, Russian Federation
| | - Debbie M. Cheng
- Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, 3rd Floor, Boston, MA, 02118, United States
| | | | - Sally Bendiks
- Department of Medicine, Section of General Internal Medicine, Boston Medical Center, Clinical Addiction Research and Education (CARE) Unit, 801 Massachusetts Avenue, 2nd Floor, Boston, MA, 02118, United States
| | - Michael Winter
- Biostatistics and Epidemiology Data Analytics Center (BEDAC), Boston University School of Public Health, 85 East Newton Street, 9th Floor, Boston, MA 02118, United States Pasteur Research Institute of Epidemiology and Microbiology, Russian Federation, Mira St. 14, St. Petersburg, 197101, Russian Federation
| | - Evgeny Krupitsky
- Pavlov University, Lev Tolstoy St. 6-8, St. Petersburg, 197022, Russian Federation
- Bekhterev National Medical Research Center for Psychiatry and Neurology, Bekhtereva St., 3, St. Petersburg, 192019, Russian Federation
| | - Jeffrey H. Samet
- Department of Medicine, Section of General Internal Medicine, Boston University School of Medicine/Boston Medical Center, Clinical Addiction Research and Education (CARE) Unit, 801 Massachusetts Avenue, 2nd Floor, Boston, MA, 02118, United States
- Department of Community Health Sciences, Boston University School of Public Health, 801 Massachusetts Avenue, 2nd Floor, Boston, MA, 02118, United States
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Teasdale CA, Hernandez C, Zerbe A, Chege D, Hawken M, El-Sadr WM. Changes in D-dimer after initiation of antiretroviral therapy in adults living with HIV in Kenya. BMC Infect Dis 2020; 20:508. [PMID: 32664854 PMCID: PMC7362533 DOI: 10.1186/s12879-020-05213-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/30/2020] [Indexed: 12/15/2022] Open
Abstract
Background Increased coagulation biomarkers are associated with poor outcomes among people living with HIV (PLHIV). There are few data available from African cohorts demonstrating the effect of antiretroviral therapy (ART) on coagulation biomarkers. Methods From March 2014 to October 2014, ART-naïve PLHIV initiating non-nucleoside reverse transcriptase inhibitor-based ART were recruited from seven clinics in western Kenya and followed for up to 12 months. Demographics, clinical history and blood specimens were collected. Logistic regression models adjusted for intrasite clustering examined associations between HIV viral load and D-Dimer at baseline. Mixed linear effects models were used to estimate mean change from baseline to 6 months overall, and by baseline viral load, sex and TB status at enrollment. Mean change in D-dimer at 6 months is reported on the log10 scale and as percentage change from baseline. Results Among 611 PLHIV enrolled, 66% were female, median age was 34 years (interquartile range (IQR) 29–43 years), 31 (5%) participants had tuberculosis and median viral load was 113,500 copies/mL (IQR: 23,600-399,000). At baseline, 311 (50.9%) PLHIV had elevated D-dimer (> 500 ng/mL) and median D-dimer was 516.4 ng/mL (IQR: 302.7–926.6) (log baseline D-dimer: 2.7, IQR: 2.5–3.0). Higher baseline D-dimer was significantly associated with higher viral load (p < 0.0001), female sex (p = 0.02) and tuberculosis (p = 0.02). After 6 months on ART, 518 (84.8%) PLHIV had achieved viral load < 1000 copies/mL and median D-dimer was 390.0 (IQR: 236.6–656.9) (log D-dimer: 2.6, IQR: 2.4–2.8). Mean change in log D-dimer from baseline to 6 months was − 0.12 (95%CI −0.15, − 0.09) (p < 0.0001) indicating at 31.3% decline (95%CI −40.0, − 23.0) in D-dimer levels over the first 6 months on ART. D-dimer decline after ART initiation was significantly greater among PLHIV with tuberculosis at treatment initiation (− 172.1, 95%CI −259.0, − 106.3; p < 0.0001) and those with log viral load > 6.0 copies/mL (− 91.1, 95%CI −136.7, − 54.2; p < 0.01). Conclusions In this large Kenyan cohort of PLHIV, women, those with tuberculosis and higher viral load had elevated baseline D-dimer. ART initiation and viral load suppression among ART-naïve PLHIV in Kenya were associated with significant decrease in D-dimer at 6 months in this large African cohort.
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Affiliation(s)
- Chloe A Teasdale
- Department of Epidemiology and Biostatistics, CUNY Graduate School of Public Health and Health Policy, 55 W125th Street, Room 543, New York, NY, 10027, USA. .,ICAP at Columbia University, Mailman School of Public Health, Columbia University, 22 W168th Street, New York, NY, 10032, USA. .,Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 W168th Street, New York, NY, 10032, USA.
| | - Cecilia Hernandez
- ICAP at Columbia University, Mailman School of Public Health, Columbia University, 22 W168th Street, New York, NY, 10032, USA
| | - Allison Zerbe
- ICAP at Columbia University, Mailman School of Public Health, Columbia University, 22 W168th Street, New York, NY, 10032, USA
| | - Duncan Chege
- ICAP at Columbia University, Mailman School of Public Health, Columbia University, 22 W168th Street, New York, NY, 10032, USA
| | - Mark Hawken
- ICAP at Columbia University, Mailman School of Public Health, Columbia University, 22 W168th Street, New York, NY, 10032, USA
| | - Wafaa M El-Sadr
- ICAP at Columbia University, Mailman School of Public Health, Columbia University, 22 W168th Street, New York, NY, 10032, USA.,Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 W168th Street, New York, NY, 10032, USA
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29
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Pryzdial ELG, Sutherland MR, Lin BH, Horwitz M. Antiviral anticoagulation. Res Pract Thromb Haemost 2020; 4:774-788. [PMID: 32685886 PMCID: PMC7354393 DOI: 10.1002/rth2.12406] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 05/28/2020] [Accepted: 06/08/2020] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel envelope virus that causes coronavirus disease 2019 (COVID-19). Hallmarks of COVID-19 are a puzzling form of thrombophilia that has elevated D-dimer but only modest effects on other parameters of coagulopathy. This is combined with severe inflammation, often leading to acute respiratory distress and possible lethality. Coagulopathy and inflammation are interconnected by the transmembrane receptor, tissue factor (TF), which initiates blood clotting as a cofactor for factor VIIa (FVIIa)-mediated factor Xa (FXa) generation. TF also functions from within the nascent TF/FVIIa/FXa complex to trigger profound changes via protease-activated receptors (PARs) in many cell types, including SARS-CoV-2-trophic cells. Therefore, aberrant expression of TF may be the underlying basis of COVID-19 symptoms. Evidence suggests a correlation between infection with many virus types and development of clotting-related symptoms, ranging from heart disease to bleeding, depending on the virus. Since numerous cell types express TF and can act as sites for virus replication, a model envelope virus, herpes simplex virus type 1 (HSV1), has been used to investigate the uptake of TF into the envelope. Indeed, HSV1 and other viruses harbor surface TF antigen, which retains clotting and PAR signaling function. Strikingly, envelope TF is essential for HSV1 infection in mice, and the FXa-directed oral anticoagulant apixaban had remarkable antiviral efficacy. SARS-CoV-2 replicates in TF-bearing epithelial and endothelial cells and may stimulate and integrate host cell TF, like HSV1 and other known coagulopathic viruses. Combined with this possibility, the features of COVID-19 suggest that it is a TFopathy, and the TF/FVIIa/FXa complex is a feasible therapeutic target.
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Affiliation(s)
- Edward L. G. Pryzdial
- Center for InnovationCanadian Blood ServicesVancouverBCCanada
- Centre for Blood Research and Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverBCCanada
| | - Michael R. Sutherland
- Center for InnovationCanadian Blood ServicesVancouverBCCanada
- Centre for Blood Research and Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverBCCanada
| | - Bryan H. Lin
- Center for InnovationCanadian Blood ServicesVancouverBCCanada
- Centre for Blood Research and Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverBCCanada
| | - Marc Horwitz
- Department of Microbiology and ImmunologyUniversity of British ColumbiaVancouverBCCanada
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30
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Mocumbi AO, Dobe I, Cândido S, Kim N. Cardiovascular risk and D-dimer levels in HIV-infected ART-naïve Africans. Cardiovasc Diagn Ther 2020; 10:526-533. [PMID: 32695632 PMCID: PMC7369281 DOI: 10.21037/cdt.2019.12.02] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 08/14/2019] [Indexed: 11/06/2022]
Abstract
Anti-retroviral therapy (ART) has decreased morbidity and mortality in HIV-infected individuals. With the adoption of the 90-90-90 strategy prevention and control of non-communicable disease, particularly knowledge of the burden and profile of cardiovascular disease, will become increasingly important. Our study assessed cardiovascular risk among recently diagnosed HIV-infected ART-naïve patients in a first referral urban hospital in a low-income country in sub-Saharan Africa. HIV-positive ART-naïve patients were submitted to cardiovascular risk assessment, clinical history, physical examination and laboratory workout, including 12-lead electrocardiography, portable transthoracic echocardiography, glycemia, lipidemia, hemogram and D-dimers. Three years after the diagnosis their vital status and occurrence of major cardiovascular events was assessed. We recruited 70 patients, all of black ethnicity (41 females; mean age 37±10.7). CD4 levels were very low (mean 21.3 cells/mL; SD 10.4). Twenty-one (26.6%) were overweight, 13 (16.7%) were obese, 19 (20.5%) had hyperglycemia and 20 patients (25.6%) had hypercholesterolemia. The median blood pressure was 119.5/79 mmHg (IQR 107-141/67-83); 20 patients (25.6%) had hypertension. Four (5.7%) patients had signs of heart failure, and left ventricular ejection fraction was reduced in 17 (25%). High levels of circulating D-dimers were found in 44 (62.8%) patients; the mean levels were 725.9 (SD 555.1). We found high occurrence of cardiovascular risk factors, left ventricular dysfunction and evidence of a pro-coagulant state in these HIV-infected ART-naïve patients. Active cardiovascular risk screening and stratification, as well as management protocols tailored to low-income settings are needed to sustain the gains obtained with increased availability of ART in Africa.
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Affiliation(s)
- Ana Olga Mocumbi
- Universidade Eduardo Mondlane, Faculdade de Medicina, Maputo, Moçambique
- Instituto Nacional de Saúde, Maputo, Moçambique
| | - Igor Dobe
- Instituto Nacional de Saúde, Maputo, Moçambique
| | | | - Nick Kim
- University of California San Diego, La Jolla, CA, USA
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31
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Siedner MJ, Bwana MB, Asiimwe S, Amanyire G, Musinguzi N, Castillo-Mancilla J, Tracy RP, Katz IT, Bangsberg DR, Hunt PW, Orrell C, Haberer JE. Timing of Antiretroviral Therapy and Systemic Inflammation in Sub-Saharan Africa: Results From the META Longitudinal Cohort Study. J Infect Dis 2020; 220:1172-1177. [PMID: 31188451 PMCID: PMC6736121 DOI: 10.1093/infdis/jiz259] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/16/2019] [Indexed: 11/14/2022] Open
Abstract
Chronic inflammation predicts complications in persons with human immunodeficiency virus infection. We compared D-dimer, soluble CD14, and interleukin 6 levels before and 12 months after antiretroviral therapy (ART) initiation, among individuals starting ART during earlier-stage (CD4 T-cell count >350/µL) or late-stage disease (CD4 T-cell count <200/µL). Female sex, older age, viral load, and late-stage disease were associated with pre-ART biomarkers (n = 661; P < .05). However, there were no differences in biomarkers by disease stage after 12 months of ART (n = 438; P > .05), owing to loss from observation and greater declines in biomarkers in late-stage initiators (P < .001). Earlier initiation of ART is associated with decreased inflammation, but levels seem to converge between earlier and later initiators surviving to 12 months.
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Affiliation(s)
- Mark J Siedner
- Harvard Medical School, Boston.,Massachusetts General Hospital, Boston.,Mbarara University of Science and Technology, Uganda.,Africa Health Research Institute, Kwa-Zulu Natal, South Africa
| | | | - Stephen Asiimwe
- Mbarara University of Science and Technology, Uganda.,Kabwohe Clinical Research Center, Uganda
| | | | | | | | | | - Ingrid T Katz
- Harvard Medical School, Boston.,Brigham and Women's Hospital, Boston
| | - David R Bangsberg
- Oregon Health & Science University-Portland State University School of Public Health, Portland
| | | | | | - Jessica E Haberer
- Harvard Medical School, Boston.,Massachusetts General Hospital, Boston
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Abstract
PURPOSE OF REVIEW This article describes the use of biomarkers in expanding our understanding of chronic non-AIDS comorbidities among persons living with HIV (PLWH) receiving antiretroviral therapy (ART). RECENT FINDINGS We review current evidence that biomarkers of chronic immune activation and inflammation associate with a broad spectrum of end-organ diseases in PLWH. We discuss how ART may impact inflammation associated with HIV infection and the degree to which inflammation persists despite effective suppression of viral replication in plasma. We then discuss the limitations of the current literature, which lacks evidence of causality and disproportionately involves a few protein biomarkers that are unable to disentangle complex and overlapping biological pathways. SUMMARY Premature end-organ disease among PLWH has been repeatedly associated with higher levels of blood biomarkers reflecting inflammation and immune activation, which, despite viral suppression and CD4 T-cell increases after ART treatment, remain elevated relative to uninfected persons. There remain important unanswered questions with implications for the development of anti-inflammatory treatment strategies aimed at mitigating excess risk for end-organ comorbidities among PLWH.
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Goedel A, Müller S, Schwerdtfeger C, Zink A, Noe S, Bongiovanni D, Haller B, Spinner CD, Bernlochner I. Influence of antiretroviral therapy and cardiovascular disease on the immature platelet fraction in patients living with HIV. Platelets 2019; 31:756-762. [PMID: 31608753 DOI: 10.1080/09537104.2019.1678114] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Cardiovascular disease is an important contributor to morbidity and mortality in people living with HIV . The immature platelet fraction (IPF) is increased in HIV-negative patients with cardiovascular disease and evidence suggests that an enlarged IPF is associated with adverse cardiovascular events. In this multi-center observational study, we aimed to investigate how the IPF in people living with HIV is influenced by antiretroviral therapy and cardiovascular disease. Subjects without cardiovascular disease that received antiretroviral therapy showed a smaller IPF accompanied by lower D-dimer and C-reactive protein (CRP) levels compared to therapy-naïve subjects (mean IPF: 2.9% vs. 3.9%, p = .016; median D-dimer: 252 µg/L vs. 623 µg/L, p < .001; median CRP: 0.2 mg/dL vs. 0.5 mg/dL, p = .004). No significant differences for the IPF, D-dimer or CRP were found between subjects on antiretroviral therapy with documented cardiovascular disease and therapy-naïve subjects. In conclusion, we observed a reduction in the IPF among subjects on therapy only in the absence of cardiovascular disease. In contrast, subjects receiving therapy that had documented cardiovascular disease showed an IPF comparable to therapy-naïve subjects. Future studies are needed to investigate if an enlarged IPF may serve as a biomarker in predicting adverse cardiovascular events in people living with HIV.
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Affiliation(s)
- A Goedel
- Department of Medicine I, Technical University of Munich, School of Medicine, University Hospital Klinikum rechts der Isar , Munich, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance , Munich, Germany
| | - S Müller
- Department of Medicine II, Technical University of Munich, School of Medicine, University Hospital Klinikum rechts der Isar , Munich, Germany
| | - C Schwerdtfeger
- Department of Medicine II, Technical University of Munich, School of Medicine, University Hospital Klinikum rechts der Isar , Munich, Germany.,DZIF (German Center for Infection Research), partner site Munich , Munich, Germany
| | - A Zink
- Department of Dermatology and Allergology, Technical University of Munich, School of Medicine, University Hospital Klinikum rechts der Isar , Munich, Germany
| | - S Noe
- Medizinisches Versorgungszentrum am Karlsplatz, HIV Clinical Care and Research Center , Munich, Germany
| | - D Bongiovanni
- Department of Medicine I, Technical University of Munich, School of Medicine, University Hospital Klinikum rechts der Isar , Munich, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance , Munich, Germany
| | - B Haller
- School of Medicine, Institute for Medical Informatics, Statistics and Epidemiology, Technical University of Munich , Munich, Germany
| | - C D Spinner
- Department of Medicine II, Technical University of Munich, School of Medicine, University Hospital Klinikum rechts der Isar , Munich, Germany.,DZIF (German Center for Infection Research), partner site Munich , Munich, Germany
| | - I Bernlochner
- Department of Medicine I, Technical University of Munich, School of Medicine, University Hospital Klinikum rechts der Isar , Munich, Germany
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Perdomo-Celis F, Taborda NA, Rugeles MT. CD8 + T-Cell Response to HIV Infection in the Era of Antiretroviral Therapy. Front Immunol 2019; 10:1896. [PMID: 31447862 PMCID: PMC6697065 DOI: 10.3389/fimmu.2019.01896] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 07/26/2019] [Indexed: 12/21/2022] Open
Abstract
Although the combined antiretroviral therapy (cART) has decreased the deaths associated with the immune deficiency acquired syndrome (AIDS), non-AIDS conditions have emerged as an important cause of morbidity and mortality in HIV-infected patients under suppressive cART. Since these conditions are associated with a persistent inflammatory and immune activation state, major efforts are currently made to improve the immune reconstitution. CD8+ T-cells are critical in the natural and cART-induced control of viral replication; however, CD8+ T-cells are highly affected by the persistent immune activation and exhaustion state driven by the increased antigenic and inflammatory burden during HIV infection, inducing phenotypic and functional alterations, and hampering their antiviral response. Several CD8+ T-cell subsets, such as interleukin-17-producing and follicular CXCR5+ CD8+ T-cells, could play a particular role during HIV infection by promoting the gut barrier integrity, and exerting viral control in lymphoid follicles, respectively. Here, we discuss the role of CD8+ T-cells and some of their subpopulations during HIV infection in the context of cART-induced viral suppression, focusing on current challenges and alternatives for reaching complete reconstitution of CD8+ T-cells antiviral function. We also address the potential usefulness of CD8+ T-cell features to identify patients who will reach immune reconstitution or have a higher risk for developing non-AIDS conditions. Finally, we examine the therapeutic potential of CD8+ T-cells for HIV cure strategies.
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Affiliation(s)
- Federico Perdomo-Celis
- Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
| | - Natalia A Taborda
- Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia.,Grupo de Investigaciones Biomédicas Uniremington, Programa de Medicina, Facultad de Ciencias de la Salud, Corporación Universitaria Remington, Medellin, Colombia
| | - Maria T Rugeles
- Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
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Hoenigl M, Moser CB, Funderburg N, Bosch R, Kantor A, Zhang Y, Eugen-Olsen J, Finkelman M, Reiser J, Landay A, Moisi D, Lederman MM, Gianella S, Adult Clinical Trials Group NWCS 411 study team. Soluble Urokinase Plasminogen Activator Receptor Is Predictive of Non-AIDS Events During Antiretroviral Therapy-mediated Viral Suppression. Clin Infect Dis 2019; 69:676-686. [PMID: 30418519 PMCID: PMC6669298 DOI: 10.1093/cid/ciy966] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 11/08/2018] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Despite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection remains associated with higher morbidity and mortality, driven, in part, by increased inflammation. Our objective was to identify associations between levels of plasma biomarkers of chronic inflammation, microbial translocation, and monocyte activation, with occurrence of non-AIDS events. METHODS Participants (141 cases, 310 matched controls) were selected from a longitudinal observational trial; all were virally suppressed on ART at year 1 and thereafter. Soluble urokinase plasminogen activator receptor (suPAR), lipopolysaccharide binding protein (LBP), beta-D-glucan (BDG), intestinal fatty-acid binding protein, oxidized low-density lipoproteins, and soluble CD163 were measured pre-ART, after 1-year of ART, and pre-event. At each time point, conditional logistic regression analysis assessed associations of the biomarkers with events and adjusted for relevant covariates to calculate odds ratios (ORs) according to 1 interquartile range (IQR) difference. RESULTS At all time points, higher levels of suPAR were associated with increased risk of non-AIDS events (OR per 1 IQR was 1.7 before ART-initiation, OR per 1 IQR was 2.0 after 1 year of suppressive ART, and OR 2.1 pre-event). Higher levels of BDG and LBP at year 1 and pre-event (but not at baseline) were associated with increased risk of non-AIDS events. No associations were observed for other biomarkers. CONCLUSIONS Elevated levels of suPAR were strongly, consistently, and independently predictive of non-AIDS events at every measured time point. Interventions that target the suPAR pathway should be investigated to explore its role in the pathogenesis of non-AIDS-related outcomes in HIV infection.
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Affiliation(s)
- Martin Hoenigl
- Division of Infectious Diseases, Department of Medicine, University of California San Diego, Austria
- Section of Infectious Diseases and Tropical Medicine, Medical University of Graz, Austria
- Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Carlee B Moser
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Nicholas Funderburg
- Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, The Ohio State University, Columbus
| | - Ronald Bosch
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Amy Kantor
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | | | - Jesper Eugen-Olsen
- Clinical Research Centre, Copenhagen University Hospital Hvidovre, Denmark
| | | | - Jochen Reiser
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| | - Alan Landay
- Division of Geriatrics and Palliative Care, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| | - Daniela Moisi
- Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Michael M Lederman
- Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Sara Gianella
- Division of Infectious Diseases, Department of Medicine, University of California San Diego, Austria
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Feinstein MJ, Hsue PY, Benjamin L, Bloomfield GS, Currier JS, Freiberg MS, Grinspoon SK, Levin J, Longenecker CT, Post. WS. Characteristics, Prevention, and Management of Cardiovascular Disease in People Living With HIV: A Scientific Statement From the American Heart Association. Circulation 2019; 140:e98-e124. [PMID: 31154814 PMCID: PMC7993364 DOI: 10.1161/cir.0000000000000695] [Citation(s) in RCA: 428] [Impact Index Per Article: 71.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
As early and effective antiretroviral therapy has become more widespread, HIV has transitioned from a progressive, fatal disease to a chronic, manageable disease marked by elevated risk of chronic comorbid diseases, including cardiovascular diseases (CVDs). Rates of myocardial infarction, heart failure, stroke, and other CVD manifestations, including pulmonary hypertension and sudden cardiac death, are significantly higher for people living with HIV than for uninfected control subjects, even in the setting of HIV viral suppression with effective antiretroviral therapy. These elevated risks generally persist after demographic and clinical risk factors are accounted for and may be partly attributed to chronic inflammation and immune dysregulation. Data on long-term CVD outcomes in HIV are limited by the relatively recent epidemiological transition of HIV to a chronic disease. Therefore, our understanding of CVD pathogenesis, prevention, and treatment in HIV relies on large observational studies, randomized controlled trials of HIV therapies that are underpowered to detect CVD end points, and small interventional studies examining surrogate CVD end points. The purpose of this document is to provide a thorough review of the existing evidence on HIV-associated CVD, in particular atherosclerotic CVD (including myocardial infarction and stroke) and heart failure, as well as pragmatic recommendations on how to approach CVD prevention and treatment in HIV in the absence of large-scale randomized controlled trial data. This statement is intended for clinicians caring for people with HIV, individuals living with HIV, and clinical and translational researchers interested in HIV-associated CVD.
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Affiliation(s)
| | - Priscilla Y. Hsue
- University of California-San Francisco School of Medicine, San Francisco, CA
| | | | | | - Judith S. Currier
- University of California-Los Angeles School of Medicine, Los Angeles, CA
| | | | | | - Jules Levin
- National AIDS Treatment Advocacy Program, New York, NY
| | | | - Wendy S. Post.
- Johns Hopkins University School of Medicine, Baltimore, MD
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Lundgren JD, Borges AH, Neaton JD. Serious Non-AIDS Conditions in HIV: Benefit of Early ART. Curr HIV/AIDS Rep 2019; 15:162-171. [PMID: 29504063 DOI: 10.1007/s11904-018-0387-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Optimal control of HIV can be achieved by early diagnosis followed by the initiation of antiretroviral therapy (ART). Two large randomised trials (TEMPRANO and START) have recently been published documenting the clinical benefits to HIV-positive adults of early ART initiation. Main findings are reviewed with a focus on serious non-AIDS (SNA) conditions. RECENT FINDINGS Data from the two trials demonstrated that initiating ART early in the course of HIV infection resulted in marked reductions in the risk of opportunistic diseases and invasive bacterial infections. This indicates that HIV causes immune impairment in early infection that is remedied by controlling viral replication. Intriguingly, in START, a marked reduction in risk of cancers, both infection-related and unrelated types of cancers, was observed. Like the findings for opportunistic infections, this anti-cancer effect of early ART shows how the immune system influences important pro-oncogenic processes. In START, there was also some evidence suggesting that early ART initiation preserved kidney function, although the clinical consequence of this remains unclear. Conversely, while no adverse effects were evident, the trials did not demonstrate a clear effect on metabolic-related disease outcomes, pulmonary disease, or neurocognitive function. HIV causes immune impairment soon after acquisition of infection. ART reverses this harm at least partially. The biological nature of the immune impairment needs further elucidation, as well as mechanisms and clinical impact of innate immune activation. Based on the findings from TEMPRANO and START, and because ART lowers the risk of onward transmission, ART initiation should be offered to all persons following their diagnosis of HIV.
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Affiliation(s)
- Jens D Lundgren
- Centre of Excellence for Health, Immunity and Infections (CHIP), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Esther Møllers Vej 6, 2100, Copenhagen Ø, Denmark.
| | - Alvaro H Borges
- Centre of Excellence for Health, Immunity and Infections (CHIP), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Esther Møllers Vej 6, 2100, Copenhagen Ø, Denmark
| | - James D Neaton
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA
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38
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Lau JS, Smith MZ, Lewin SR, McMahon JH. Clinical trials of antiretroviral treatment interruption in HIV-infected individuals. AIDS 2019; 33:773-791. [PMID: 30883388 DOI: 10.1097/qad.0000000000002113] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
: Despite the benefits of antiretroviral therapy (ART) for people living with HIV, there has been a long-standing research interest in interrupting ART as a strategy to minimize adverse effects of ART as well as to test interventions aiming to achieve a degree of virological control without ART. We performed a systematic review of HIV clinical studies involving treatment interruption from 2000 to 2017 to describe the differences between treatment interruption in studies that contained and didn't contain an intervention. We assessed differences in monitoring strategies, threshold to restart ART, duration and adverse outcomes of treatment interruption, and factors aimed at minimizing transmission. We found that treatment interruption has been incorporated into 159 clinical studies since 2000 and is increasingly being included in trials to assess the efficacy of interventions to achieve sustained virological remission off ART. Great heterogeneity was noted in immunological, virological and clinical monitoring strategies, as well as in thresholds to recommence ART. Treatment interruption in recent intervention studies were more closely monitored, had more conservative thresholds to restart ART and had a shorter treatment interruption duration, compared with older treatment interruption studies that didn't include an intervention.
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Vorapaxar for HIV-associated inflammation and coagulopathy (ADVICE): a randomised, double-blind, placebo-controlled trial. Lancet HIV 2018; 5:e553-e559. [PMID: 30257802 PMCID: PMC6237199 DOI: 10.1016/s2352-3018(18)30214-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/08/2018] [Accepted: 08/10/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Increased D-dimer concentrations are associated with poor cardiovascular and other clinical outcomes in people with treated HIV infection. Proteinase activated receptor-1 (PAR-1) is activated by thrombin and overexpressed by immune cells from HIV-infected people. We aimed to study the efficacy of vorapaxar, a licensed inhibitor of PAR-1, in reducing HIV-associated hypercoagulation and inflammation. METHODS This was a multicentre, double-blind, randomised, placebo-controlled trial done in seven hospital clinics in Australia and the USA. Eligible participants were HIV-infected, aviraemic, were receiving stable antiretroviral therapy, and had D-dimer concentrations greater than 200 ng/mL. We randomly assigned participants (1:1) using computer-generated block lists of size two to receive vorapaxar (2·5 mg orally daily) or matched placebo for 12 weeks. Participants were reviewed and had a blood sample taken at weeks 1, 4, 8, and 12 during treatment, and at a final visit at week 18. The primary endpoint was treatment group difference in changes from baseline D-dimer concentrations after 8-12 weeks of treatment, and was assessed in the modified intention-to-treat population (participants who had at least one dose of study drug or one follow-up visit). This trial is registered with ClinicalTrials.gov, number NCT02394730, and is closed to new participants. FINDINGS Between Oct 21, 2015, and July 14, 2017, 65 eligible patients were randomly assigned to the placebo group (n=31) or vorapaxar group (n=34). One patient from the vorapaxar group did not receive any study drug, and the modified intention-to-treat population was comprised of 33 patients. D-dimer concentrations after 8-12 weeks of treatment did not differ significantly between groups (difference -0·02 log10 ng/mL, 95% CI -0·10 to 0·05; p=0·56). Vorapaxar treatment was safe and well tolerated in this cohort. There were 161 adverse events (n=84 in the placebo group and n=77 in the vorapaxar group), and five protocol-defined serious adverse events that required hospital admission for more than 24 h (n=2 in the placebo group and n=3 in the vorapaxar group). One patient ceased taking vorapaxar because of an adverse event. There were 25 bleeding events, 23 of which were mild, one was moderate, and one was severe. INTERPRETATION Vorapaxar had no effect on D-dimer concentrations in HIV-infected patients receiving stable antiretroviral therapy but at risk of poor outcomes. Alternative approaches are needed to reduce hypercoagulation, inflammation, and adverse long-term outcomes in patients with treated HIV infection. FUNDING Australian National Health and Medical Research Council, US National Cancer Institute, National Institutes of Health.
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Kiefer EM, Hoover DR, Shi Q, Dusingize JC, Sinayobye JD, Anastos K. Longitudinal evaluation of markers of inflammation in HIV-positive and HIV-negative Rwandan women. HIV Med 2018; 19:734-744. [PMID: 30160347 DOI: 10.1111/hiv.12665] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2018] [Indexed: 12/29/2022]
Abstract
OBJECTIVES African women are disproportionately affected by HIV infection and may experience non-AIDS-related complications associated with inflammation. High-sensitivity C-reactive protein (hsCRP), d-dimer and transthyretin have been examined as inflammatory markers elsewhere, but it is unclear how they change over time in HIV-negative or HIV-positive African women with or without antiretroviral therapy (ART) initiation. METHODS We examined hsCRP, d-dimer and transthyretin levels at baseline and at follow-up of ≥2 years in 185 HIV-negative and 510 HIV-positive Rwandan women who were ART naïve at study entry. Generalized estimating equations for each marker were used to investigate the association with HIV infection/CD4 count, ART and follow-up time. RESULTS Compared with HIV-negative women, HIV-positive women had higher hsCRP and d-dimer and lower transthyretin concentrations, with greater differences at lower CD4 counts. After adjusting for CD4 count and other factors, ART was not significantly associated with log hsCRP (P = 0.36) at follow-up, but was independently associated with lower log d-dimer (P = 0.03) and higher transthyretin (P = 0.0008) concentrations. At ≥ 2 years of follow-up, hsCRP had not significantly changed in any group but log d-dimer had decreased significantly in all groups. Transthyretin declined significantly over time in HIV-negative women and HIV-positive non-ART initiators, but increased significantly in HIV-positive ART initiators. CONCLUSIONS HIV infection and advanced immune suppression were associated with higher hsCRP and d-dimer and lower transthyretin concentrations. ART (independently of CD4 changes) was significantly associated with decreases in d-dimer and increases in transthyretin, but, in contrast to other studies, was not associated with decreases in hsCRP. We found no change in hsCRP over time in any group.
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Affiliation(s)
- E M Kiefer
- Department of Internal Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
| | - D R Hoover
- Department of Statistics/Biostatistics, Institute for Health, Health Care Policy and Aging Research, Rutgers University, Piscataway, NJ, USA
| | - Q Shi
- Department of Public Health, New York Medical College, Valhalla, NY, USA
| | - J C Dusingize
- Department of Medicine, University of Queensland, Brisbane, Qld, Australia
| | | | - K Anastos
- Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
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Njuguna B, Kiplagat J, Bloomfield GS, Pastakia SD, Vedanthan R, Koethe JR. Prevalence, Risk Factors, and Pathophysiology of Dysglycemia among People Living with HIV in Sub-Saharan Africa. J Diabetes Res 2018; 2018:6916497. [PMID: 30009182 PMCID: PMC5989168 DOI: 10.1155/2018/6916497] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 04/03/2018] [Accepted: 04/15/2018] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE To review available literature on the prevalence, risk factors, pathophysiology, and clinical outcomes of dysglycemia among people living with HIV (PLHIV) in sub-Saharan Africa (SSA). METHODS Database search on PUBMED for eligible studies describing the prevalence, risk factors, pathophysiology, or clinical outcomes of dysglycemia in SSA PLHIV. RESULTS Prevalence of diabetes mellitus (DM) and pre-DM among SSA PLHIV ranged from 1% to 26% and 19% to 47%, respectively, in 15 identified studies. Older age and an elevated body mass index (BMI) were common risk factors for dysglycemia. Risk factors potentially more specific to PLHIV in SSA included exposure to older-generation thymidine analogues or protease inhibitors, malnutrition at ART initiation, a failure to gain fat mass on treatment, and elevated serum lipids. There is evidence of higher nephropathy and neuropathy rates among PLHIV in SSA with comorbid DM compared to HIV-negative individuals with DM. CONCLUSION There is a need for longitudinal studies to enhance understanding of the risk factors for dysglycemia among PLHIV in SSA, further research into optimal therapies to reduce pre-DM progression to DM among SSA PLHIV, and studies of the burden and phenotype of diabetic complications and other health outcomes among PLHIV with comorbid DM in SSA.
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Affiliation(s)
- Benson Njuguna
- Moi Teaching and Referral Hospital, P.O. Box 4606-30100, Eldoret, Kenya
| | - Jepchirchir Kiplagat
- Academic Model Providing Access to Healthcare (AMPATH), P.O. Box 4606-30100, Eldoret, Kenya
| | - Gerald S. Bloomfield
- Duke Clinical Research Institute, Duke Global Health Institute, Duke University, 2400 Pratt Street, Durham, NC 27710, USA
| | - Sonak D. Pastakia
- Purdue University College of Pharmacy, P.O. Box 5760 Eldoret 30100, Kenya
| | - Rajesh Vedanthan
- Zena and Michael A. Wiener Cardiovascular Institute, Department of Medicine and Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, P.O. Box 1030, New York, NY 10029, USA
| | - John R. Koethe
- Division of Infectious Diseases, Vanderbilt University Medical Center, A2200-MCN 1161 21st Avenue South, Nashville, TN 37232, USA
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Delgado-Vélez M, Lasalde-Dominicci JA. The Cholinergic Anti-Inflammatory Response and the Role of Macrophages in HIV-Induced Inflammation. Int J Mol Sci 2018; 19:ijms19051473. [PMID: 29772664 PMCID: PMC5983673 DOI: 10.3390/ijms19051473] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 04/11/2018] [Accepted: 04/29/2018] [Indexed: 12/20/2022] Open
Abstract
Macrophages are phagocytic immune cells that protect the body from foreign invaders and actively support the immune response by releasing anti- and proinflammatory cytokines. A seminal finding revolutionized the way macrophages are seen. The expression of the neuronal alpha7 nicotinic acetylcholine receptor (α7-nAChR) in macrophages led to the establishment of the cholinergic anti-inflammatory response (CAR) in which the activation of this receptor inactivates macrophage production of proinflammatory cytokines. This novel neuroimmune response soon began to emerge as a potential target to counteract inflammation during illness and infection states. Human immunodeficiency virus (HIV)-infected individuals suffer from chronic inflammation that persists even under antiretroviral therapy. Despite the CAR’s importance, few studies involving macrophages have been performed in the HIV field. Evidence demonstrates that monocyte-derived macrophages (MDMs) recovered from HIV-infected individuals are upregulated for α7-nAChR. Moreover, in vitro studies demonstrate that addition of an HIV viral constituent, gp120IIIB, to uninfected MDMs also upregulates the α7-nAChR. Importantly, contrary to what was expected, activation of upregulated α7-nAChRs in macrophages does not reduce inflammation, suggesting a CAR disruption. Although it is reasonable to consider this receptor as a pharmacological target, additional studies are necessary since its activity seems to differ from that observed in neurons.
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Affiliation(s)
- Manuel Delgado-Vélez
- Molecular Sciences Research Center, University of Puerto Rico, San Juan 00926, Puerto Rico.
| | - José A Lasalde-Dominicci
- Molecular Sciences Research Center, University of Puerto Rico, San Juan 00926, Puerto Rico.
- Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan 00931, Puerto Rico.
- Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan 00931, Puerto Rico.
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Brief Report: Higher ART Adherence Is Associated With Lower Systemic Inflammation in Treatment-Naive Ugandans Who Achieve Virologic Suppression. J Acquir Immune Defic Syndr 2018; 77:507-513. [PMID: 29346185 PMCID: PMC5844840 DOI: 10.1097/qai.0000000000001629] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Residual systemic inflammation persists despite suppressive antiretroviral therapy (ART) and is associated with non-AIDS clinical outcomes. We aimed to evaluate the association between ART adherence and inflammation in Ugandans living with HIV who were predominantly receiving nevirapine-based ART with a thymidine analog backbone and were virologically suppressed by conventional assays. METHODS Plasma concentrations of interleukin-6 (IL-6), D-dimer, soluble (s)CD14, sCD163, and the kynurenine/tryptophan ratio, in addition to CD8 T-cell activation, were measured at baseline and 6 months after ART initiation in treatment-naive adults who achieved an undetectable plasma HIV RNA (<400 copies/mL) at their 6-month visit. Adherence was measured through medication event monitoring system and calculated as the ratio of observed/prescribed device openings per participant. We fit adjusted linear regression models to estimate the association between ART adherence and the log-transformed plasma concentrations of inflammatory biomarkers. RESULTS We evaluated 282 participants (median age, 35 years; 70% women). The median (interquartile range) adherence was 93% (84-98). In the adjusted analyses, for every 10% increase in average ART adherence, we found a 15% [P < 0.0001; 95% confidence interval (CI), -21.0 to -7.9], 11% (P = 0.017; 95% CI, -18.3 to -2.0), and 3% (P = 0.028; 95% CI, -5.0 to -0.3) decrease in IL-6, D-dimer, and sCD14, respectively. CONCLUSIONS Higher ART adherence was associated with lower levels of biomarkers of inflammation, immune activation, and coagulopathy among Ugandans living with HIV who achieved viral suppression shortly after ART initiation. This suggests that ART adherence could have biological consequences beyond viral suppression. Whether ART adherence optimization in virologically suppressed individuals could reduce residual inflammation remains unknown.
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Di Stefano M, D'Andrea G, Zoboli F, Faleo G, Fasano M, Martinelli D, Margaglione M, Santantonio TA, Fiore JR. Preliminary Data From the Study of Coagulative Profile of HIV Infected Individuals Suggest a Role For Point Mutations in the Gene in Protein S Deficiency in Individuals Undergoing Highly Antiretroviral Therapy. Open AIDS J 2018; 12:6-10. [PMID: 29576814 PMCID: PMC5850486 DOI: 10.2174/1874613601812010006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 12/22/2017] [Accepted: 01/21/2018] [Indexed: 12/13/2022] Open
Abstract
Background: HIV infection is a known prothrombotic condition but factors involved are still controversial. A role for antiretrovirals, especially protease inhibitors, was advocated. Objectives: The study aimed to analyze the levels of anticoagulant proteins in virally suppressed HIV-infected subjects treated with different anti-retroviral regimens. Materials and Methods: Forty-four patients were included in the study. C and PS, D-Dimers and Fibrinogen levels were determined as well as APC-resistance. PROS1 gene was sequenced in a group of patient. Results: Twelve of the 44 subjects (27%) showed reduced levels of PS, while lower levels of PC were found only in 2 patients (4,5%). No difference in the mean values of PC and PS was found stratifying the study population by antiretroviral regimen administrated (p>0.05). Three patients had higher levels of D-Dimer concentrations and in two of these patients, an association between higher D-Dimer values and lower levels of PS was observed; but however no correlation was found by statistical analysis. PROS1 gene analysis was performed in 26 of the 44 HIV-1 patients and the subjects with low levels of PS had mutation in the fifteen exon of PROS 1 gene. While among individuals with normal levels, this mutation was observed only in 8/18 (44%) of the cases (p=0,0072). Conclusion: The majority of patients with low PS levels also had mutations in the fifteen exon of PROS 1 gene. Genetic determinants, deserving further investigations, rather than antiretrovirals might cause PS deficiency in HIV-1 positive patients.
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Affiliation(s)
- Mariantonietta Di Stefano
- Department of Clinical and Experimental Medicine, Section of Infectious Diseases, University of Foggia, Viale L. Pinto 71131 Foggia, Italy.,Medical Genetics, University of Foggia, Viale L. Pinto 71131 Foggia, Italy
| | - Giovanna D'Andrea
- Medical Genetics, University of Foggia, Viale L. Pinto 71131 Foggia, Italy
| | - Fabio Zoboli
- Department of Clinical and Experimental Medicine, Section of Infectious Diseases, University of Foggia, Viale L. Pinto 71131 Foggia, Italy
| | - Giuseppina Faleo
- Department of Clinical and Experimental Medicine, Section of Infectious Diseases, University of Foggia, Viale L. Pinto 71131 Foggia, Italy
| | - Massimo Fasano
- Department of Clinical and Experimental Medicine, Section of Infectious Diseases, University of Foggia, Viale L. Pinto 71131 Foggia, Italy
| | - Domenico Martinelli
- Department of Medical Sciences, Section of Hygiene, University of Foggia, Apulia Regional Epidemiological Observatory, Viale L. Pinto 71131 Foggia, Italy
| | | | - Teresa A Santantonio
- Department of Clinical and Experimental Medicine, Section of Infectious Diseases, University of Foggia, Viale L. Pinto 71131 Foggia, Italy
| | - Josè R Fiore
- Department of Clinical and Experimental Medicine, Section of Infectious Diseases, University of Foggia, Viale L. Pinto 71131 Foggia, Italy
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Baker JV, Sharma S, Grund B, Rupert A, Metcalf JA, Schechter M, Munderi P, Aho I, Emery S, Babiker A, Phillips A, Lundgren JD, Neaton JD, Lane HC. Systemic Inflammation, Coagulation, and Clinical Risk in the START Trial. Open Forum Infect Dis 2017; 4:ofx262. [PMID: 29308409 PMCID: PMC5751061 DOI: 10.1093/ofid/ofx262] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 11/20/2017] [Indexed: 12/12/2022] Open
Abstract
Background The Strategic Timing of AntiRetroviral Treatment (START) trial demonstrated that immediate (at CD4+ >500 cells/µL) vs deferred (to CD4+ <350 cells/µL or AIDS) antiretroviral therapy (ART) initiation reduced risk for AIDS and serious non-AIDS (SNA). We investigated associations of inflammation, coagulation, and vascular injury biomarkers with AIDS, SNA or death, and the effect of immediate ART initiation. Methods Biomarkers were measured from stored plasma prior to randomization and at month 8. Associations of baseline biomarkers with event risk were estimated with Cox regression, pooled across groups, adjusted for age, gender, and treatment group, and stratified by region. Mean changes over 8 months were estimated and compared between the immediate and deferred ART arms using analysis of covariance models, adjusted for levels at entry. Results Baseline biomarker levels were available for 4299 START participants (92%). Mean follow-up was 3.2 years. Higher levels of IL-6 and D-dimer were the only biomarkers associated with risk for AIDS, SNA or death, as well as the individual components of SNA and AIDS events (HRs ranged 1.37-1.41 per 2-fold higher level), even after adjustment for baseline CD4+ count, HIV RNA level, and other biomarkers. At month 8, biomarker levels were lower in the immediate arm by 12%-21%. Conclusions These data, combined with evidence from prior biomarker studies, demonstrate that IL-6 and D-dimer consistently predict clinical risk across a broad spectrum of CD4 counts for those both ART-naïve and treated. Research is needed to identify disease-modifying treatments that target inflammation beyond the effects of ART.
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Affiliation(s)
- Jason V Baker
- Department of Medicine University of Minnesota, Minneapolis, Minnesota.,Division of Biostatistics School of Statistics, University of Minnesota, Minneapolis, Minnesota
| | - Shweta Sharma
- Division of Infectious Diseases, Hennepin County Medical Center, Minneapolis, Minnesota
| | - Birgit Grund
- Division of Biostatistics, School of Public Health University of Minnesota, Minneapolis, Minnesota
| | - Adam Rupert
- Leidos Biomedical Research Inc., Frederick, Maryland
| | - Julia A Metcalf
- National Institute of Allergy and Infectious Diseases, Division of Clinical Research, Bethesda, Maryland
| | - Mauro Schechter
- Projeto Praça Onze, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Inka Aho
- Division of Infectious Diseases, Helsinki University Hospital, Helsinki, Finland
| | - Sean Emery
- Faculty of Medicine, University of Queensland, Brisbane, Australia.,Kirby Institute, University of New South Wales, Sydney, Australia
| | - Abdel Babiker
- MRC Clinical Trials Unit, University College London, London, UK
| | - Andrew Phillips
- HIV Epidemiology and Biostatistics Group, University College London, London, UK
| | - Jens D Lundgren
- CHIP, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - James D Neaton
- Division of Infectious Diseases, Hennepin County Medical Center, Minneapolis, Minnesota
| | - H Clifford Lane
- National Institute of Allergy and Infectious Diseases, Division of Clinical Research, Bethesda, Maryland
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Feinstein MJ, Bogorodskaya M, Bloomfield GS, Vedanthan R, Siedner MJ, Kwan GF, Longenecker CT. Cardiovascular Complications of HIV in Endemic Countries. Curr Cardiol Rep 2017; 18:113. [PMID: 27730474 DOI: 10.1007/s11886-016-0794-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Effective combination antiretroviral therapy (ART) has enabled human immunodeficiency virus (HIV) infection to evolve from a generally fatal condition to a manageable chronic disease. This transition began two decades ago in high-income countries and has more recently begun in lower income, HIV endemic countries (HIV-ECs). With this transition, there has been a concurrent shift in clinical and public health burden from AIDS-related complications and opportunistic infections to those associated with well-controlled HIV disease, including cardiovascular disease (CVD). In the current treatment era, traditional CVD risk factors and HIV-related factors both contribute to an elevated risk of myocardial infarction, stroke, heart failure, and arrhythmias. In HIV-ECs, the high prevalence of persons living with HIV and growing prevalence of CVD risk factors will contribute to a growing epidemic of HIV-associated CVD. In this review, we discuss the epidemiology and pathophysiology of cardiovascular complications of HIV and the resultant implications for public health efforts in HIV-ECs.
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Affiliation(s)
- Matthew J Feinstein
- Division of Cardiovascular Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL, USA.
| | - Milana Bogorodskaya
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.,Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH, USA
| | - Gerald S Bloomfield
- Division of Cardiology, Department of Medicine, Duke Clinical Research Institute, Duke University, Durham, NC, USA
| | - Rajesh Vedanthan
- Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mark J Siedner
- Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Gene F Kwan
- Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Christopher T Longenecker
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.,Division of Cardiology, Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH, USA
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Gilotra TS, Geraci SA. C-Reactive Protein as an Independent Cardiovascular Risk Predictor in HIV+ Patients: A Focused Review of Published Studies. J Clin Med Res 2017; 9:891-899. [PMID: 29038665 PMCID: PMC5633088 DOI: 10.14740/jocmr3154w] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 09/08/2017] [Indexed: 12/23/2022] Open
Abstract
Patients infected with the human immunodeficiency virus (HIV+) are living longer and at heightened risk for developing cardiovascular events (CVEs). Commonly used prediction tools appear to misrepresent their CVE risk to varying degrees and in varying directions. Inclusion of markers of cellular infection, chronic immune activation and/or systemic inflammation into risk models might provide better predictive accuracy. Observational studies assessing the relationship of high-sensitivity C-reactive protein (hs-CRP) to CVE in HIV+ patients have reported inconsistent findings. This review of published studies attempted to determine if the available evidence supports its potential use in new models for stable, treated HIV+ patients. We searched the PubMed database using keywords and combinations of “HIV” AND “cardiovascular risk” AND “CRP”. Papers presenting original analyses, associating hs-CRP concentration as an independent variable to hard cardiovascular outcomes (myocardial infarction and cardiovascular death), or to hard CVE as part of a composite endpoint, were included. Five observational studies met inclusion/exclusion criteria for review. Three papers identified an association between elevated hs-CRP and CVE, while two others failed to find any significant association. All reports were heterogeneous in terms of independent variables, controls, and designs. The larger and more rigorous studies, employing higher rates of confounder controls and more objective endpoints in their composites, showed positive associations. Though not conclusive, the preponderance of the evidence at this time supports CRP as a potentially valuable factor to be studied in prospective cardiovascular risk prediction investigations in HIV+ patients.
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Affiliation(s)
- Tarvinder S Gilotra
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Stephen A Geraci
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,Division of Cardiology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
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Melvin AJ, Warshaw M, Compagnucci A, Saidi Y, Harrison L, Turkova A, Tudor-Williams G, and the PENPACT-1 (PENTA 9/PACTG 390/ANRS 103) Study Team. Hepatic, Renal, Hematologic, and Inflammatory Markers in HIV-Infected Children on Long-term Suppressive Antiretroviral Therapy. J Pediatric Infect Dis Soc 2017; 6:e109-e115. [PMID: 28903520 PMCID: PMC5907869 DOI: 10.1093/jpids/pix050] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 06/03/2017] [Indexed: 11/12/2022]
Abstract
BACKGROUND Data on long-term toxicity of antiretroviral therapy (ART) in HIV-infected children are sparse. PENPACT-1 was an open-label trial in which HIV-infected children were assigned randomly to receive protease inhibitor (PI)- or nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based ART. METHODS We examined changes in clinical, immunologic, and inflammatory markers from baseline to year 4 in the subset of children in the PENPACT-1 study who experienced viral suppression between week 24 and year 4 of ART. Liver enzyme, creatinine, and cholesterol levels and hematologic parameters were assessed during the trial. Cystatin C, high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), d-dimer, and soluble CD14 (sCD14) were assayed from cryopreserved specimens. RESULTS Ninety-nine children (52 on PI-based and 47 on NNRTI-based ART) met inclusion criteria. The median age at initiation of ART was 6.5 years (interquartile range [IQR], 3.7-13.4 years), and 22% were aged <3 years at ART initiation; 56% of the PI-treated children received lopinavir/ritonavir, and 70% of NNRTI-treated children received efavirenz initially. We found no evidence of significant clinical toxicity in either group; growth, liver, kidney, and hematologic parameters either remained unchanged or improved between baseline and year 4. Total cholesterol levels increased modestly, but no difference between the groups was found. IL-6 and hs-CRP levels decreased more after 4 years in the NNRTI-based ART group. The median change in IL-6 level was -0.35 pg/ml in the PI-based ART group and -1.0 in the NNRTI-based ART group (P = .05), and the median change in hs-CRP level was 0.25 µg/ml in the PI-based ART group and -0.95 µg/ml in the NNRTI-based ART group (P = .005). CONCLUSION These results support the safety of prolonged ART use in HIV-infected children and suggest that suppressive NNRTI-based regimens can be associated with lower levels of systemic inflammation.
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Affiliation(s)
- Ann J Melvin
- Division of Pediatric Infectious Disease, Department of Pediatrics, University of Washington and Seattle Children’s Research Institute
| | - Meredith Warshaw
- Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | | | | | - Linda Harrison
- Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Anna Turkova
- Medical Research Council, Clinical Trials Unit, London, United Kingdom; and
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Juega-Mariño J, Bonjoch A, Pérez-Alvarez N, Negredo E, Bayes B, Bonet J, Clotet B, Romero R. Prevalence, evolution, and related risk factors of kidney disease among Spanish HIV-infected individuals. Medicine (Baltimore) 2017; 96:e7421. [PMID: 28906351 PMCID: PMC5604620 DOI: 10.1097/md.0000000000007421] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Prevalence of kidney disease (KD) is increasing among human immunodeficiency virus (HIV)-infected population. Different factors have been related, varying on different published series.The objectives were to study prevalence of KD in those patients, its evolution, and associated risk factors.An observational cohort study of 1596 HIV-positive patients with cross-sectional data collection in 2008 and 2010 was conducted. We obtained clinical and laboratory markers, and registered previous or current treatment with tenofovir (TDF) and indinavir (IDV). The sample was divided according to estimated glomerular filtration rate (eGFR) by modification of diet in renal disease (MDRD) equation. Group 1: eGFR ≤60 mL/min/1.73 m; group 2: eGFR >60 mL/min/1.73 m.Among the patients, 76.4% were men, mean age (SD) 45 ± 9 years, time since diagnose of HIV 14 ± 7 years, and 47.2% of the patients received previous treatment with TDF and 39.1% with IDV. In 2008, eGFR ≤60: 4.9% (91.4% of them in chronic kidney disease [CKD] stage 3, eGFR 59-30 mL/min); this group was older, presented higher fibrinogen levels, and more patients were treated previously with TDF and IDV. In 2010, eGFR ≤60: 3.9% (87.1% stage 3 CKD). The 2.4% of cohort showed renal improvement and 1.3% decline of renal function over time. The absence of hypertension and treatment with TDF were associated with improvement in eGFR. Increased age, elevated fibrinogen, decreased albumin, diabetes mellitus, hyperTG, and worse virological control were risk factors for renal impairment.The HIV-positive patients in our area have a CKD prevalence of 4% to 5% (90% stage 3 CKD) associated with ageing, inflammation, worse immune control of HIV, TDF treatment, and metabolic syndrome.
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Affiliation(s)
- Javier Juega-Mariño
- Servicio de Nefrología, Hospital Germans Trias i Pujol, Badalona
- Universitat Autónoma de Barcelona
| | - Anna Bonjoch
- Unitat VIH, Fundació Lluita contra la SIDA, Servicio de Medicina Interna, Hospital Germans Trias i Pujol, Badalona
| | - Nuria Pérez-Alvarez
- Unitat VIH, Fundació Lluita contra la SIDA, Servicio de Medicina Interna, Hospital Germans Trias i Pujol, Badalona
| | - Eugenia Negredo
- Unitat VIH, Fundació Lluita contra la SIDA, Servicio de Medicina Interna, Hospital Germans Trias i Pujol, Badalona
- Universitat de Vic-Universitat Central de Catalunya, Barcelona
| | - Beatriu Bayes
- Servicio de Nefrología, Hospital Germans Trias i Pujol, Badalona
| | - Josep Bonet
- Servicio de Nefrología, Hospital Germans Trias i Pujol, Badalona
- Universitat Autónoma de Barcelona
| | - Buenaventura Clotet
- Unitat VIH, Fundació Lluita contra la SIDA, Servicio de Medicina Interna, Hospital Germans Trias i Pujol, Badalona
- Universitat de Vic-Universitat Central de Catalunya, Barcelona
- IrsiCaixa Foundation, Badalona, Spain
| | - Ramon Romero
- Servicio de Nefrología, Hospital Germans Trias i Pujol, Badalona
- Universitat Autónoma de Barcelona
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50
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Schechter ME, Andrade BB, He T, Richter GH, Tosh KW, Policicchio BB, Singh A, Raehtz KD, Sheikh V, Ma D, Brocca-Cofano E, Apetrei C, Tracy R, Ribeiro RM, Sher A, Francischetti IMB, Pandrea I, Sereti I. Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy. Sci Transl Med 2017; 9:eaam5441. [PMID: 28855397 PMCID: PMC5755598 DOI: 10.1126/scitranslmed.aam5441] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 07/11/2017] [Indexed: 01/05/2023]
Abstract
In HIV infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious chronic complications such as cardiovascular and thromboembolic disease. A better understanding of inflammatory and coagulation pathways in HIV infection is needed to optimize clinical care. Markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-AIDS events. We identified a specific subset of monocytes that express tissue factor (TF), persist after virological suppression, and trigger the coagulation cascade by activating factor X. This subset of monocytes expressing TF had a distinct gene signature with up-regulated innate immune markers and evidence of robust production of multiple proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, ex vivo and in vitro upon lipopolysaccharide stimulation. We validated our findings in a nonhuman primate model, showing that TF-expressing inflammatory monocytes were associated with simian immunodeficiency virus (SIV)-related coagulopathy in the progressive [pigtail macaques (PTMs)] but not in the nonpathogenic (African green monkeys) SIV infection model. Last, Ixolaris, an anticoagulant that inhibits the TF pathway, was tested and potently blocked functional TF activity in vitro in HIV and SIV infection without affecting monocyte responses to Toll-like receptor stimulation. Strikingly, in vivo treatment of SIV-infected PTMs with Ixolaris was associated with significant decreases in D-dimer and immune activation. These data suggest that TF-expressing monocytes are at the epicenter of inflammation and coagulation in chronic HIV and SIV infection and may represent a potential therapeutic target.
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Affiliation(s)
- Melissa E Schechter
- Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Bruno B Andrade
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil
- Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Instituto Brasileiro para a Investigação da Tuberculose, Fundação José Silveira, Salvador 40210-320, Brazil
- Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Tianyu He
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - George Haret Richter
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Kevin W Tosh
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Benjamin B Policicchio
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Amrit Singh
- HIV Pathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Kevin D Raehtz
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Virginia Sheikh
- HIV Pathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Dongying Ma
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Egidio Brocca-Cofano
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Cristian Apetrei
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Russel Tracy
- Department of Pathology and Laboratory Medicine, The Robert Larner, M.D. College of Medicine University of Vermont, Burlington, VT 05405, USA
| | - Ruy M Ribeiro
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87544, USA
- Laboratório de Biomatemática, Faculdade de Medicina, Universidade de Lisboa, Lisboa 1649-028, Portugal
| | - Alan Sher
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ivo M B Francischetti
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ivona Pandrea
- Center for Vaccine Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Irini Sereti
- HIV Pathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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