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. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection.

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Kuller, Lewis H, Tracy, Russell, Belloso, Waldo, Wit, Stephane De, Drummond, Fraser, Lane, H. Clifford, Ledergerber, Bruno, Lundgren, Jens, Neuhaus, Jacqueline, Nixon, Daniel, Paton, Nicholas I, Neaton, James D, for the INSIGHT SMART Study Group·2008·PLoS Medicine
DOI 10.1371/journal.pmed.0050203PMC PMC2570418
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Abstract

BACKGROUND: In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis. METHODS AND FINDINGS: Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case-control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0-4.1; p = 0.05), 8.3 (95% CI, 3.3-20.8; p < 0.0001), and 12.4 (95% CI, 4.2-37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case-control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1-3.1; p = 0.02) to 1.5 (95% CI, 0.8-2.8) and 1.4 (95% CI, 0.8-2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively. CONCLUSIONS: IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.

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Crossref · 10.1371/journal.pmed.0050203

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Figures

Figure 1 SMART Study Design and Flow Diagram for Case–Control Study
Figure 1 SMART Study Design and Flow Diagram for Case–Control StudyCC0 · PubMed Central
Figure 2 SMART Study Design and Flow Diagram for Random Sample
Figure 2 SMART Study Design and Flow Diagram for Random SampleCC0 · PubMed Central
Figure 3 Change in Log10 IL-6 (pg/ml) from Baseline to 1 mo According to HIV-RNA Level at 1 mo for Participants in the Drug Conservation (DC) Group (CD4+ Guided Intermittent ART) with an HIV-RNA level 400 Copies/ml or Less at Baseline
Figure 3 Change in Log10 IL-6 (pg/ml) from Baseline to 1 mo According to HIV-RNA Level at 1 mo for Participants in the Drug Conservation (DC) Group (CD4+ Guided Intermittent ART) with an HIV-RNA level 400 Copies/ml or Less at BaselineCC0 · PubMed Central
Figure 4 Change in Log10 D-dimer (μg/ml) from Baseline to 1 mo According to HIV-RNA Level at 1 mo for Participants in the Drug Conservation (DC) Group (CD4+ Guided Intermittent ART) with an HIV-RNA level 400 Copies/ml or less at Baseline
Figure 4 Change in Log10 D-dimer (μg/ml) from Baseline to 1 mo According to HIV-RNA Level at 1 mo for Participants in the Drug Conservation (DC) Group (CD4+ Guided Intermittent ART) with an HIV-RNA level 400 Copies/ml or less at BaselineCC0 · PubMed Central

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Citations

Cites

Show all 42 references

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Metadata

Authors
Kuller, L. H., Tracy, R., Belloso, W., Wit, S. D., Drummond, F., Lane, H. C., Ledergerber, B., Lundgren, J., Neuhaus, J., Nixon, D., Paton, N. I., Neaton, J. D., & for the INSIGHT SMART Study Group
Affiliations
  • University of Pittsburgh (US)
  • University of Vermont (US)
  • Hospital Italiano de Buenos Aires (AR)
  • UNSW Sydney (AU)
  • National Institutes of Health (US)
  • University Hospital Zurich (CH)
  • University of Copenhagen (DK)
  • University of Minnesota (US)
  • Virginia Commonwealth University (US)
  • Medical Research Council (GB)
Corresponding author
Neaton, James D
ORCID
Venue
PLoS Medicine
Publisher
Public Library of Science (PLoS)
Published
2008-10-21
Volume
5
Issue
10
Pages
e203
ISSN
  • 1549-1277 (ISSN-L)
  • 1549-1676
DOI
10.1371/journal.pmed.0050203
PMC
PMC2570418
OpenAlex
W2153136696
Cited by
1,617
References
42
Citations by year
2026: 40 · 2025: 42 · 2024: 57 · 2023: 56 · 2022: 70 · 2021: 77 · 2020: 98 · 2019: 82 · 2018: 105 · 2017: 86 · 2016: 120 · 2015: 129 · 2014: 146 · 2013: 142 · 2012: 118
FWCI
53.14
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Medicine (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion, cc-by)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • D-Scholarship@Pitt (University of Pittsburgh) (acceptedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, cc-by)
  • National University of Singapore (submittedVersion)
  • VCU Scholars Compass (Virginia Commonwealth University) (submittedVersion, public-domain)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Bristol-Myers Squibb
  • Pfizer
  • GlaxoSmithKline
  • Gilead Sciences
  • Wake Forest University
  • Johns Hopkins University
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (U01 AI46362, U01AI046362, U01AI042170)
Topics
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS Research and Interventions
  • Health Sciences › Medicine › Infectious Diseases › HIV-related health complications and treatments
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
Keywords
HIV infection, all-cause mortality, inflammatory markers, coagulation markers, C-reactive protein, interleukin-6, D-dimer, prothrombin fragment 1+2, amyloid A, antiretroviral therapy interruption, viral rebound, thrombosis, fibrinolysis, tissue factor
MeSH terms
Serum Amyloid P-Component, Serum Amyloid A Protein, Blood Coagulation, C-Reactive Protein, Cause of Death, Female, Fibrin Fibrinogen Degradation Products, Follow-Up Studies, Humans, Inflammation, Male, Multicenter Studies as Topic, Biomarkers, HIV Infections, Interleukin-6, Survival Rate, Logistic Models, Odds Ratio, Case-Control Studies, Randomized Controlled Trials as Topic, Treatment Outcome, Anti-HIV Agents

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