Interleukin 6 Is a Stronger Predictor of Clinical Events Than High-Sensitivity C-Reactive Protein or D-Dimer During HIV Infection

Borges, Álvaro H.; O'Connor, Jemma; Phillips, Andrew; Neaton, James D.; Grund, Birgit; Neuhaus, Jacqueline; Vjecha, Michael J.; Calmy, Alexandra; Koelsch, Kersten K.; Lundgren, Jens D

doi:10.1093/infdis/jiw173

Cited by 98 publications

(87 citation statements)

References 48 publications

(57 reference statements)

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“…This finding may underscore the complexities in cytokine signaling and suggest the need for different biomarkers as measures of inflammation to predict these outcomes. Cytokines, particularly IL-6 [31, 32], do predict clinical outcomes; for more subtle changes in pharmacology, other biomarkers of inflammation, such as soluble immune cell markers, cellular immune phenotypes, or kallistatin [33] may better predict changes that could influence drug toxicity and efficacy, and should be explored further.…”

Section: Discussionmentioning

confidence: 99%

Concentrations of Pro-Inflammatory Cytokines Are Not Associated with Senescence Marker p16INK4a or Predictive of Intracellular Emtricitabine/Tenofovir Metabolite and Endogenous Nucleotide Exposures in Adults with HIV Infection

et al. 2016

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ObjectivesAs the HIV-infected population ages, the role of cellular senescence and inflammation on co-morbid conditions and pharmacotherapy is increasingly of interest. p16INK4a expression, a marker for aging and senescence in T-cells, is associated with lower intracellular concentrations of endogenous nucleotides (EN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs). This study expands on these findings by determining whether inflammation is contributing to the association of p16INK4a expression with intracellular metabolite (IM) exposure and endogenous nucleotide concentrations.MethodsSamples from 73 HIV-infected adults receiving daily tenofovir/emtricitabine (TFV/FTC) with either efavirenz (EFV) or atazanavir/ritonavir (ATV/r) were tested for p16INK4a expression, and plasma cytokine and intracellular drug concentrations. Associations between p16INK4a expression and cytokine concentrations were assessed using maximum likelihood methods, and elastic net regression was applied to assess whether cytokines were predictive of intracellular metabolite/endogenous nucleotide exposures.ResultsEnrolled participants had a median age of 48 years (range 23–73). There were no significant associations between p16INK4a expression and cytokines. Results of the elastic net regression showed weak relationships between IL-1Ra and FTC-triphosphate and deoxyadenosine triphosphate exposures, and MIP-1β, age and TFV-diphosphate exposures.ConclusionsIn this clinical evaluation, we found no relationships between p16INK4a expression and cytokines, or cytokines and intracellular nucleotide concentrations. While inflammation is known to play a role in this population, it is not a major contributor to the p16INK4a association with decreased IM/EN exposures in these HIV-infected participants.

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Section: Discussionmentioning

confidence: 99%

Concentrations of Pro-Inflammatory Cytokines Are Not Associated with Senescence Marker p16INK4a or Predictive of Intracellular Emtricitabine/Tenofovir Metabolite and Endogenous Nucleotide Exposures in Adults with HIV Infection

et al. 2016

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“…Increases in many chronic diseases would be expected with prolonged life expectancy,6 but a key factor contributing to excess rates of non‐AIDS events among treated HIV+ patients includes persistent abnormalities in systemic inflammation and coagulation activity 7, 8, 9. Higher levels of biomarkers such as d ‐dimer and interleukin‐6 (IL‐6)8, 9, 10 among HIV+ patients have been shown to be positively associated with anemia,11 cancer,12 cardiovascular disease,10 type 2 diabetes,13 progression to AIDS,14 and composite non‐AIDS related clinical events and all‐cause mortality 7, 8, 15. However, a mechanistic basis for the connection between HIV‐associated alterations in coagulation activity and risk for a broad spectrum of non‐AIDS defining diseases has yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

In silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus

Brummel‐Ziedins

Gissel

Neuhaus

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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BackgroundEffective HIV treatment with antiretroviral therapy has prolonged survival and shifted causes of death to non‐AIDS illnesses such as cardiovascular disease. We have shown that inflammation and HIV viral load associate with pro‐ and anticoagulant factor imbalances resulting in increased thrombin generation when mathematically modeled. We explore the hypothesis that factor compositional imbalance, corresponding to increased in silico thrombin generation, predicts mortality among HIV+ persons.MethodsIn a nested case‐control study of HIV+ individuals on continuous antiretroviral therapy in two large trials, we evaluated cases (any non‐violent mortality, n = 114) and matched controls (n = 318). Thrombin generation in response to a tissue‐factor initiator for each individual was calculated by a mathematical model incorporating levels of factors (F)II, V, VII, VIII, IX, X, antithrombin, tissue factor pathway inhibitor, and protein C (PC) measured at study entry to the trials. In silico thrombin generation metrics included clot time, maximum rate (MaxR), maximum level (MaxL), and area under the curve (AUC).ResultsLevels of antithrombin and PC decreased, while FV and FVIII were higher in cases vs controls. This resulted in a more procoagulant phenotype with increased MaxR, MaxL, and AUC in cases compared to controls (P < 0.05 for all).ConclusionsAntithrombin, FV, FVIII, and PC were the major contributors to the increased thrombin generation associated with mortality risk. Our results suggest that mortality in HIV is associated with an increase in in silico thrombin generation via altered balance of pro‐ and anticoagulant factors, likely due to an inflammatory response signal, and resulting coagulopathy.

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“…The question as to how combination antiretroviral therapy (cART) influences cancer risk has been debated since the beginning of the AIDS epidemics. During HIV infection, cancer risk seems to be determined by a complex interaction between prolonged life expectancy [1], traditional risk factors [11-12], pro-oncogenic viruses co-infection, potentially direct oncogenic effects of HIV [13-15], cART toxicity [16, ••17, •18] and activated inflammation and coagulation [19-23]. It is thus difficult to disentangle the direct effect of cART on cancer risk from other factors postulated to pay a role in carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…From our studies, PI-based regimens were linked to higher levels of IL-6 [70], a cytokine involved in all stages of cancer development [71]. Elevated plasma levels of IL-6 and other biomarkers of activated inflammation and coagulation were linked to future risk of both infection-related and infection-unrelated malignancies among HIV+ persons [19-21;23]. In one randomised trial, participants switching away from PI-based regimens experienced significant reductions in IL-6 levels when compared to participants continuously receiving PIs [72].…”

Section: Introductionmentioning

confidence: 99%

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Combination antiretroviral therapy and cancer risk

Borges¹

2017

Current Opinion in HIV and AIDS

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Purpose to review the newest research about the effects of combination antiretroviral therapy (cART) on cancer risk Recent findings HIV+ persons are at increased risk of cancer. As this risk is higher for malignancies driven by viral and bacterial co-infections, classifying malignancies into infection-related and infection-unrelated has been an emerging trend. Cohorts have detected major reductions in the incidence of Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) following cART initiation among immunosuppressed HIV+ persons. However, recent randomized data indicate that cART reduces risk of KS and NHL also during early HIV infection before overt immunosuppression occurs. Long term effects of cART exposure on cancer risk are not well defined; according to basic and epidemiological research, there might be specific associations of each cART class with distinct patterns of cancer risk. Summary The relationship between cART exposure and cancer risk is complex and nuanced. It is an intriguing fact that, whether initiated during severe immunosuppression or not, cART reduces risk of KS and NHL. Further research should identify mediators of the benefit of immediate cART initiation in reducing cancer risk, understand the relationship between long term cART exposure and cancer incidence, and assess whether adjuvant anti-inflammatory therapies can reduce cancer risk during treated HIV infection.

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Interleukin 6 Is a Stronger Predictor of Clinical Events Than High-Sensitivity C-Reactive Protein or D-Dimer During HIV Infection

Abstract: IL-6 is a stronger predictor of fatal events than of CVD and non-AIDS-defining malignancies. Adjuvant antiinflammatory and antithrombotic therapies should be tested in HIV-infected individuals.

Cited by 98 publications

References 48 publications

Concentrations of Pro-Inflammatory Cytokines Are Not Associated with Senescence Marker p16INK4a or Predictive of Intracellular Emtricitabine/Tenofovir Metabolite and Endogenous Nucleotide Exposures in Adults with HIV Infection

Concentrations of Pro-Inflammatory Cytokines Are Not Associated with Senescence Marker p16INK4a or Predictive of Intracellular Emtricitabine/Tenofovir Metabolite and Endogenous Nucleotide Exposures in Adults with HIV Infection

In silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus

Combination antiretroviral therapy and cancer risk

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