Persistently Elevated Serum Interleukin-6 Predicts Mortality Among Adults Receiving Combination Antiretroviral Therapy in Botswana: Results from a Clinical Trial

McDonald, Bethan; Moyo, Sikhulile; Gabaitiri, Lesego; Gaseitsiwe, Simani; Bussmann, Hermann; Koethe, John R.; Musonda, Rosemary; Makhema, Joseph; Novitsky, Vladimir; Marlink, Richard; Wester, C. William; Essex, Max

doi:10.1089/aid.2012.0309

Cited by 34 publications

(29 citation statements)

References 29 publications

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“…53,54 As obesity prevalence among people living with HIV rises, 17 further investigation into the long-term implications of this weight gain is needed. Future prospective studies should assess whether intentional weight loss or similar interventions affect inflammatory processes similarly in HIV infected and uninfected people.…”

Section: Discussionmentioning

confidence: 99%

HIV and Obesity Comorbidity Increase Interleukin 6 but Not Soluble CD14 or D-Dimer

Taylor

So‐Armah

Tate

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Objectives Obesity prevalence among people living with HIV (HIV+) is rising. HIV and obesity are pro-inflammatory states, but their combined effect on inflammation (measured by interleukin 6, IL-6), altered coagulation (D-dimer), and monocyte activation (soluble CD14, sCD14) is unknown. We hypothesized inflammation increases when obesity and HIV infection co-occur. Methods The VACS survey cohort is a prospective, observational, longitudinal study of predominantly male, HIV+ veterans and veterans uninfected with HIV; a subset provided blood samples. Inclusion criteria for this analysis were: body mass index (BMI) ≥ 18.5 kg/m2 and with biomarker measurements. Dependent variables were IL-6, sCD14, and D-dimer quartiles. Obesity/HIV status was the primary predictor. Unadjusted and adjusted logistic regression models were constructed. Results Data were analyzed for 1477 HIV+ and 823 uninfected participants. Unadjusted median IL-6 levels were significantly higher and sCD14 levels were significantly lower in obese/HIV+ when compared with non-obese/uninfected people (p-value <0.01 for both). In adjusted analyses, the odds ratio (OR) for increased IL-6 in obese/HIV+ was 1.76 (95%CI: 1.18, 2.47) when compared with non-obese/uninfected, and obesity/HIV+ remained associated with lower odds of elevated sCD14. We did not detect a synergistic association of co-occurring HIV and obesity on IL-6 or sCD14 elevation. D-dimer levels did not differ significantly between BMI/HIV status groups. Conclusion HIV-obesity comorbidity is associated with elevated IL-6, decreases in sCD14 and no significant difference in D-dimer. These findings are clinically significant as previous studies show these biomarkers are associated with mortality. Future studies should assess whether other biomarkers show similar trends and potential mechanisms for the unanticipated sCD14 and D-dimer findings.

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Section: Discussionmentioning

confidence: 99%

HIV and Obesity Comorbidity Increase Interleukin 6 but Not Soluble CD14 or D-Dimer

Taylor

So‐Armah

Tate

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…Multiple biomarker studies have identified a higher IL-6 level as a predictor of subsequent mortality 9,22,23 . A number of explanations could account for the lack of association between IL-6 levels and death found in our study.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Immunologic Predictors of Death After an Acute Opportunistic Infection: Results from ACTG A5164

Grant

Komarow

Sánchez³

et al. 2014

HIV Clinical Trials

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Background In the pre-ART era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era. Objective Determine clinical and immunological predictors of death after an OI. Methods We used clinical data and stored plasma from ACTG A5164, a multi-center study evaluating the optimal timing of ART during a non-tuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both. Results The median CD4+ T-cell count in study participants at baseline was 29 cells/uL. 64% had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death. Conclusions In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI.

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“…Interestingly, IL-6 production is associated with severe pathogenicity in HIV infection in humans and SIV infection in RM (38)(39)(40)(41). For example, SIVsmmPBj8 infection of RM results in death within a few weeks and induces significant IL-6 production, which may be a cause or effect of the pathogenic course of infection (42).…”

Section: Figmentioning

confidence: 99%

Magnitude and Quality of Cytokine and Chemokine Storm during Acute Infection Distinguish Nonprogressive and Progressive Simian Immunodeficiency Virus Infections of Nonhuman Primates

Keating

Heitman

et al. 2016

J Virol

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Acute human immunodeficiency virus (HIV) infection represents a period of intense immune perturbation and activation of the host immune system. Study of the eclipse and viral expansion phases of infection is difficult in humans, but studies in nonpro- IMPORTANCENHP models of HIV infection constitute a powerful tool with which to study viral pathogenesis in order to gain critical information for a better understanding of HIV infection in humans. Here we studied progressive and nonprogressive simian immunodeficiency virus (SIV) infection models in both natural and nonnatural host NHP species. Regardless of the pathogenicity of the virus infection and regardless of the NHP species studied, the magnitude of viremia, as measured by area under the curve, during the first 4 weeks of infection correlated positively with viremia in chronic infection. The magnitude of cytokine and chemokine responses during primary infection also correlated positively with both acute-phase and chronic viremia. However, the pattern and levels of specific cytokines and chemokines produced differed between nonprogressive and progressive SIV infection models. The qualitative differences in the early immune response in pathogenic and nonpathogenic infections identified here may be important determinants of the subsequent disease course.

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Persistently Elevated Serum Interleukin-6 Predicts Mortality Among Adults Receiving Combination Antiretroviral Therapy in Botswana: Results from a Clinical Trial

Cited by 34 publications

References 29 publications

HIV and Obesity Comorbidity Increase Interleukin 6 but Not Soluble CD14 or D-Dimer

HIV and Obesity Comorbidity Increase Interleukin 6 but Not Soluble CD14 or D-Dimer

Clinical and Immunologic Predictors of Death After an Acute Opportunistic Infection: Results from ACTG A5164

Magnitude and Quality of Cytokine and Chemokine Storm during Acute Infection Distinguish Nonprogressive and Progressive Simian Immunodeficiency Virus Infections of Nonhuman Primates

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