Pre-ART Levels of Inflammation and Coagulation Markers Are Strong Predictors of Death in a South African Cohort with Advanced HIV Disease

Project Phidisa, Pretoria, South Africa.
PLoS ONE (Impact Factor: 3.23). 03/2012; 7(3):e24243. DOI: 10.1371/journal.pone.0024243
Source: PubMed

ABSTRACT Levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer predict mortality in HIV patients on antiretroviral therapy (ART) with relatively preserved CD4+ T cell counts. We hypothesized that elevated pre-ART levels of these markers among patients with advanced HIV would be associated with an increased risk of death following the initiation of ART.
Pre-ART plasma from patients with advanced HIV in South Africa was used to measure hsCRP, IL-6 and D-dimer. Using a nested case-control study design, the biomarkers were measured for 187 deaths and two controls matched on age, sex, clinical site, follow-up time and CD4+ cell counts. Odds ratios were estimated using conditional logistic regression. In addition, for a random sample of 100 patients, biomarkers were measured at baseline and 6 months following randomization to determine whether ART altered their levels.
Median baseline biomarkers levels for cases and controls, respectively, were 11.25 vs. 3.6 mg/L for hsCRP, 1.41 vs. 0.98 mg/L for D-dimer, and 9.02 vs. 4.20 pg/mL for IL-6 (all p<0.0001). Adjusted odds ratios for the highest versus lowest quartile of baseline biomarker levels were 3.5 (95% CI: 1.9-6.7) for hsCRP, 2.6 (95%CI 1.4-4.9) for D-dimer, and 3.8 (95% CI: 1.8-7.8) for IL-6. These associations were stronger for deaths that occurred more proximal to the biomarker measurements. Levels of D-dimer and IL-6, but not hsCRP, were significantly lower at month 6 after commencing ART compared to baseline (p<0.0001).
Among patients with advanced HIV disease, elevated pre-ART levels of hsCRP, IL-6 and D-dimer are strongly associated with early mortality after commencing ART. Elevated levels of inflammatory and coagulation biomarkers may identify patients who may benefit from aggressive clinical monitoring after commencing ART. Further investigation of strategies to reduce biomarkers of inflammation and coagulation in patients with advanced HIV disease is warranted.
Parent study: NCT00342355.

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Available from: Julia A Metcalf, Sep 28, 2015
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    • "Acute and chronic HIV infection triggers the release of inflammatory mediators and cytokines. In patients with advanced HIV disease, elevated C-reactive protein (CRP), IL-6 and D-dimer levels before initiating HAART are strongly associated with early mortality [17]. These inflammatory mediators have previously been evaluated in HIV/AIDS patients to stratify cardiovascular risk, disease progression, infection diagnosis and prognosis [18-20]. "
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    ABSTRACT: In recent years, the incidence of sepsis has increased in critically ill HIV/AIDS patients, and the presence of severe sepsis emerged as a major determinant of outcomes in this population. The inflammatory response and deregulated cytokine production play key roles in the pathophysiology of sepsis; however, these mechanisms have not been fully characterized in HIV/AIDS septic patients. We conducted a prospective cohort study that included HIV/AIDS and non-HIV patients with septic shock. We measured clinical parameters and biomarkers (C-reactive protein and cytokine levels) on the first day of septic shock and compared these parameters between HIV/AIDS and non-HIV patients. We included 30 HIV/AIDS septic shock patients and 30 non-HIV septic shock patients. The HIV/AIDS patients presented low CD4 cell counts (72 [7-268] cells/mm(3)), and 17 (57%) patients were on HAART before hospital admission. Both groups were similar according to the acute severity scores and hospital mortality. The IL-6, IL-10 and G-CSF levels were associated with hospital mortality in the HIV/AIDS septic group; however, the CRP levels and the surrogates of innate immune activation (cytokines) were similar among HIV/AIDS and non-HIV septic patients. Age (odds ratio 1.05, CI 95% 1.02-1.09, p=0.002) and the IL-6 levels (odds ratio 1.00, CI 95% 1.00-1.01, p=0.05) were independent risk factors for hospital mortality. IL-6, IL-10 and G-CSF are biomarkers that can be used to predict prognosis and outcomes in HIV/AIDS septic patients. Although HIV/AIDS patients are immunocompromised, an innate immune response can be activated in these patients, which is similar to that in the non-HIV septic population. In addition, age and the IL-6 levels are independent risk factors for hospital mortality irrespective of HIV/AIDS disease.
    PLoS ONE 07/2013; 8(7):e68730. DOI:10.1371/journal.pone.0068730 · 3.23 Impact Factor
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    • "Higher levels of inflammatory and coagulation markers are strongly related to death from any cause in people taking ART in developed countries [10]. Pre-ART levels of some of the same markers predicted death after ART began in a randomized trial involving 1771 members of the South African Defence Force and their dependents [11]. Lotty Ledwaba (Project Phidisa, Pretoria) conducted a case-control comparison nested in a randomized trial comparing different antiretroviral regimens. "
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    ABSTRACT: Studies in several sub-Saharan African countries demonstrated that the expansion of antiretroviral therapy (ART) access is not only beneficial for people living with HIV, but also results in significant declines in tuberculosis and malaria incidence and prevalence, bolstering arguments for earlier and increased ART access and contributing to a growing understanding of co-epidemic dynamics. Several studies demonstrated that using standard triple-drug ART in resource-limited settings can reduce vertical transmission by as much as less than 1% if continued throughout breastfeeding. The Nevirapine Resistance Study (NEVEREST) results provided proof of concept that nevirapine could be used as part of a paediatric second-line regimen, despite exposure to nevirapine prophylaxis for vertical transmission, following successful suppression on a lopinavir/ritonavir-based regimen. A South African study found that high pre-treatment levels of inflammatory and coagulation markers were strong predictors of death, reflecting similar findings in high-income countries and reinforcing the shift towards viewing HIV as a chronic, inflammatory disease. An early study of a new integrase inhibitor (S/GSK1349572) indicated strong potency and limited cross-resistance with raltegravir, the only integrase inhibitor currently approved for treatment.
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