For everyone who lived through the period prior to the advent of combination antiretroviral therapy (ART), the vanquishing of the opportunistic diseases of severe immune deficiency – such as PML, MAC, CMV retinitis and other horrors – is a source of profound relief. But as concerns about OIs have diminished, another longer-term worry has begun to emerge in the form of inflammation. At the time combination ART first became available, the evidence of the role of immune activation in driving progression to AIDS was just beginning to gain acceptance among the research community. Understandably, however, the main focus was on the damage that persistent activation was doing to the immune system (e.g. T cell loss and dysfunction) and relatively little attention was paid to the potential impact on other organ systems and health outcomes. There were exceptions, such as dementia, where the contribution of inflammation in the brain was well described, and HIV-associated nephropathy (HIVAN), which had been linked to inflammation in the kidneys, but problems such as arteriosclerosis and cardiovascular disease were largely off the radar screen.
This all changed radically a few years ago when results of the SMART (Strategic Timing of AntiRetroviral Therapy) trial were announced and published. The goal of SMART was to evaluate whether ART could be used intermittently to keep CD4 T-cell counts out of the danger zone for opportunistic infections, as opposed to using ART continuously. Based on individual anecdotes and smaller studies, many hoped that intermittent ART would at least be equivalent to continuous, and might even be superior in terms of quality of life due to reduced side effects. But the SMART results were unequivocal, showing that intermittent ART was associated with a doubling of the risk of serious illness and death compared to continuous ART. The absolute risk of illness and death was relatively low in both arms (around 3% and 1.5% respectively) but the difference was highly statistically significant and the large sample size of 5,472 people meant the findings were unusually robust. Differences between the arms were also seen at all CD4 strata and not just the lowest. Most of the illnesses that occurred were not AIDS-defining events based on the CDC criteria, but cardiovascular, kidney and liver disease and cancers.
The researchers who conducted SMART collaborated with specialists from outside of the HIV research field to analyze factors linked to illness and mortality in the trial. One such expert, Lewis Kuller, led a study that showed that biomarkers of inflammation (specifically IL-6 and D-dimer) were strongly linked to mortality in SMART, with odds ratios that dwarfed the associations Kuller had previously documented in non-HIV-infected elderly people.
These findings have led to an explosion of research into inflammatory biomarkers and health outcomes in HIV infection. Four new studies are appended below. The first paper from the Journal of Infectious Diseases, by Jacqueline Neuhaus and colleagues, shows that biomarkers of inflammation, coagulation, and kidney function were significantly higher among SMART participants (on or off ART) compared to a control group comprised of two large population-based studies named MESA and CARDIA. Even when the analysis was restricted to participants on ART with viral load levels less than 400 copies/ml, all the measured biomarkers (high‐sensitivity C‐reactive protein, IL-6, D-dimer and cystatin C) were significantly elevated compared to controls. Of note, the laboratory measurements were all done in the same centralized laboratory using the same methods. The second JID paper takes a different tack and looks at correlations between baseline levels of several immune activation markers and clinical events after starting ART. Several markers were associated with illness and mortality even when analysis was restricted to events that only occurred after 51 weeks or more of ART.
Two additional papers look at C-reactive protein in different settings: in a study just published in the Journal of AIDS, researchers in Rakai, Uganda show that CRP levels increase during disease progression in their cohort of HIV-positive people despite a lack of evidence of microbial translocation. The second study investigates high sensitivity CRP (hsCRP) and other inflammatory biomarkers among HIV-positive children at the Rainbow Babies and Children's Hospital in Cleveland. The researchers report that hsCRP levels were significantly higher in children with HIV compared to matched uninfected controls, but other biomarkers did not show significant differences. The majority of the children in the study were on ART with viral loads less than 50 copies/ml. A measurement of the health of the carotid artery called intima-media thickness (IMT) was associated with hsCRP levels (as has been reported in adults), raising the concern that HIV infection may increase risk of cardiovascular disease across all age groups.
On a related note, the Forum for Collaborative HIV Research is sponsoring a public meeting on the subject of HIV infection and cardiovascular disease at the Doubletree Hotel, Washington, DC from 10am to 5pm on June 23. Registration is free and available online although the information on the meeting only seems to have gone out via email and it is not yet on the forum’s website. For those unable to attend in person the meeting is also slated to be webcast.
The Journal of Infectious Diseases 2010;201:1783–1785
DOI: 10.1086/652751
EDITORIAL COMMENTARY
Inflammation and Complications of HIV Disease
Michael P. Dubé and Fred R. Sattler
Department of Medicine and Division of Infectious Diseases, Keck School of Medicine, University of Southern California, Los Angeles
The Journal of Infectious Diseases 2010;201:1788–1795
DOI: 10.1086/652749
Markers of Inflammation, Coagulation, and Renal Function Are Elevated in Adults with HIV Infection
Jacqueline Neuhaus,1 David R. Jacobs, Jr,1 Jason V. Baker,1,2 Alexandra Calmy,7 Daniel Duprez,1 Alberto La Rosa,8 Lewis H. Kuller,3 Sarah L. Pett,9 Matti Ristola,10 Michael J. Ross,4 Michael G. Shlipak,5 Russell Tracy,6 and James D. Neaton,1 for the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) Strategies for Management of Anti‐Retroviral Therapy (SMART), Multi‐Ethnic Study of Atherosclerosis (MESA), and Coronary Artery Development in Young Adults (CARDIA) Research Groupsa
1University of Minnesota and 2Hennepin County Medical Center, Minneapolis, Minnesota; 3University of Pittsburgh, Pittsburgh, Pennsylvania; 4Mount Sinai School of Medicine, New York, New York; 5University of California, San Francisco; 6University of Vermont, Burlington; 7Geneva University Hospital, Geneva, Switzerland; 8Asociacion Civil Impacta Salud y Educacion, Lima, Peru; 9University of New South Wales, Sydney, Australia; 10Helsinki University Central Hospital, Helsinki, Finland
Background. Human immunodeficiency virus (HIV) replication and immune activation may increase inflammation and coagulation biomarkers. Limited data exist comparing such biomarkers in persons with and without HIV infection.
Methods. For persons 45–76 years of age, levels of high‐sensitivity C‐reactive protein (hsCRP), interleukin (IL)–6, D‐dimer, and cystatin C were compared in 494 HIV‐infected individuals in the Strategies for Management of Anti‐Retroviral Therapy (SMART) study and 5386 participants in the Multi‐Ethnic Study of Atherosclerosis (MESA) study. For persons 33–44 years of age, hsCRP and IL‐6 levels were compared in 287 participants in the SMART study and 3231 participants in the Coronary Artery Development in Young Adults (CARDIA) study.
Results. hsCRP and IL‐6 levels were 55% (P<.001) and 62% (P<.001) higher among HIV‐infected participants than among CARDIA study participants. Compared with levels noted in MESA study participants, hsCRP, IL‐6, D‐dimer, and cystatin C levels were 50%, 152%, 94%, and 27% higher, respectively (P<.001, for each), among HIV‐infected participants. HIV‐infected participants receiving antiretroviral therapy who had HIV RNA levels 400 copies/mL had levels higher (by 21% to 60%) (P<.001) than those in the general population, for all biomarkers.
Conclusions. hsCRP, IL‐6, D‐dimer, and cystatin C levels are elevated in persons with HIV infection and remain so even after HIV RNA levels are suppressed with antiretroviral therapy. Additional research is needed on the pathophysiology of HIV‐induced activation of inflammatory and coagulation pathways, to guide potential interventions.
The Journal of Infectious Diseases 2010;201:1796–1805
DOI: 10.1086/652750
Robert C. Kalayjian,1 Rhoderick N. Machekano,1 Nesrine Rizk,1 Gregory K. Robbins,3 Rajesh T. Gandhi,3 Benigno A. Rodriguez,2 Richard B. Pollard,4 Michael M. Lederman,2 and Alan Landay5
1MetroHealth Medical Center and 2University Hospitals–Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; 3Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;4University of California–Davis Medical Center, Sacramento; 5Rush Medical College, Chicago, Illinois
Background. To identify inflammatory pathways that may contribute to the pathogenesis of human immunodeficiency virus (HIV) disease, we explored associations between AIDS or death and different inflammatory markers, including selected soluble tumor necrosis factor superfamily receptors (sTNFRs) and ligands, interleukin (IL)–6, and CD8 T cell activation, in individuals treated with highly active antiretroviral therapy (HAART).
Methods. A case‐control study of subjects in AIDS Clinical Trials Group (ACTG) protocols 384 and 5015, who were matched according to the CD4 cell count and plasma viral load at baseline, was performed using conditional logistic regression.
Results. Higher pretreatment concentrations of sTNFR‐1, sCD27, sCD40L, and plasma IL‐6 were associated with a new AIDS‐defining illness or death in separate models adjusted for age, sex, hemoglobin, and the latest CD4 cell counts. In additional models that excluded case patients with opportunistic infections, sTNFR‐1, sCD27, and sCD40L were each associated with a new AIDS‐defining malignancy or death that developed at a median of 51 weeks after initiation of HAART, by which time the majority of subjects had a CD4 cell count of >200 cells/cm3 and had achieved a plasma viral load of <50 copies/mL.
Conclusion. These data are compatible with a model in which these soluble inflammatory markers identify pathways that may contribute to the pathogenesis of HIV disease progression, pathways that might not be a direct consequence of ongoing HIV type 1 replication.
J Acquir Immune Defic Syndr. 2010 May 12. [Epub ahead of print]
Redd AD, Eaton KP, Kong X, Laeyendecker O, Lutalo T, Wawer MJ, Gray RH, Serwadda D, Quinn TC; on behalf of the Rakai Health Sciences Program.
From the Laboratory of Immunoregulation, Division of Intramural research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Population, Family, and Reproductive Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; Rakai Health Sciences Program, Kalisizo, Uganda; and School of Public Health, Makerere University, Kampala, Uganda.
Abstract
INTRODUCTION: Microbial translocation has been implicated as a contributing factor to the heightened immune activation observed during HIV-1 disease progression. When examined in a longitudinal study of HIV-1 seroconverters in Rakai, Uganda, microbial translocation was not associated with HIV-1 disease progression. However, the role of general immune activation in HIV disease progression in this population was not fully examined. METHODS: Longitudinal serum samples of HIV-1 seroconverters in three HIV-1 disease progression groups [long-term nonprogressors (LTNP), standard progressors (SP), and rapid progressors (RP)] from Rakai, Uganda, were tested for levels of C-reactive protein (CRP), a marker for immune activation. RESULTS: CRP levels significantly increased in the SP group (P < 0.0001) but not in the RP group or the LTNP group. CRP levels during the first year post-HIV seroconversion in the RP group were significantly higher than those observed in the LTNP group (P < 0.05). For the entire population, CRP levels negatively correlated with lipopolysaccharide levels (P < 0.05) and were not associated with endotoxin antibody levels. CONCLUSIONS: This study suggests that in this population, increased immune activation is significantly associated with HIV-1 disease progression but not microbial translocation.
Atherosclerosis. 2010 Apr 24. [Epub ahead of print]
Ross AC, O'Riordan MA, Storer N, Dogra V, McComsey GA.
Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH, United States.
Abstract
OBJECTIVES: HIV+ patients are at increased risk of cardiovascular disease (CVD). Inflammation plays a role in adults, but has not yet been assessed in HIV+ children. We compared proinflammatory cytokines and adhesion molecules in HIV+ children versus healthy controls, and assessed their relationship to carotid intima-media thickness (IMT). METHODS: Evaluations were performed on 27 HIV+ children and 30 HIV-healthy controls (2-21 years) who were prospectively enrolled in our pediatric cohort. Measurements included internal carotid artery (ICA) and common carotid artery (CCA) IMT, fasting lipids, insulin, proinflammatory markers (TNF-alpha, soluble TNF receptors (sTNFR-I, -II), IL-6, high sensitivity C-reactive protein (hsCRP), myeloperoxidase (MPO)), and adhesion molecules (soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1 (sVCAM-1), von Willebrand factor). RESULTS: Among HIV+, mean age was 11 years, 33% males, 70% black. 96% acquired HIV vertically; median CD4 count (CD4%) was 1058 (35%) cells/ml; 96% were on antiretroviral therapy (ART); 70% had HIV-1 RNA <50copies/ml. Groups were similar in age, race, sex, BMI, proinflammatory cytokines, adhesion markers, and carotid IMT except for hsCRP which was higher in HIV+ (P<0.001). In multiple regression analyses, hCRP, age, and female sex were positively associated with IMT. ART duration and sTNFR-II were positively associated with sVCAM-1. CONCLUSIONS: This study shows increased hsCRP in HIV+ children compared to healthy controls. As seen in adults, hCRP was associated with carotid IMT, which support a role for inflammation in CVD risk of HIV+ children
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