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Inflammation-Related Morbidity and Mortality
Among HIV-Positive Adults: How Extensive Is It?
 
 
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JAIDS Jan 2018 - Hart, Brian B. BA*; Nordell, Anna D. MS ; Okulicz, Jason F. MD , ; Palfreeman, Adrian MD; Horban, Andrzej MD; Kedem, Eynat MD; Neuhaus, Jacqueline MS*; Jacobs, David R. Jr PhD; Duprez, Daniel A. MD, PhD ; Neaton, James D. PhD*for the INSIGHT SMART and ESPRIT Groups
 
"This adds some support to our hypothesis that the consequences of underlying inflammation are broader than the end-organ diseases referred to as serious non-AIDS conditions.....Morbidity and mortality associated with activation of inflammatory and coagulation pathways include conditions other than AIDS, CVD, and non-AIDS cancer events. Effective inflammation-dampening interventions could greatly affect the health of people with HIV.
 
ChrIRD grade 4 events accounted for 49% of the participants with a grade 4 event. The most common ChrIRD events were gastroenteritis (8 participants), hepatic cirrhosis (7), acute renal failure (6), and acute pancreatitis (6). The most common non-ChrIRD grade 4 events were depression (7), back pain (5), inguinal hernia (5), and suicide attempt (5)
 
In conclusion, we found that IL-6 and D-dimer were strongly associated with grade 4 events. These events are associated with an increased risk of death, and among participants on suppressive ART with CD4+ counts &8805; 300 cells/mm3, occur at a much higher rate than AIDS, CVD, and non-AIDS cancer events. Our findings showed that potentially life-threatening conditions associated with the activation of inflammatory and coagulation pathways due to HIV are more extensive than AIDS and SNAs which heretofore have been considered
 
Grade 4 events represent a variety of potentially life-threatening conditions. We used findings from a recent study in the general population to categorize grade 4 events as those likely to have an inflammatory component as a predominant pathology. ChrIRD events represented 49% of the participants with grade 4 events, and these events were more strongly associated with baseline IL-6 than non-ChrIRD events. However, the associations of baseline D-dimer with ChrIRD and non-ChrIRD events were similar-both significant and of a magnitude similar to the association with CVD. Given the positive, but moderate, correlation between IL-6 and D-dimer,16,29 in the setting of HIV, there may be larger number of grade 4 events due to HIV-induced activation of inflammatory and coagulation pathways than we classified as ChrIRD. Although more research on the extent of morbidity and mortality due to inflammation is needed, it seems clear that there are a number of conditions associated with an increased risk of death other than AIDS and those that we and others have considered "serious non-AIDS conditions" that are influencing the health of patients with HIV and that could be targets of intervention trials that aim to reduce inflammation.
 
It is possible that the associations of IL-6 and D-dimer with grade 4 events may be different among patients with higher nadir CD4+ cell counts. IL-6 levels are inversely related to nadir CD4+ counts30 but D-dimer levels are positively associated with nadir CD4+ cell counts"
 
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Objective: To determine the rate of grade 4, potentially life-threatening events not attributable to AIDS, cardiovascular disease (CVD), or non-AIDS cancer among participants on antiretroviral therapy and to describe associations of these events with interleukin-6 (IL-6) and D-dimer.
 
Design: Cohort study.
 
Methods: HIV-infected participants on antiretroviral therapy (N = 3568) with an HIV-RNA level ≤ 500 copies/mL were followed for grade 4, AIDS, CVD, non-AIDS cancer, and all-cause mortality events. Grade 4 events were further classified masked to biomarker levels as reflecting chronic inflammation-related disease (ChrIRD) or not (non-ChrIRD). Associations of baseline IL-6 and D-dimer with events were studied using Cox models.
 
Results: Over a median follow-up of 4.3 years, 339 participants developed a grade 4 event (22.9 per 1000 person-years); 165 participants developed a ChrIRD grade 4 event (10.7 per 1000 person-years). Grade 4 events were more common than AIDS (54 participants), CVD (132), and non-AIDS cancer (80) events, any of which developed in 252 participants (17.1 per 1000 person-years). Grade 4 and AIDS events were associated with similar risks of death. Higher IL-6 [hazard ratio (HR) = 1.19 per doubling of biomarker; P = 0.003] and D-dimer (HR = 1.23; P < 0.001) levels were associated with an increased risk of grade 4 events. IL-6 associations were stronger for ChrIRD (HR = 1.38; P < 0.001) than non-ChrIRD grade 4 events (HR = 1.11; P = 0.21).
 
Conclusions: Morbidity and mortality associated with activation of inflammatory and coagulation pathways include conditions other than AIDS, CVD, and non-AIDS cancer events. Effective inflammation-dampening interventions could greatly affect the health of people with HIV.
 
INTRODUCTION
 
A shift from AIDS-related causes of morbidity and mortality to non-AIDS causes such as non-AIDS malignancy, liver cirrhosis, end-stage renal disease, and serious cardiovascular events occurred in patients with HIV nearly 1 decade ago because of the use of potent antiretroviral therapy (ART).1 A recent review examined the evidence suggesting a link between a persistent inflammatory state, even with suppressive ART, and morbidity and mortality attributed to these conditions termed serious non-AIDS events (SNAs) in HIV studies.2
 
As in studies in the general population,3-5 higher levels of inflammatory and coagulation markers have been associated with an increased risk of all-cause mortality,6-8 cardiovascular disease (CVD),9-12 and cancer13 in people with HIV. Furthermore, markers of systemic inflammation, such as interleukin-6 (IL-6), and markers of coagulation, such as D-dimer, are elevated with HIV infection, despite effective ART.14
 
In 2 recent reports,15,16 IL-6 and D-dimer were strongly related to all-cause mortality among participants with HIV. Most of the deaths in these analyses were not attributable to AIDS or serious non-AIDS conditions such as CVD and cancer. This raises the question whether serious conditions other than AIDS, CVD, and cancer that have heretofore not been studied, are a consequence of underlying increased inflammation and coagulation. In this article, we use data from 2 large international trials to describe rates of potentially life-threatening events not attributable to AIDS, CVD, or non-AIDS cancer and assess whether these events have an inflammatory component by studying their association with IL-6 and D-dimer.
 
DISCUSSION
 
Consistent with 2 other reports, which included participants with lower CD4+ counts, we show that grade 4 events are a major source of morbidity among participants with HIV.26,27 Among the participants in our cohort, all of whom had CD4+ counts &8805; 300 cells/mm3 at study entry, the rate of grade 4 events was 3-6 times higher than AIDS, CVD (expanded to include less serious events and CVD events that did not meet ERC criteria), or non-AIDS cancer considered separately and was higher than the rate of these 3 outcomes considered as a single composite outcome.
 
Everyone in our investigation was taking suppressive ART. Thus, we can only speculate whether the grade 4 events are due to underlying HIV disease or to ART. In the Strategic Timing of AntiRetroviral Treatment (START) trial, which compared immediate versus deferred ART in participants with much higher nadir CD4+ counts, rates of grade 4 events and unscheduled hospitalizations were small and not significantly different between the 2 ART strategies.28 This suggests that among participants with higher nadir CD4+ counts, grade 4 events are more likely due to underlying HIV disease and other comorbidities such as hepatitis coinfection, demographics (age and race), and lifestyle factors (eg, hypertension) than ART.
 
We found that baseline measurements of IL-6 and D-dimer, often measured several years before the event, were strongly related to the risk of grade 4 events. The biomarker associations with grade 4 events were similar in strength to those for CVD and non-AIDS cancer, 2 non-AIDS conditions which have been widely studied in HIV.1 This adds some support to our hypothesis that the consequences of underlying inflammation are broader than the end-organ diseases referred to as serious non-AIDS conditions.
 
Grade 4 events represent a variety of potentially life-threatening conditions. We used findings from a recent study in the general population to categorize grade 4 events as those likely to have an inflammatory component as a predominant pathology. ChrIRD events represented 49% of the participants with grade 4 events, and these events were more strongly associated with baseline IL-6 than non-ChrIRD events. However, the associations of baseline D-dimer with ChrIRD and non-ChrIRD events were similar-both significant and of a magnitude similar to the association with CVD. Given the positive, but moderate, correlation between IL-6 and D-dimer,16,29 in the setting of HIV, there may be larger number of grade 4 events due to HIV-induced activation of inflammatory and coagulation pathways than we classified as ChrIRD. Although more research on the extent of morbidity and mortality due to inflammation is needed, it seems clear that there are a number of conditions associated with an increased risk of death other than AIDS and those that we and others have considered "serious non-AIDS conditions" that are influencing the health of patients with HIV and that could be targets of intervention trials that aim to reduce inflammation.
 
It is possible that the associations of IL-6 and D-dimer with grade 4 events may be different among patients with higher nadir CD4+ cell counts. IL-6 levels are inversely related to nadir CD4+ counts30 but D-dimer levels are positively associated with nadir CD4+ cell counts.29 In a recent review article,2 it was suggested that the drivers of inflammation may be different in those who initiate ART early after infection compared with later as in this investigation. This result poses the question of whether the associations of IL-6 and D-dimer with grade 4 events depend on the nadir CD4+ count. The findings from our investigation have implications for the design of trials of novel interventions that target inflammation in HIV. Such trials might be more efficiently performed with composite primary or secondary outcomes that include not only AIDS, CVD, and non-AIDS cancer events but also other inflammatory conditions such as all or a subset of grade 4 events.
 
Strengths of our study include the size of the cohort and the systematic collection of AIDS, CVD, non-AIDS cancer, and grade 4 events over a median follow-up of 4.3 years. Weaknesses include the absence of data on the occurrence of grade 4 events before enrollment. Grade 4 events occurring during follow-up may not be incident events (eg, they could be a worsening of a preexisting condition). Also, although events reviewed by the ERC had extensive documentation, documentation of grade 4 events typically consisted of 2 or 3 terms that defined the medical event. Thus, classification of grade 4 events as CVD and as ChrIRD or non-ChrIRD is imperfect. In addition, some grade 4 events may have been scheduled hospitalizations for procedures/conditions which were not life threatening. Finally, although the median baseline CD4+ count was 547 cells/mm3 for our cohort, the median nadir CD4+ count was 210 cells/mm3. As previously suggested, it will be important to understand the relative rate of grade 4, AIDS, CVD, and non-AIDS cancer and associations of these events with IL-6 and D-dimer among individuals with higher nadirs. In conclusion, we found that IL-6 and D-dimer were strongly associated with grade 4 events. These events are associated with an increased risk of death, and among participants on suppressive ART with CD4+ counts &8805; 300 cells/mm3, occur at a much higher rate than AIDS, CVD, and non-AIDS cancer events. Our findings showed that potentially life-threatening conditions associated with the activation of inflammatory and coagulation pathways due to HIV are more extensive than AIDS and SNAs which heretofore have been considered.

 
 
 
 
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