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Inflammation, HIV, HCV & Alcohol in HIV+
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from Jules: 24% had high inflammation score associated with increased mortality risk....This patient cohort had high rates of alcohol use, HCV, cocaine/heroin use and smoking and 41% were African-American.......observational cohort study [HIV-Longitudinal Interrelationships of Viruses and Ethanol (HIV-LIVE)].....Recruitment for the HIV-LIVE cohort occurred from a previous cohort study; an intake clinic for HIV-infected patients; HIV primary care and specialty clinics at two hospitals; homeless shelters; drug treatment programs. Previous studies have found mortality associated with inflammation AND the development of non-AIDS comorbidities, but this study was conducted largely in HIV+ with a history of substance, only 62% were on ART, and I think an important message is that lifestyle of these individuals contributes to higher inflammation risk which contributes to higher mortality risk. Yes HCV can contribute to inflammation, as any ongoing viral disease can, like HIV, as well illicit drug use particularly heroin and cocaine abuse.
"There was a significant association between inflammatory burden score and mortality [hazard ratio = 2.18.....The finding that
higher inflammatory burden (having 3 cytokines in the highest quartile) ......participants in the HIV-LIVE cohort represent a population at risk for chronic inflammation, with frequent alcohol or other drug use and HCV coinfection, and we accounted for these cofactors in the analysis......Consistent with prior studies, we observed significant associations between age, CD4+ cell count, HCV, cocaine/heroin use and mortality ......In summary, high levels of IL-6 are associated with mortality in a cohort of HIV-infected persons with alcohol problems and high burden of HCV coinfection. This study supports the hypothesis that chronic inflammation, and specifically elevation in levels of cytokine IL-6, may lead to an increased risk of death in patients with HIV."
Systemic Effects of Inflammation on Health during Chronic HIV Infection - (10/17/13)
Associations of Inflammatory Markers With AIDS and Non-AIDS Clinical Events After Initiation of Antiretroviral Therapy: AIDS Clinical Trials Group A5224s, a Substudy of ACTG A5202 - (01/21/14)
Heavy alcohol users (31%) & cocaine/heroin users (49.8%) were included in this study, 76% smoked, 50% had HCV, 41% were African-American, 25% females.
Recruitment for the HIV-LIVE cohort occurred from a previous cohort study; an intake clinic for HIV-infected patients; HIV primary care and specialty clinics at two hospitals; homeless shelters; drug treatment programs; subject referrals......24% at baseline were in the highest inflammation burden category but 161 of the 400 patients in this analysis were in the 2 higher inflammatory burden category, in this study analysis those in the highest burden category had statistically significant increased risk for mortality but not those in the 2nd highest category (see table 2: An additional independent variable of interest was inflammatory burden score, defined as the number of biomarkers (0, 1, 2, 3) in the highest quartile.
There was a significant association between inflammatory burden score and mortality [hazard ratio = 2.18 ......participants in the HIV-LIVE cohort represent a population at risk for chronic inflammation, with frequent alcohol or other drug use and HCV coinfection,
and we accounted for these cofactors in the analysis......Consistent with prior studies, we observed significant associations between age, CD4+ cell count, HCV, cocaine/heroin use and mortality [33-35]. Interestingly, among covariates, current heavy alcohol use and smoking were not associated with mortality, possibly because of competing risks.......In summary, high levels of IL-6 are associated with mortality in a cohort of HIV-infected persons with alcohol problems and high burden of HCV coinfection. This study supports the hypothesis that chronic inflammation, and specifically elevation in levels of cytokine IL-6, may lead to an increased risk of death in patients with HIV.
In the fully adjusted model (not shown in Table 2) which simultaneously included IL-6, CRP, and all other covariates, IL-6 levels were independently associated with mortality [hazard ratio (95% CI) 2.57 (1.58-4.82), P<0.01]. The association with CRP was attenuated and no longer significant [1.59 (0.93-2.72), P=0.09]. Among covariates, age, cocaine/heroin use, CD4 cell count less than 200, and HCV infection were associated with mortality [hazard ratio (95% CI) 1.04 (1.01-1.08) P=40.01, 1.91 (1.18-3.11) P<0.01, 3.13 (1.97-4.96) P<0.01, and 1.93 (1.12-3.32) P=0.02, respectively] [31].
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Inflammatory cytokines and mortality in a cohort of HIV-infected adults with alcohol problems
AIDS: Post Acceptance Jan 7 2014
Fuster, Daniel; Cheng, Debbie M.; Quinn, Emily K.; Armah, Kaku A.; Saitz, Richard; Freiberg, Matthew S.; Samet, Jeffrey H.; Tsui, Judith I.
aClinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Boston Medical Center and Boston University School of Medicine, bDepartment of Biostatistics, cData Coordinating Center, Boston University School of Public Health, Boston, Massachusetts, dDepartment of Epidemiology, University of Pittsburgh Graduate School of Public Health, eDivision of General Internal Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, fDepartment of Epidemiology, and gDepartment of Community Health Sciences, Boston University School of Public Health, Boston, Massachusetts, USA.
Abstract
Background: HIV infection leads to chronic inflammation and alterations in levels of inflammatory cytokines. The association between cytokine levels and mortality in HIV infection is not fully understood.
Methods: We analyzed data from a cohort of HIV-infected adults with alcohol problems who were recruited in 2001-2003, and were prospectively followed until 2010 for mortality using the National Death Index. The main independent variables were inflammatory biomarkers [interleukin-6 (IL-6), IL-10, tumor necrosis factor-[alpha], C-reactive protein, serum amyloid A, monocyte chemotactic protein-1, and cystatin-C], measured at baseline in peripheral blood and categorized as high (defined as being in the highest quartile) vs. low. A secondary analysis was conducted using inflammatory burden score, defined as the number of biomarkers in the highest quartile (0, 1, 2 or >=3). Cox models were used to assess the association between both biomarker levels and inflammatory burden with mortality adjusting for potential confounders.
Results: Four hundred HIV-infected patients were included (74.8% men, mean age 42 years, 50% hepatitis C virus-infected). As of 31 December 2009, 85 patients had died. In individual multivariable analyses for each biomarker, high levels of IL-6 and C-reactive protein were significantly associated with mortality [hazard ratio = 2.49 (1.69-5.12), P <0.01] and [hazard ratio = 1.87 (1.11-3.15), P = 0.02], respectively. There was also a significant association between inflammatory burden score and mortality [hazard ratio = 2.18 (1.29-3.66) for >=3 vs. 0, P = 0.04]. In the fully adjusted multivariable analysis, high levels of IL-6 remained independently associated with mortality [hazard ratio = 2.57 (1.58-4.82), P <0.01].
Conclusion: High IL-6 levels and inflammatory burden score were associated with mortality in a cohort of HIV-infected adults with alcohol problems.
Introduction
Individuals with HIV are living longer [1], but the survival benefit is not observed in all subgroups, particularly those who use alcohol or other drugs [2].
Besides well known mortality predictors like CD4 cell count, HIV RNA, access to and adherence to antiretroviral therapy (ART), comorbidities, and substance
abuse [2-4], there is a growing interest in chronic inflammation [5,6]. Increased inflammation is a concern in an aging HIV-infected population, as HIV leads to
alterations in inflammatory cytokines and coagulation marker levels despite ART [7].
Increased levels of interleukin-6 (IL-6), a pro-inflammatory cytokine, and fibrinogen, an acute-phase protein, are associated with greater HIV RNA levels [8] and advanced HIV infection [9]. IL-6 is associated with mortality in some cohorts of HIV-infected patients [5,6], but not in all [10]. Others have shown that C-reactive protein (CRP), another acute-phase reactant, and fibrinogen are predictors of mortality, even with CD4 cell counts more than 500 cells/ml [6]. Cystatin-C levels, a surrogate biomarker of kidney function, have also been associated with mortality [11]. Furthermore, studies in the early ART era found associations between IL-10 and tumor necrosis factor-a (TNF-a) and mortality [12,13]. Chronic inflammation in HIV-infected patients is believed to increase non-AIDS mortality, especially cardiovascular mortality. However, information about the impact of serum amyloid A (SAA) and monocyte chemotactic protein-1 (MCP-1), two biomarkers of atherosclerosis on mortality in HIV infection is scarce [14,15].
The majority of studies of biomarkers of inflammation and mortality in HIV infection have been performed in randomized clinical trials of ART initiation and
interruption [5,16], and the association of cytokine levels and mortality in other settings is not well understood. Studies have often focused on individual biomarkers, and have rarely adjusted for biomarkers simultaneously in order to determine independent effects. Both alcohol use and chronic hepatitis C virus (HCV) infection are also associated with increased inflammation in HIV-infected patients that can be partially explained by increased intestinal permeability [17]. There is a need to study the impact of biomarkers of inflammation in HIV-infected patients with alcohol problems and high prevalence of HCV coinfection, and to adjust for these covariates in order to understand whether the effects of inflammation are independent.
In this study, we explored the association between inflammatory biomarker levels [IL-6, IL-10, TNF-a, CRP, SAA, MCP-1, and cystatin-C] and mortality
in a cohort of HIV-infected patients with alcohol problems.
Study design
This was a prospective analysis of patients included in an observational cohort study [HIV-Longitudinal Interrelationships of Viruses and Ethanol (HIV-LIVE)],
in which assessments occurred every 6 months over a maximum of 42 months [18].
Participants
Recruitment for the HIV-LIVE cohort occurred from a previous cohort study; an intake clinic for HIV-infected patients; HIV primary care and specialty clinics at two hospitals; homeless shelters; drug treatment programs; subject referrals; and flyers. Enrollment occurred between August 2001 and July 2003, and the last study visit occurred in 2006. Eligibility criteria have been described in detail elsewhere [19]. Briefly, participants had to be HIV-infected adults with at least two affirmative responses to the CAGE alcohol-screening questionnaire [20], or physician investigator diagnosis of alcoholism; and had to speak English or Spanish. Exclusion criteria were cognitive impairment [21,22] and inability to provide informed consent [19]. The Institutional Review Boards of Boston Medical Center and Beth Israel Deaconess Medical Center approved this study.
Results
Between 2001 and 2003, 400 participants were enrolled in the HIV-LIVE cohort and, as of 31 December 2009, 85 participants had died. Median follow-up was 6.7 years and included 2688.5 person-years; mortality rate was 3.16 deaths/100 person-years (95% CI 2.56-3.91). Table 1 shows the baseline characteristics of the study participants. The median (interquartile range) levels of inflammatory biomarkers for the entire sample were as follows: IL-6 2.75 (1.52-4.81) pg/ml, IL-10 5.03 (3.08-8.20) pg/ml, TNF-a 7.15 (4.85-9.70) pg/ml, CRP 1.48 (0.60-3.47)mg/ml, cystatin-C 0.77 (0.67-0.91) ng/ml, MCP-1 577 (397-815) pg/ml, and SAA 3.2 (1.8-6.4)mg/ml.
Examining each biomarker separately, and adjusting for age, gender, race, heavy alcohol and cocaine/heroin use, smoking, HCV infection, ART, CD4+ cell count, and HIV RNA, we found that IL-6 [hazard ratio 2.94 (1.69-5.12) P<0.01] and CRP [hazard ratio 1.87 (1.11-3.15), P=0.02] were associated with mortality (Table 2). Inflammatory burden at least 3 was also associated with mortality [hazard ratio 2.18 (1.29-3.66), P<0.01].
In the fully adjusted model (not shown in Table) which AQ5 simultaneously included IL-6, CRP, and all other covariates, IL-6 levels were independently associated with mortality [hazard ratio (95% CI) 2.57 (1.58-4.82), P<0.01]. The association with CRP was attenuated and no longer significant [1.59 (0.93-2.72), P=0.09]. Among covariates, age, cocaine/heroin use, CD4+ cell count less than 200, and HCV infection were associated with mortality [hazard ratio (95% CI) 1.04 (1.01-1.08) P=0.01, 1.91 (1.18-3.11) P<0.01, 3.13 (1.97-4.96) P<0.01, and 1.93 (1.12-3.32) P1/40.02, respectively] [31].
Discussion
In this exploratory study, high IL-6 levels were independently associated with mortality in HIV-infected adults with alcohol problems, even after adjustment for
ART use, CD4+ cell count, HIV RNA, alcohol, drug use, and HCV. In addition, having an inflammatory burden at least 3 was also associated with mortality.
These results are consistent with previous literature [5,32], but this study adds that IL-6 is the more prominent cytokine in independently predicting mortality. IL-6 levels are increased in those with elevated HIV RNA and in those who interrupt ART [8]. Given that IL-6 levels remain elevated after the introduction of ART [16], it seems that ART is not able to fully overcome the chronic inflammatory state present in HIV-infected patients.
CRP was associated with mortality in the individually adjusted models, which is also consistent with prior research [6]. However, our study adds to the literature by finding that after adjustment for IL-6, CRP was not significantly associated with mortality. The finding that higher inflammatory burden (having 3 cytokines in
the highest quartile) is associated with mortality is also consistent with prior research [32]. Previously in this cohort, investigators found that inflammatory burden was independently associated with HIV and HCV replication [29]; this study contributes further to demonstrate that inflammatory burden predicts mortality.
We also found that, in the unadjusted analysis, cystatin-C, IL-10, and TNF-a were associated with mortality, consistent with prior research [11-13]. However, in the adjusted analysis, these associations were no longer significant. Confounding may account for these results, but it is also possible that we might be underpowered to detect associations between mortality and each biomarker.
Consistent with prior studies, we observed significant associations between age, CD4+ cell count, HCV, cocaine/heroin use and mortality [33-35]. Interestingly, among covariates, current heavy alcohol use and smoking were not associated with mortality, possibly because of competing risks.
Strengths of the present study are a moderate sample size, extended follow-up period, a large panel of biomarkers, and the use of inflammatory burden score.
Also, participants in the HIV-LIVE cohort represent a population at risk for chronic inflammation, with frequent alcohol or other drug use and HCV coinfection, and we accounted for these cofactors in the analysis.
This study has several limitations. First, we measured biomarker levels in serum at baseline; it is possible that serum levels do not reflect the levels in other body compartments. Also, changes in biomarkers or biomarkers closer to time of death might have a greater impact on mortality [5]. Second, the modest number of outcomes might have limited our ability to detect associations between other biomarkers besides IL-6 and all-cause mortality. In addition, the relatively small
numbers of outcomes did not allow us to examine relationships between biomarkers and cause-specific types of deaths (such as death from cardiovascular disease); however, the majority of deaths were related to HIV or HCV. Third, time-dependent covariates were measured up to 2006, whereas mortality data could be extracted until 2010.
Conclusion
In summary, high levels of IL-6 are associated with mortality in a cohort of HIV-infected persons with alcohol problems and high burden of HCV coinfection.
This study supports the hypothesis that chronic inflammation, and specifically elevation in levels of cytokine IL-6, may lead to an increased risk of death in patients with HIV.
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