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Inflammatory Markers Linked to Frailty in HIV-Positive MACS Men
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3rd International Workshop on HIV and Aging, November 5-6, 2012, Baltimore
Mark Mascolini
Markers of inflammation including interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) had higher concentration in HIV-positive men with frailty than without frailty in the Multicenter AIDS Cohort Study (MACS) [1]. Marker levels were slightly higher in HIV-positive than HIV-negative MACS members, but not significantly so.
Research presented at this workshop demonstrated that HIV-positive 50- to 64-year-old men in MACS have a higher prevalence of clinically defined frailty than similarly aged HIV-negative MACS men [2]. And a previously reported MACS analysis determined that persistent frailty-like phenotype before starting antiretrovirals independently predicted AIDS or death [3]. Because frailty is associated with higher expression of inflammatory markers, particularly IL-6, in the general population, MACS investigators conducted this analysis of frailty and inflammation in HIV-positive and negative MACS cohort members, who are gay.
The MACS investigators hypothesized that "markers of inflammation will be higher in men expressing the frailty phenotype than in men not expressing it, after adjustment for covariates and conditions known to affect inflammation." Frailty means screening positive for three or more of the following five conditions: unintentional weight loss, low hand grip strength, slow walking speed, self-reported exhaustion, and self-reported low physical activity. For this study the investigators defined frailty as screening positive at two consecutive study visits within 1 year, and they defined nonfrailty as screening negative at two consecutive visits.
The vast majority of HIV-positive men in this analysis was taking antiretrovirals and had an undetectable viral load. Of 863 men studied, 128 (15%) met the study definition of frailty and 735 did not. Frailty-positive visit pairs proved significantly more prevalent in HIV-positive than HIV-negative men in two age groups: 50 to 59 years old (14.8% versus 8.1%, P < 0.05) and 60 to 69 (19.9% versus 10%, P < 0.05). Men under 50 or over 69 did not differ in frailty visits by HIV status.
Compared with nonfrail men, those with frailty included a higher proportion of current smokers (46% versus 28%) and higher proportions with chronic HCV infection (27% versus 9%), diabetes among those with known diabetes status (26% versus 13%), kidney disease among those with known kidney status (40.5% versus 16%), and clinically defined depression (51% versus 18%) (P < 0.05 for all).
The inflammatory biomarker analysis involved 602 men, 393 HIV-positive and frailty negative, 72 HIV-positive and frailty positive, 117 HIV-negative and frailty-negative, and 20 HIV-negative and frailty-positive. Among HIV-positive men, all the inflammatory markers tested had significantly higher levels in men with frailty than in men without frailty:
-- IL-6: 1.32 vs 0.94 pg/mL*
-- IL-8: 19.36 vs 13.90 pg/mL*
-- TNF-alpha: 11.66 vs 9.48 pg/mL*
-- IP10: 278.1 vs 219.9 pg/mL**
-- MCP-4: 1021.5 vs 904.2 pg/mL**
-- TARC: 694.4 vs 478.2 pg/mL**
*P < 0.05 after adjustment for age, ethnicity, study site, and education level; not significant after adjustment for comorbidities.
**P < 0.05 after adjustment for age, ethnicity, study site, education, and comorbidities (body mass index, smoking, HCV, depression [CES-D >16], hypertension, diabetes, dyslipidemia, kidney disease, liver disease, cancer).
C-reactive protein levels were also significantly higher in HIV-positive men with frailty than in those without frailty (P = 0.002 after adjustment for age, ethnicity, study site, and education level).
In contrast, among HIV-negative men, levels of MCP-4 were significantly lower in those with than without frailty in the analysis that included comorbidities. None of the other biomarker levels differed significantly between frailty-positive and frailty-negative men in the HIV-negative group.
The MACS team suggested that higher levels of IL-6, TNF-alpha, and C-reactive protein in HIV-positive men with versus without frailty suggest monocyte/macrophage activation. Higher concentrations of IP10 could indicate T-cell activation. They noted that they measured biomarkers before they tested men for frailty, but they could not determine frailty onset in this study. The investigators plan a longitudinal analysis of inflammatory biomarkers and frailty.
References
1. Margolick J, Jacobson L, Lopez J, et al. Frailty and circulating concentrations of proinflammatory cytokines and chemokines in HIV-infected and -uninfected men in the Multicenter AIDS Cohort Study (MACS). 3rd International Workshop on HIV and Aging. November 5-6, 2012, Baltimore. Abstract O_13.
2. Althoff K, Jacobson LP, Cranson RD, et al. Comorbidities and AIDS predict the frailty phenotype in men with treated HIV-1 infection. 3rd International Workshop on HIV and Aging. November 5-6, 2012, Baltimore. Abstract O_12. http://www.natap.org/2012/AGE/AGE_09.htm.
3. Desquilbet L, Jacobson LP, Fried LP, et al. A frailty-related phenotype before HAART initiation as an independent risk factor for AIDS or death after HAART among HIV-infected men. J Gerontol A Biol Sci Med Sci. 2011;66:1030-1038. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156632/.
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