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Frailty Doubles Death Risk in HIV+ Men,
With Only Modest Impact of Inflammation

  6th International Workshop on HIV and Aging
October 5-6, 2015, Washington, DC
Mark Mascolini
Having 3 of 4 signals of frailty independently predicted mortality in older HIV-positive US men who have sex with men (MSM) [1]. Markers of inflammation accounted for only a small part of this frailty-related risk.
A frailty-related phenotype before combination antiretroviral therapy (ART) begins predicts both subsequent mortality and increased systemic inflammation [2], noted Multicenter AIDS Cohort Study (MACS) investigators who conducted this analysis. The new study involved MACS men at least 50 years old and taking ART during a period from January 1, 2001 to March 31, 2010.
The investigators recorded the first occurrence of frailty-related phenotype, which meant at least three of four self-reported conditions: (1) unintentional weight loss of at least 10 pounds, (2) physical health problems causing difficulty doing work/activities, (3) health problems causing difficulty walking several blocks, and (4) health problems causing difficulty performing vigorous activities. MACS statisticians treated levels of three inflammatory markers as time-varying covariates in Cox proportional hazard models describing risk of death: soluble tumor necrosis factor receptor type 2 (sTNF-r2), interleukin-6 (IL-6), and C-reactive protein (CRP). These models accounted for age as the time scale.
Of the 761 MACS MSM studied, 25% were black, 32% overweight, 11% obese, and 27% current smokers. Half (52%) had hypertension, 11% diabetes, 12% HCV infection, and 8% an estimated glomerular filtration rate below 60 mL/min. They had taken ART for a median of 6.4 years, median current CD4 count stood at 513, and median nadir CD4 count measured 269. One third of the group had a detectable viral load.
During follow-up 173 men (23%) had a visit with frailty-related phenotype, and 84 men (11%) died. Of the 173 men with frailty-related phenotype, 121 (70%) had that phenotype at 4 or more study visits. Kaplan-Meier analysis indicated a higher all-cause death rate in men with frailty-related phenotype than in those without the phenotype (about 25% versus about 12% by age 60).
Univariate analysis determined that having the frailty-related phenotype more than tripled the risk of death (hazard ratio [HR] 3.53). Adding a detectable viral load to the model lowered the risk to 3.09, and adding a detectable viral load plus a CD4 count under 350 lowered the risk to 2.69. Individually adding IL-6, CRP, and TNFaR2 to the model lowered the death risk only modestly. In the final model combining a detectable viral load, a CD4 count below 350, and all three inflammatory markers, frailty-related phenotype still more than doubled the risk of death (HR 2.3), and that association remained statistically significant.
The MACS team concluded that in men taking ART, "frailty-related phenotype is highly positively associated with mortality, an effect that appears to be mediated to a small extent by sTNF-r2, and a lesser extent by IL-6 and hsCRP."
1. Ng DK, Erlandson KM, Jacobson LP, et al. The effect of frailty-related phenotype on death is independent of three inflammatory markers among HIV-infected men receiving antiretroviral therapy. 6th International Workshop on HIV and Aging. October 5-6, 2015, Washington, DC. Abstract 2.
2. 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://biomedgerontology.oxfordjournals.org/content/66A/9/1030.long