Associations of L-Ferritin and Tim-1 with frailty measures in people with HIV: a cross-sectional and longitudinal study

Abstract

BackgroundPeople with HIV are at high risk of frailty. Iron transport is key to energy production and is dysregulated by HIV and inflammation. We previously linked higher cerebrospinal fluid levels of the iron transporter heavy-chain-ferritin (Fth1) to better cognition in people with HIV. Here, we evaluated whether higher levels of serum Fth1 and light-chain-ferritin (Ftl), and lower levels of urine T-cell immunoglobulin-and-mucin domain (Tim)-1 (Fth1 receptor) are associated with better frailty measures in people with HIV. MethodsSerum Fth1, Ftl, inflammation markers (IL-6, sTNFR2), and urine Tim-1 were quantified by ELISA in 324 AIDS Clinical Trials Group Study A5322 enrollees at entry. Prefrailty and frailty were assessed using Fried's criteria. Relationships among baseline biomarker concentrations, HIV clinical variables and demographic variables were tested using Pearson's χ2 test, non-parametric tests for trend, or Spearman's correlations. Multivariable regression models evaluated cross-sectional and longitudinal Fth1, Ftl, and Tim-1 associations with prefrail and frail status, average 4-metre walk time, and grip strength in all people with HIV and by sex. FindingsAt study entry, 127 (40%) of 321 participants were prefrail and 15 (4%) of 321 were frail (mean age 52 years [SD 7·3]]; 61 (19%) of 321 were female and 260 (81%) of 321 were male; and 306 (96%) of 319 were virally suppressed). Serum Fth1 was correlated with Ftl (rho 0·14; p<0·01), but not to urine Tim-1. In univariate analyses, Tim-1 was higher (ptrend=0·06) and Ftl lower (ptrend=0·02) across non-frail, prefrail, and frail groups. Higher Tim-1 was associated with prefrailty (odds ratio [OR] 1·5; p<0·01) and combined prefrailty and frailty (OR 2·3; p=0·01) versus non-frail people with HIV. Higher Ftl was associated with faster 4 m walk time (β –0·045; p<0·01), lower odds of weak grip (OR 0·49; p<0·01), and less frailty, particularly in female participants (OR 0·28; p=0·03). In multivariable-adjusted analyses, higher Ftl was associated with faster 4 m walk time and better grip strength (both p<0·05), reduced odds of combined prefrailty and frailty versus non-frailty (adjusted OR 0·56 in all people with HIV and 0·29 in female participants, both p<0·05 for levels greater than or equal to the median versus less than the median) and lower odds of weak grip (OR 0·50; p<0·05). Ftl concentrations in the highest versus lowest quartile were associated with lower odds of slow 4 m walk time in female participants (OR 0·060; p<0·05). Higher Tim-1 was associated with combined prefrailty and frailty versus non-frailty (OR 2·6; p<0·05). Serum Fth1 was not associated with frailty measures. InterpretationIncreased urine Tim-1 is a marker of risk for prefrailty and frailty in people with HIV. Higher serum Ftl is associated with preserved motor function and less prefrailty or frailty, particularly in female individuals. Future studies will explore causal pathways. FundingNational Institutes of Health grant (to AK): 5R03 MH123291-02; National Institute of Allergy and Infectious Diseases, National Institute of Mental Health, National Institute on Aging, and National Institute of Diabetes and Digestive and Kidney Diseases.