Frailty Linked to Inflammation, Low Sex Hormone Levels in Men With HIV

In a study of HIV-positive men, frailty was linked to higher levels of inflammation markers and lower levels of testosterone and dehydroepiandrosterone (DHEA). Compared with HIV-negative non-frail men, HIV-positive non-frail men had greater immune senescence and immune activation, the study found.

Clinically defined frailty and ongoing inflammation and immune activation have emerged as hallmarks of antiretroviral-controlled HIV infection. Research links frailty before antiretroviral therapy (ART) begins to lower AIDS-free and overall survival in people who achieve virologic suppression on ART. Other work ties both frailty and HIV infection to greater inflammation, immune impairment and hormonal abnormalities. To explore the impact of HIV infection with or without frailty on these associations, Multicenter AIDS Cohort Study (MACS) researchers conducted this analysis.

The MACS prospectively studies HIV-positive men who have sex with men (MSM) and MSM at risk of HIV at four sites across the United States. Cohort members make twice-yearly visits for thorough evaluations. For this analysis, researchers identified frailty by considering four self-reported subjective measures: weight loss, exhaustion, low activity level and slowness. The researchers classified a man as frail if he had (1) two or more visits meeting three or four frailty criteria or (2) one visit meeting three or four criteria and two subsequent visits meeting one or two criteria.

The MACS team compared a group of HIV-positive men without AIDS and with frailty to HIV-positive men who never met any frailty criteria. They also compared non-frail HIV-positive men to HIV-negative men who never met frailty criteria. The researchers matched non-frail HIV-positive and negative men to frail HIV-positive men by age and year of first visit; they also matched HIV-positive frail men to HIV-positive non-frail men by ART use.

For each participant, the investigators measured levels of inflammation markers (hsCRP, IL-6, sTNFR1, sTNFR2), markers of immune activation (percentages of CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ T cells), markers of immune senescence (percentages of CD4+CD28- and CD8+CD28- T cells) and levels of hormones and hormone regulators (free testosterone, DHEA, IGF-1 and HOMA-IR). They used linear regression analysis adjusted for age, black race, obesity, smoking status and comorbid conditions to explore differences between groups of men.

The analysis included 155 men with HIV and frailty, 141 non-frail men with HIV and 150 non-frail men without HIV. Median ages of the three groups lay between 47 and 49 years and blacks made up 33% of the frail HIV group, 28% of the non-frail HIV group and 17% of the non-frail HIV-negative group. Respective proportions of current smokers were 46%, 21% and 13%. Similar proportions of frail and non-frail men with HIV were taking ART (74.8% and 72.3%).

Adjusted analysis determined that, among men with HIV, those with frailty had higher levels of the inflammation markers IL-6 (52% higher, P < .001) and hsCRP (69% higher, P < .001). Among non-frail men, the inflammation marker sTNFR2 was 22% higher with than without HIV (P < .001). Among men with HIV, markers of immune activation or senescence did not differ significantly by frailty status. But, compared with HIV-negative non-frail men, HIV-positive non-frail men had significantly higher levels of the immune senescence markers CD4+CD28- or CD8+CD28- T cells and significantly higher levels of immune activation markers CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ T cells (all P < .001).

Further adjusted analysis determined that, among men with HIV, frailty was associated with significantly lower free testosterone (17% lower, P = .02) and DHEA (18% lower, P = .04) and marginally worse insulin resistance (20% higher HOMA-IR, P = .051). Among non-frail men, those with HIV had significantly worse insulin resistance (26% higher HOMA-IR, P = .003) but no substantial difference in DHEA, free testosterone or IGF-1.

Among men with HIV, the MACS team concludes, frailty is associated with increased inflammation and lower hormone levels, independently of comorbid conditions. They suggest that "interventions targeting these pathways should be evaluated to determine the impact on prevention or reversal of frailty among HIV-infected men." But, because of the cross-sectional design of this study and the small (though significant) differences between frail and non-frail men, the researchers believe their findings "cannot provide a basis for recommending testosterone or DHEA-S replacement or anti-inflammatory therapy as a treatment for frailty."

The authors note that studies of how DHEA affects physical function in the general elderly population are inconclusive, and the frailty benefits of testosterone replacement therapy remain controversial. DHEA is available as an over-the-counter supplement.