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New Frailty HIV-Specific Index- see table below listing 37-item frailty list index used in this study / What is Frailty in HIV ??? / 52% Pre-Frail at 48 in this study
 
 
  Download the PDF here
 
Download the PDF here
 
.....average age was only 48 (40-56) 52% were pre-frail, only 3.1% frail; immune depletion, activation, inflammation, immune senescence contribute to frailty in HIV+. Frailty in HIV may be uniquely different than the general population. In this study a new unique 37 item list displays what might be considered 37 risk factors for frailty in HIV.
 
The dynamic association between Frailty, CD4 and CD4/CD8 ratio in people aging with HIV PLOS Feb 14 2019 - Giovanni GuaraldiI1*, Stefano Zona1, Ana Rita SilvaID2, Marianna Menozzi1, Giovanni Dolci1, Jovana Milic3, Federica Carli1, Cristina Mussini1 1 Infectious Diseases Clinic, University of Modena and Reggio Emilia, Modena, Italy, 2 Department of Infectious Diseases, Hospital BeatrizAˆ ngelo, Loures, Portugal, 3 Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
 
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212283#sec009
 
New Frailty HIV-Specific Index- see table below listing 37-item frailty list index used in this study.....
 
.........."With the aging of PLWH, we urgently need to better understand how the progression of frailty might be prevented or delayed among this group"....frailty risk factors in HIV+ include CD4 below 900 & the lower the CD4 the greater frailty risk was -see graph, cd4/cd8 ratio inversed (<1), which is common in HIV, immune depletion, immune activation, increased levels of inflammation markers, immune senescence, comorbid conditions, greater number of combed conditions can cause frailty [history of drug abuse]. In this study where average age was only 48 (40-56) 52% were pre-frail, only 3.1% frail......."it has been shown that PLWH with CD4 count between 500 and 750 cells still display increased risk of AIDS compared to PLWH with higher CD4 counts.....Our interpretation is that CD4 count above 900 cell/μl is not a prognostic marker in aging PLWH and in our model the major driver for frailty in this population are rather traditional risk factors as age and gender."
 
In conclusion, our findings of a dynamic relationship between current CD4 count and frailty highlight the complexity of the relationship between immune function, aging, and frailty among PLWH. We identified a cut-off of 900 cells/μL, below which further depletion of CD4 cell count is associated with increased frailty. Lower CD4/CD8 ratio, a surrogate marker of immune activation, is associated with severity of frailty both below and above this cut-off of 900 CD4 cells/μL.
 
In this study, our primary objective was to assess if a large cohort of people aging with HIV demonstrates this U-shaped relationship between current CD4 count and severity of frailty on both down-sloping and up-sloping portions of the U-curve. Our secondary objective was to assess the relationship between frailty severity and current CD4/CD8 ratio. We hypothesized that CD4/CD8 ratio would be inversely associated with frailty in both portions. With the aging of PLWH, we urgently need to better understand how the progression of frailty might be prevented or delayed among this group.....This inconsistency may reflect the fact that immune status and aging contribute to frailty in complex ways....CD4 cell depletion is associated with a shortened life expectancy, in part due to an increased risk for inflammatory, age-related chronic conditions, including heart disease and cancers [17-19]. Conversely, higher CD4 counts are associated with longer life expectancy and appear to be protective against these diseases....Greater severity of frailty may be associated with lower CD4 counts among some patients, while also being associated with higher CD4 counts among patients who survive to older ages and accumulate traditional risk factors for age-related diseases and frailty, independently of effective antiretroviral therapy.
 
We included 2,915 participants, accounting for 10,686 total observations with median number of 4 observations per patient (IQR 2-7, range: 1-16). The observation follow-up period was 4.2 years (IQR 2.1-6.1). In this time frame 36 patients died: 11 of cancer, 4 of CVD, 5 of liver failure, 1 1 in a motor vehicle collision, 15 of unknown causes.
 
The mean age of the cohort at last observation was 48 ± 8.2, and 68% were men.
 
Table 1 summarizes demographic and clinical characteristics of the study population at baseline: median current CD4 count was 567 (418-747), current CD4/CD8 = 0.71 (IQR 0.48-1.00, data available in 2030 observations, and median duration of HIV infection was 19 (IQR 13-24) years.
 
At baseline, median frailty index score was 0.31 (IQR 0.24-0.39), PFP was available in 482 patients. As classified by the frailty phenotype categories, 3.1% (15) of participants were considered to be frail, 51.9% (250) were pre-frail, and 45.0% (217) of participants were robust.
 
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WHAT IS FRAILTY DEFINITION IN HIV+
 
Greater severity of frailty may be associated with lower CD4 counts among some patients, while also being associated with higher CD4 counts among patients who survive to older ages and accumulate traditional risk factors for age-related diseases and frailty, independently of effective antiretroviral therapy [24].
 
Further complicating this relationship, immune depletion and chronic immune activation each appear to contribute to risk for inflammatory, age-related diseases among PLWH [25]. Both chronic HIV infection and aging lead to T cell activation and progressive accumulation of terminally differentiated T cells (e.g. CD8+ effector cells), a reduction in naïve T cells, a lower CD4/CD8 ratio, and increased levels of multiple inflammatory markers [26]. This leads to a state of immune senescence characterized by low-level chronic inflammation and an impaired ability to mount adequate immune response to challenges [27]. CD4/CD8 ratio is a surrogate marker of immune senescence [28], and is inversely correlated with the risk for inflammatory and/or age-related disease [7,29-32]......Interestingly a marker of immune activation, namely CD4/CD8 ratio is always associated with frailty, regardless current CD4 cell count.
 
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Introduction
 
Aging is associated with an increased risk of several adverse health outcomes, including illnesses, disabilities and death. The aging process has great inter-variability, and those at increased risk of adverse outcomes are said to be frail [1,2]. This is also true within groups of people suffering from the same disease, including people living with HIV (PLWH) [3-5].
 
With the aging of PLWH, we urgently need to better understand how the progression of frailty might be prevented or delayed among this group. Current CD4+ T-cell count is the modifiable covariate most often associated with frailty [3-10]. This relationship has proven tricky to understand, as several recent reports identified no association between CD4 cell count and severity of frailty, especially among study participants with higher current CD4 cell counts [11-14].
 
This inconsistency may reflect the fact that immune status and aging contribute to frailty in complex ways [15,16]. CD4 cell depletion is associated with a shortened life expectancy, in part due to an increased risk for inflammatory, age-related chronic conditions, including heart disease and cancers [17-19]. Conversely, higher CD4 counts are associated with longer life expectancy and appear to be protective against these diseases [20,21]. This can paradoxically confer risk of other age-related conditions, given that people with higher CD4 counts generally live longer and the strongest risk factor for frailty and for many chronic inflammatory diseases is aging itself [22].
 
Based on this understanding, our group previously proposed a theoretical U-shaped association between current CD4 count and frailty severity among PLWH [23].
 
Greater severity of frailty may be associated with lower CD4 counts among some patients, while also being associated with higher CD4 counts among patients who survive to older ages and accumulate traditional risk factors for age-related diseases and frailty, independently of effective antiretroviral therapy [24].
 
Further complicating this relationship, immune depletion and chronic immune activation each appear to contribute to risk for inflammatory, age-related diseases among PLWH [25]. Both chronic HIV infection and aging lead to T cell activation and progressive accumulation of terminally differentiated T cells (e.g. CD8+ effector cells), a reduction in naïve T cells, a lower CD4/CD8 ratio, and increased levels of multiple inflammatory markers [26]. This leads to a state of immune senescence characterized by low-level chronic inflammation and an impaired ability to mount adequate immune response to challenges [27]. CD4/CD8 ratio is a surrogate marker of immune senescence [28], and is inversely correlated with the risk for inflammatory and/or age-related disease [7,29-32].
 
In this study, our primary objective was to assess if a large cohort of people aging with HIV demonstrates this U-shaped relationship between current CD4 count and severity of frailty on both down-sloping and up-sloping portions of the U-curve.
 
Our secondary objective was to assess the relationship between frailty severity and current CD4/CD8 ratio. We hypothesized that CD4/CD8 ratio would be inversely associated with frailty in both portions.
 
37-item frailty index
 
pdf attached
 

index

Discussion
 
We analysed a large sample of people aging with HIV, with a relatively low prevalence of phenotypically frail individuals.
 
We identified a hook-shaped relationship between severity of frailty (assessed by a frailty index of 37 health variables that describes potential age-related health problems) and current CD4 count.
 
In this study, we chose to describe frailty using a validated frailty index which has the advantage of being a continuous variable to be plotted with the numerical value of CD4 or CD4/CD8. We arbitrary defined frailty using a cut off value above the median in the cohort (FI>0.31). This frailty categorisation is not comparable with the physical frailty phenotype case definition, nevertheless it can be understood as the pre-frailty status depicted by Fried definition and present in 52% of our patients' cohort. However, we have previously shown in a study comparing FI and PFP evaluated in the same population that FI had a stronger association with age, nadir CD4 count, comorbidities, falls, and disability, suggesting that this tool is more applicable in clinical settings [38].
 
An inverse relationship between frailty severity and CD4 count was identified below a cut-off of 900 cells/μL. We believe that this cut off is clinically significant to be used in PLWH. First, this value is universally recognised as acceptable even in HIV negative individuals. Second, this value is increasingly reached in more recently HIV-infected individuals who promptly start ART [39]. Third, it has been shown that PLWH with CD4 count between 500 and 750 cells still display increased risk of AIDS compared to PLWH with higher CD4 counts [40].
 
The inverse relationship between current CD4 count and frailty severity was not evident above 900 cells/μL, and a borderline-significant positive relationship was observed after adjustment for covariates. This observation requires more investigation. Our interpretation is that CD4 count above 900 cell/μl is not a prognostic marker in aging PLWH and in our model the major driver for frailty in this population are rather traditional risk factors as age and gender.
 
Previously published data on the relationship between the degree of frailty and CD4 count have shown varied results. Inverse relationships between current CD4 count and frailty have been identified among patients presenting for HIV care [3,6,8,9], people living with HIV in the community [10], and HIV-positive cohorts of men who have sex with men [5,24], in women [7], and in people who inject drugs [4]. Other recent studies have conversely identified no relationship between current CD4 count and frailty. Among studies of HIV outpatients [11,13], HIV-positive injection drug users [14], and men who have sex with men [12], frail and non-frail participants were similar in terms of age and current CD4 count, but differed in sex, comorbid conditions, smoking status, and markers of immune activation and inflammation.
 
Interestingly a marker of immune activation, namely CD4/CD8 ratio is always associated with frailty, regardless current CD4 cell count.
 
One previously reported study identified an inverse relationship between CD4/CD8 ratio and frailty among people with HIV [7]. A second study identified a non-significant trend towards lower CD4/CD8 ratios in people who were identified as frail compared to those who were non-frail [6].
 
A desirable intervention to prevent or delay the progression of frailty in HIV patients is early initiation of antiretroviral therapy, supporting recovery of the immune system. This strategy, already supported by START trial [41] should be confirmed with regards to this outcome.
 
Our data should be interpreted with caution, given the cross-sectional nature of the study: inferences about causality and the independent contributions of immune status and of aging to frailty cannot be assessed. More longitudinal research on the relationship between immune status and frailty is needed.
 
In conclusion, our findings of a dynamic relationship between current CD4 count and frailty highlight the complexity of the relationship between immune function, aging, and frailty among PLWH. We identified a cut-off of 900 cells/μL, below which further depletion of CD4 cell count is associated with increased frailty. Lower CD4/CD8 ratio, a surrogate marker of immune activation, is associated with severity of frailty both below and above this cut-off of 900 CD4 cells/μL.

 
 
 
 
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