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Fw: Breaking, Clinically Relevant HIV/AIDS Research From CROI 2012

Posted Mar 08 2012 12:00am

Subject: NATAP/CROI: Frailty/Muscle Loss in HIV Increases Mortality & is Common

NATAP  http://natap.org/
______________________________ _________________



Frailty & Muscle Loss Increase Mortality & Are Common in HIV+

from Jules Levin at CROI Live in Seattle. This poster session is a
breakthrough in that it is identifying that muscle loss & frailty are
fairly common in HIV+ persons & they increase mortality. AND HCV & HBV
contribute to frailty in one study below.read this
"Frailty is a significant predictor of mortality among both HIV+ and
at-risk IDU....... Impaired functional capacity is strongly associated
with lower bone density and lower muscle mass in middle-aged HIV-1+
persons......Co-morbidity Is Predictive of Muscle Strength in HIV+
Veterans: Results from the VACS Index....
Overall, 40% of SUN study participants aged ≤50 years with
well-controlled HIV infection were pre-frail or frail. The significant
association of pre-frailty and frailty with a history of opportunistic
infection suggests earlier diagnosis of HIV infection and prevention of
opportunistic infections may reduce risk for frailty.......Prevalence
of low muscle mass increases with age. The highest prevalence was found
in the 41- to 50-year age group. Predictors of FFMi change appear to be
associated with age, lipoatrophy recovery, and time. FFMi is associated
with all-cause mortality in HIV+ patients, suggesting that this
biological entity can provide prognostic information, in HIV+
patients..........We have recently demonstrated that patients with
prior exposure to nucleoside analog ARV, which inhibit DNA
polymerase-γ, accumulate acquired mitochondrial DNA (mtDNA) mutations
in skeletal muscle, in an apparent acceleration of the process seen in
normal aging. Here we explore an in vivo functional correlate in aging
HIV+ patients. Abnormalities of resting muscle pH handling have been
associated with fatigue and may contribute to functional decline in
this patient group."




Frailty and Pre-frailty in a Contemporary Cohort of HIV+ Adults

Nur Onen*1, P Patel2, J Baker3, L Conley2, J Brooks2, T Bush2, M
Kojic4, J Hammer5, E Overton6, and SUN Study Investigators

1Washington Univ Sch of Med in St Louis, MO, US; 2CDC, Atlanta, GA, US;
3Hennepin County Med Ctr, Univ of Minnesota, Minneapolis, US; 4Miriam
Hosp, Providence, RI, US; 5Denver Infectious Disease Consultants, CO,
US; and 6Univ of Alabama at Birmingham, US

Background:  HIV+ persons can become prematurely pre-frail and frail;
however, pre-frailty prevalence and risk factors for both frail and
pre-frail states have not been fully elucidated.

Methods:  Using data from a contemporary prospective observational
cohort of HIV+ adults (SUN Study), we determined the percentages of
non-frail, pre-frail, and frail participants at the most recent study
visit by the respective presence of 0, 1 to 2, and ≥3 of 5 established
frailty criteria as shown in the table. We evaluated associations with
pre-frailty/frailty using logistic regression analysis.

Results:  Of 308 SUN Study participants assessed—79% men, 58%
non-Hispanic white, median age 47 years (interquartile range 41 to 53),
95% on combination ART, median CD4 cell count 650 cells/mm3 (IQR 467 to
799), and 93% HIV RNA <400 copies/mL—57% were non-frail, 38% pre-frail,
and 5% frail 
(61%, 36%, and 4%, respectively, among the 199 [65%]
participants aged ≤50 years). Prevalence of frailty criteria are
presented in the table; exhaustion and physical inactivity
predominated.
 In multivariate analysis, pre-frail/frail vs non-frail
participants were more likely of non-white race/ethnicity (54% vs 33%;
adjusted odds ratio 3.24; 95% confidence interval 1.78 to 5.91), to
have had an AIDS-defining opportunistic infection (35% vs 15%; aOR
2.55, 95%CI 1.29 to 5.02), to have poorer median perceived health
scores on the SF-12 health survey
 (1, IQR 1 to 2 vs 2, IQR 1 to 3; aOR
2.12, 95%CI 1.49 to 3.03), to have higher median PHQ-9 depression
scores (6, IQR 2 to 11 vs 3, IQR 0 to 5; aOR 1.11, 95%CI 1.04 to 1.18)
and to be older (median age 48 years, IQR 44 to 54 vs 46 years, IQR 40
to 52; aOR 1.04, 95%CI 1.01 to 1.07). Lower CD4 cell count nadir,
female sex, and unemployment were not independently associated with
pre-frailty/frailty.

Conclusions:  Overall, 40% of SUN study participants aged ≤50 years
with well-controlled HIV infection were pre-frail or frail.
 The
significant association of pre-frailty and frailty with a history of
opportunistic infection suggests earlier diagnosis of HIV infection and
prevention of opportunistic infections may reduce risk for frailty.
Racial disparities warrant further investigation.
-------------------

Low Muscle Mass in HIV+ Patients: Prevalence, Predictors, and Clinical
Implication


Giovanni Guaraldi*1, S Zona1, A Silva2, G Orlando1, F Carli1, A
Santoro1, N Crupi2, G Ligabue1, C Mussi1, and L Ferruci3

1Univ of Modena and Reggio Emilia, Italy; 2Hosp de Joaquim Urbano,
Porto, Portugal; and 3Natl Inst on Aging, NIH, Baltimore, MD, US

Background:  In HIV+ patients, muscle mass measured as fat free mass
index (FFMi = FFM/h2) in DXA has never been characterized in large
epidemiological cohorts. We aimed:  to describe the prevalence of low
muscle mass using t- and z-score, per age decades, defined as <–2 SD
from the mean FFMi for an Italian Caucasian population, respectively,
for the same age or in the age strata 30 to 39 years; to identify
predictors of FFMi change; and to assess the association between FFMi
and all-cause mortality in a large HIV+ cohort.

Methods:  This observational prospective study included all consecutive
patients from 2005 to 2011 who underwent at least 2 DXA scans,
performed 1 year apart. Univariate and multivariable longitudinal
linear regressions were built to evaluate FFMI change-associated
factors. Co-variates included in the models were:  age, sex, body mass
index (BMI), physical activity; change in leg fat percentage (assessed
with DXA), in visceral adipose tissue (VAT), and in total adipose
tissue of the abdomen (TAT) (assessed with abdominal CT); NRTI, NNRTI,
and PI cumulative exposure; CD4 nadir and recovery; vitamin D plasma
level; and time between DXA scans. A Cox model was built to predict the
impact of FFMi on all cause mortality after adjustment for age and sex.

Results:  A total of 1696 HIV+ patients (1046 men) were analyzed.
Median observation follow-up period was 3.5 years (IQR 2 to 5); 96% of
patients were on ART, and during the follow-up period 37 died. BMI
change and FFMI change appeared stable over time (ß = 0.001, p = 0.111;
ß = 0.001, p = 0.070, respectively). In men, the prevalence of low
muscle mass using t- and z-scores was 0.2% and 8.5%, respectively
. In
women, the prevalence of low muscle mass using t- and z-scores was 0%
and 1.5%, respectively. The highest prevalence of low muscle mass was
detected in the 41- to 50-year age group strata (t-score 0.5% and
z-score 16%). Predictors of FFMi change were:  age (ß = –0.01, p =
0.002), change of leg fat percentage (as a surrogate for lipoatrophy
recovery) (ß = –0.05, p <0.001), and time between DXA scans (ß = 0.17,
p = 0.013). FFMi was associated with all-cause mortality (HR 0.87,
95%CI 0.78 to 0.98) after adjustment for age and sex.

Conclusions:  Prevalence of low muscle mass increases with age. The
highest prevalence was found in the 41- to 50-year age group.
Predictors of FFMi change appear to be associated with age, lipoatrophy
recovery, and time
. FFMi is associated with all-cause mortality in HIV+
patients, suggesting that this biological entity can provide prognostic
information, in HIV+ patients.
---------------------

Frailty Predicts Mortality in a Cohort of HIV+ and At-risk IDU

Damani Piggott*, A Muzaale, S Mehta, T Brown, S Leng, and G Kirk

Johns Hopkins Univ, Baltimore, MD, US

Background:  Frailty, a syndrome of diminished physiologic reserve with
increased stressor vulnerability, predicts hospitalization, disability,
and mortality in older HIV– adults. We have previously observed a
significant association between frailty and HIV+, particularly advanced
HIV infection, among injection drug users (IDU). In this study, we
evaluated the impact of frailty on mortality in a cohort of aging HIV+
and at-risk IDU.

Methods:  Frailty was assessed biannually from 2005 to 2008 among
current and former IDU in the ALIVE cohorts and was defined by the
presence of ≥3 of 5 standard criteria:  weakness (grip strength), slow
gait speed, weight loss, low physical activity, and exhaustion. Cox
proportional hazards models with time-varying co-variates were used to
estimate the risk (hazard ratios with 95% confidence intervals) for
all-cause mortality among frail persons relative to their robust
counterparts (defined by the absence of any criteria) and to non-frail
persons.

Results:  For 1230 subjects at baseline, the median age was 48 years,
89% were African American, 418 (34%) were female, and 351 (29%) were
HIV+. The prevalence of frailty was 9%, while 31% met no frailty
criteria. In Cox multivariable analysis of 3365 person-visits,
increasing age and HIV status were associated with increased mortality
risk.
 Adjusting for age, race/ethnicity, gender, educational level, and
HIV status, frail persons had a 3.4-fold increased risk of death
relative to robust persons
 (HR 3.42, 95%CI 1.66 to 7.03). In stratified
analysis, increased mortality risk with frailty was observed among both
HIV– persons (HR 2.91, 95%CI 1.06 to 7.96) and HIV+ persons (HR 4.05,
95%CI 1.39 to 11.8). Controlling for advanced HIV infection (CD4 <350,
HIV RNA+), frailty remained a significant predictor of mortality (HR
3.13, 95%CI 1.25 to 7.82). In comparison to non-frail persons, similar
associations of frailty with mortality were observed.

Conclusions:  Frailty is a significant predictor of mortality among
both HIV+ and at-risk IDU
. Frailty provides prognostic information even
when accounting for advanced HIV disease suggesting that standardized
assessment may inform prediction of significant clinical endpoints.
Further exploration of the biological mechanisms and clinical utility
of frailty may aid management of aging HIV+ persons.
------------------------

Mitochondrial Function in vivo in Aging HIV+ Patients

Brendan Payne* M Trenell2, K Hollingsworth2, J Baxter3, V Lee4, E
Wilkins3, A Price1, and P Chinnery2

1Royal Victoria Infirmary, Newcastle upon Tyne, UK; 2Newcastle Univ,
Newcastle upon Tyne, UK; 3Northern Manchester Gen Hosp, UK; and
4Manchester Royal Infirmary, UK

Background:  We have recently demonstrated that patients with prior
exposure to nucleoside analog ARV, which inhibit DNA polymerase-γ,
accumulate acquired mitochondrial DNA (mtDNA) mutations in skeletal
muscle, in an apparent acceleration of the process seen in normal
aging. Here we explore an in vivo functional correlate in aging HIV+
patients.

Methods:  We recruited older HIV+ patients in clinical care (n = 24;
age 48 to 74 years) and age-matched controls (HIV–). Phosphorus
magnetic resonance spectroscopy (31P-MRS) was performed using a 3-T
scanner. Spectra were obtained from gastrocnemius/soleus at rest and
during recovery from brief exercise. Key measures were:  adenosine
triphosphate (ATP) production during recovery (as Qmax (ADP), maximal
rate of adenosine diphosphate (ADP) clearance; τ1/2 (PCr), half-life of
phosphocreatine); and pH handling. In HIV+ subjects, comparison was
made with cellular mitochondrial function by COX (cytochrome c oxidase)
histochemistry of lower-limb muscle biopsy.

Results:  Basal parameters of ATP metabolism differed between subjects
groups:  ADP (mean ±SD) HIV+ 10.2±0.7 mM, HIV– 9.5±0.5 mM (p = 0.001);
PCr HIV+ 41.0±15.2 mM, HIV– 30.7±2.1 mM (p = 0.003). Furthermore, basal
ADP levels in HIV+ subjects correlated with biopsy COX defect (r =
0.45, p = 0.032). In contrast, dynamic measures of ATP production
during exercise recovery were similar in HIV+ and control subjects Qmax (ADP) (mean±SD) HIV+ 26.6±18.6 mM/min, HIV– 23.0±10.2 mM/min; τ1/2
(PCr) HIV+ 29.9±13.4 s, HIV– 27.5±8.3 s. There was more variance seen
in the HIV+ than the HIV– group, however no disease or treatment
variable was significantly correlated with ATP production rate, nor was
cellular COX defect. HIV+ subjects showed disordered pH handling
compared with HIV– controls as evidenced by higher basal pH (mean±SD,
7.07±0.03 vs 7.04±0.02, p = 0.001) and post-recovery pH (7.09±0.03 vs
7.06±0.02, p = 0.008) but similar exertional minimum pH (6.98±0.13 vs
7.00±0.03, ns). Resting pH correlated with COX defect (r = 0.42, p =
0.044).

Conclusions:  The altered basal ATP metabolite levels in HIV+ subjects
coupled with preserved dynamic function, despite cellular mitochondrial
defects on biopsy, suggests functional compensation to an acquired
mtDNA defect, once therapy has been switched to a cleaner agent.
Abnormalities of resting muscle pH handling have been associated with
fatigue and may contribute to functional decline in this patient group.
-----------------------

Functional Impairment Is Associated with Low Bone and Muscle Mass in
Middle-aged HIV-1+ Persons


Kristine Erlandson*, A Allshouse, C Jankowski, S MaWhinney, W Kohrt,
and T Campbell
Univ of Colorado Denver, Aurora, US

Background:  Physical function impairment may be accelerated in the
presence of osteoporosis, obesity, or sarcopenia. HIV+ persons have
early physical impairment, but little is known about the contributions
of bone or body composition changes to impairment in persons aging with
HIV-1.

Methods:  We conducted a prospective study of 45- to 65-year-old HIV-1+
subjects who had been on ART >6 months and whose plasma HIV-1 RNA <48
copies/mL. Low functioning (LF) and high functioning (HF) subjects were
identified by deficits on both Fried’s frailty criteria and the Short
Physical Performance Battery and were matched by age, gender, and time
since HIV diagnosis. Bone, fat, and muscle were assessed by
densitometry. Osteoporosis was defined as T-score ≤–2.5, osteopenia as
T-score <–1 but >–2.5, sarcopenia as appendicular skeletal muscle index
(ASMI) <5.45 kg/m2 (female) and <7.26 kg/m2 (male). Insulin-like growth
factor (IGF)-1 and IGF-binding protein (BP)-3 were measured. Stratified
logistic regression for categorical variables and linear mixed effects
regression for continuous variables were estimated to account for
correlation within matched pairs. Body mass index (BMI), tobacco, and
nadir CD4+ T cells were adjusted in models of bone loss.

Results:  We identified 30 LF and matched them to 48 HF subjects; mean
age 52.7 years, CD4 T cell 598, 96% HIV-1 viral load <48 copies/mL, 18%
female, 77% white, 17% Hispanic. LF and HF were similar in age,
duration of ART, tenofovir use, and CD4 T- cells (all p >0.2). LF
subjects had significantly lower BMD and T scores at the hip and spine;
differences remained significant in multivariate analyses.
 Although all
persons with BMI <18.5 kg/m2 were LF, LF trended toward higher relative
body fat content. LF subjects had a greater prevalence of sarcopenia
(50% vs 25%, p = 0.04), lower lean mass, and lower IGF-1/IGFBP3.


Conclusions:  Impaired functional capacity is strongly associated with
lower bone density and lower muscle mass in middle-aged HIV-1+ persons. 

Whether bone or muscle loss is the result of disuse due to impairment,
or if low muscle or bone mass, mediated through effects of IGF-1, leads
to impairment by progressive weakness or inflammatory pathways remains
to be established. Further studies should investigate the role of
increased muscle/bone mass and increased IGF-1 on preserving functional
independence as persons with HIV age.
--------------------------

Co-morbidity Is Predictive of Muscle Strength in HIV+ Veterans: Results
from the VACS Index


Krisann Oursler*1, J Tate2, T Gill2, K Crothers3, T Brown4, S Crystal5,
J Womack2, D Leaf6, J Sorkin1, A Justice2, and Veterans Aging Cohort
Study Project Team

1Univ of Maryland Sch of Med and Publ Hlth and VA Maryland Hlthcare
System, Baltimore, US; 2Yale Univ Sch of Med and Publ Hlth and VA
Connecticut Hlthcare System, New Haven, US; 3Univ of Washington,
Seattle, US; 4Johns Hopkins Univ, Baltimore, MD, US; 5Rutgers Univ, New
Brunswick, NJ, US; and 6Univ of California, Los Angeles Sch of Med and
Greater Los Angeles VA Hlthcare System, US

Background:  Despite improved survival, HIV+ adults have increased risk
for physical disability due to muscle weakness, poor ambulatory
function, and low cardiorespiratory fitness. The objective of this
study was to determine whether the VACS Index, a comprehensive index of
generalized organ injury based on routine clinical laboratory data, is
associated with hand-grip and leg-strength, 6-minute walk distance, and
cardiorespiratory fitness (peak oxygen consumption, VO2 peak).

Methods:  HIV+ patients enrolled in the Veterans Aging Cohort Study
(VACS) participated in this cross-sectional study at the Baltimore VA
Medical Center from 2004 to 2007. The VACS Index was calculated
incorporating hemoglobin, FIB-4, eGFR, hepatitis C infection, CD4
count, HIV-1 viral load, and age; higher score reflected greater
co-morbidity. Analyses included nonparametric correlation (Spearman’s
rank) and linear regression models.

Results:  We included 2 women and 53 men:  91% African American race,
mean age of 52 (SD 7) years. The VACS Index was inversely correlated
with hand-grip strength (r = –0.36, p = 0.01) and lower extremity
strength (quadriceps, r = –0.45, p <0.01), but was not significantly
associated with 6-minute walk distance (r = –0.26, p = 0.07) or VO2
peak (r = –0.13, p = 0.3). A 20-point higher VACS Index score was
associated with a 10% lower leg strength (mean 76 newtons; 95%CI –124
to –29; p <0.001; see the figure), which remained significant after
adjustment for muscle cross-sectional area (p = 0.04). The VACS Index
explained 34% of the variance in specific leg strength. In contrast, an
index restricted to CD4 count, viral load, and age did not correlate
with any of these measures (p >0.08).

Conclusions:  In this sample of predominantly African American men
ranging in age from 31 to 72 years, the VACS Index was significantly
associated with upper and lower extremity strength
. The VACS Index may
be valuable for identification of patients at high risk for disability
due to muscle weakness. Association of Leg Strength with the VACS Index.
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