|David Alain Wohl, MD – The University of North Carolina at Chapel Hill
“HIV medicine has transitioned from an oncological mode created to manage a progressive and complicated fatal disease to a model that more closely resembles a diabetes clinic, where lab metrics are used to plot a long-term course that avoids complications. For our patients to not only survive but thrive we need a new way to support them that recognizes their outsized risk for physical and psychological co-morbidities and the entrenched toxic social and emotional challenges that feed these conditions and, also, make addressing them difficult. The next leap forward in HIV management could be the development of a comprehensive approach to co-morbidity detection and intervention – one that can be readily implemented across HIV clinics, be they in Birmingham or Boston. Designing and implementing such a program, with input from experts in prevention and geriatric medicine, can be yet another example of HIV care leading the way.”
Each medical conference has a vibe. The data, the venue, and even the host city, can shape the mood of the attendees as they crisscross on the escalators and queue at the food courts, toting their brightly-colored conference backpacks. CROI 2017 was like the Seattle weather that week in February – partly sunny with cloud-streaked blue skies but the occasional day of rain. With cheekily named sessions showcasing generally positive results, there was a collective nod of approval as we continue to close gaps, expand treatment, and identify new targets to mess with. At the same time, there were gloomy footnotes pointing to seemingly intractable challenges, like getting ART and PrEP to all in need and addressing high rates of co-morbidities, especially among our aging HIV-infected patients.
CROI, above all else, offers guidance on how to optimize well-being for those living with HIV infection, whether through avoidance of a particular antiretroviral or by adopting an intervention to prevent a comorbidity. At this year’s conference, there were no findings to suggest HIV+ people or their providers do anything radically different. There were the expected echoes of prior messages regarding the higher risk of frailty and its components among those who are HIV-infected, the dangers of smoking and substance use, as well as not wholly surprising data regarding the effects of protease inhibitors on cardiovascular disease (CVD) risk. But, the together, the data form a booming chorus, extolling us to move from tabulating the acronymic conditions (this means use of these short terms: CVD, DM, CKD, HTN, etc) that can pile-on to make long-term HIV survival miserable, to tackling them.
As suggested by the studies described below, approaches to prevent and treat co-morbid conditions that disproportionately hit people living with HIV are not hidden and undiscovered. It is not for the want of some novel (read: expensive) anti-inflammatory that HIV-positive people suffer a stroke or get lung cancer. Tools that can dramatically reduce co-morbidities abound. The problem is that we as HIV providers have yet to fully grasp them.
CVD Prevention Model
There are studies that sound alarms about a problem, and others that provide guidance on how to actually fix the problem. A nice study modeling the impact of several interventions to blunt the rise in CVD among people living with HIV conducted by a Dutch team is one of the latter (1). The interventions explored in this simulation included the very early start of ART, avoidance of protease inhibitors (see below) and abacavir, smoking cessation (see below), and intensified treatment of hypertension and dyslipidemia. Complete (100%) and partial (50%) uptake of each individual intervention was explored individually in the model, which used data collected in the ATHENA Cohort to populate the simulated patient population.
These simulations predicted all the selected interventions to have a positive effect in reducing CVD from now to 2030, but to very different extents. Earlier ART had the least impact, and cardio-friendly ART was only slightly better. In contrast, the traditional and time-tested interventions of smoking cessation and optimization of blood pressure and lipids were predicted to prevent many more CVD events, even if only half-heartedly embraced.
The Bottom Line: Although modeling studies are inherently imperfect, this complex exercise supports other data (and some common sense) regarding CVD prevention in HIV-positive people. We can fuss over ART regimen composition, but it is smoking, hypertension, lipids, glucose control and other routine health maintenance components that are the bigger tickets worth punching to prevent CVD and almost certainly other co-morbid disease.
So, the good news is that the tools we can use to beat back the specter of CVD are widely available and supported by decades of implementation research. The bad news is that we have not been as successful as need to be to apply these CVD prevention interventions to the management of HIV. This is highlighted by an analysis of data from the NA-ACCORD cohort study that found a persistent, albeit narrowing, gap between guideline indications for statin therapy and the prescription of a statin over time (2). In 2013, 53% of HIV-positive patients at NA-ACCORD clinics for whom a statin was indicated had not been prescribed this medication.
The magic bullet for HIV aging may not be some novel anti-inflammatory molecule but medications that can be found on the Walmart $4 list. Identifying effective ways to incorporate health maintaining interventions into our HIV clinics and achieve patient acceptance and adherence to these, sometimes unpopular, measures, may go a long way to addressing the age-related problems that HIV-infected persons disproportionately endure – and be a more efficient way to spend HIV research dollars.
Quantifying the Risk of Cancer after Smoking Cessation
It is a non-alternative fact (i.e., a plain old fact) that smoking causes cancer and that the risk of malignancy drops over time with smoking cessation. However, the extent that cancer risk can be expected to decline after quitting is not clear among those with HIV-infection, who appear to be more susceptible to the carcinogenic effects of cigarette smoking than those uninfected with HIV. To get at this, D:A:D investigators looked at cancers developing in those who were cancer free when entering the cohort study, and then explored associations with smoking history (3). Of 1,980 incident cancers, 242 were lung cancer, and 487 smoking-related non-lung cancers. Smoking history was categorized as never smoker, current smoker, ex-smoker at baseline, and ex-smoker during the study follow-up. At baseline, only 31% had never smoked. As expected, smokers had higher risks for lung and the other related cancers compared to never smokers. After cessation of smoking, the overall risk of cancer, as well as the risk of non-lung smoking-related cancers, dropped over the next 5+ years; however, the risk of lung cancer remained largely unchanged after quitting.
The Bottom Line: These are concerning data in that they suggest a durable effect of smoking on cancer risk that is not appreciably ameliorated by smoking cessation. This finding is in contrast to studies in the HIV-uninfected and remains unexplained. Although this is a large cohort of HIV-positive people, the number of lung cancers was small at 242 and relatively few ex-smokers had been followed long term. Therefore, with more time, additional data will be available to confirm or adjust this finding.
Meanwhile, as abundantly suggested, getting HIV-infected people to stop smoking is second only to ART as a health priority. The message from this study must not be that stopping smoking will not reduce the risk of cancer, but that it will, here it did for both non-lung smoking cancers and cancers overall.
Knowing Frailty when you see it
Think frail and conjured is the image of a stooped elder, a strong breeze away from a fractured hip and subdural hematoma. However, frailty is more complicated and is based in a theoretical framework to better understand and predict the risk for morbidity, hospitalization, and death by taking into account loss of body mass, strength, endurance, gait speed, and physical activity.
A number of studies have convinced us that the frailty phenotype is more common among HIV-infected people, although as is the case for most all age-related complications the exact magnitude of any contribution by the virus and/or ART to this risk remains murky. At CROI, there were additional reports regarding frailty, its prevalence and determinants, that underscore the need for HIV providers to appreciate the forest of this concept, more than the trees of conditions such as CVD and osteoporosis that can contribute to it:
•An analysis of 954 patients age 40 years and older (15% greater than age 60), participating in ACTG ART treatment trials and regularly assessed for fragility and neurocognitive impairment (NCI) found that the risk of falls, worsening disability, and death were highest in those with frailty compared to those with NCI alone (4). The combination of NCI and frailty was the riskiest. Of the select adverse events, falls were the most common. The authors point is that attention to frailty may be a more appropriate target for intervention than NCI.
•That the road to frailty can be a two-way street was made clear by an analysis from the ALIVE Cohort in Baltimore (5). This study enrolls and follows HIV-infected and -uninfected participants with a history of injection drug use. A strength of this cohort is that the uninfected participants suffer from many of the same conditions and environmental stresses experienced by HIV-infected people and that can confound other studies where the controls are less well-matched. Looking at the “frailty transitions” of over 1,300 ALIVE participants (a third HIV+), decreased frailty progression and increased frailty recovery were both associated with major sociodemographic characteristics including education attainment and employment. Having fewer co-morbidities, including depression, was also associated with the frailty outcomes. After adjustment for these factors, HIV infection was still associated with risk of frailty progression and lower likelihood of frailty recovery. In the fully adjusted models, HIV virologic suppression, elevated CD4 nadir (>500/mm3) and absence of a prior AIDS diagnosis were all significantly associated with reduced frailty progression and improved frailty recovery. An inflammation index based on blood IL-6 and sTNFR1 levels and applied to a subset of participants found an association between frailty progression and recovery with the inflammation index in the expected directions, , i.e. lower inflammation markers are associated with increased survival and higher inflammation markers are associated with frail progression (from Jules: remember, exercise & healthy diet like the Mediterranean diet reduce inflammation markers). This study nicely highlights not just the mutable disease-specific targets for intervention to prevent and recover from frailty, such as early and successful HIV treatment and co-morbidity treatment and prevention, but also the environmental factors that contribute to poor health. These were quite potent and included depression, education, and employment – structural issues that are not only the fodder for headlines but also have direct effects on our health.
The Bottom Line: HIV care providers need to become more familiar with frailty. There have been many CME programs on aging and inflammation, and shifting attention to what may be an overarching issue of frailty and pre-frailty is warranted given the prevalence of this syndrome and its impact on health. Just as we have seen cardiologists, neurologists, and nephrologists specialize in relevant HIV-related conditions, it is time we reached out to geriatricians to do likewise. A handful of HIV clinics have already adopted a geriatrics model and more need to follow. For example, falls risk assessments, which I suspect no card-carrying HIV provider knows how to do properly, can identify those who are at greatest risk and most likely to benefit from intervention. Those with peripheral neuropathy, which enhances falls risk, deserve particular attention. These data suggest we may help our patients more by assessing for frailty than many of the things we do such as listening to their chest with a stethoscope.
The Die is Cast at the START
The START trial famously demonstrated that earlier ART administration prevented AIDS and serious non-AIDS events. In addition, this study, like others, found an association between markers of inflammation and coagulation and these events. Expanding on this latter work, the team examined baseline (i.e., pre-ART) inflammation markers (IL-6, hsCRP, serum amyloid A [SAA], sICAM, sVCAM), an immune activation marker (IL-27), and a coagulation marker (D-dimer) and clinical outcomes among the 2,124 participants in the immediate ART group and the 2,175 participants in the deferred ART group (6).
After adjustment for age, gender, treatment arm, and region, higher levels of D-dimer and IL-6 were associated with risk for both AIDS and serious non-AIDS events. In addition, SAA and sICAM were associated with AIDS. AIDS events were driven by TB disease and non-AIDS events by CVD. IL-6 was associated with CVD risk.
The Bottom Line: Having elevated markers of inflammation and coagulation can’t be a good thing and once again we see that to be the case. Among those entering the START trial, those harboring higher levels of IL-6 and D-dimer had a heightened risk of AIDS and serious non-AIDS events. This makes sense and points to these markers being an indicator of a brewing badness that may not be clinically evident (and may not even be HIV-related). Although there was some adjustment performed it is not clear what role pre-treatment CD4 cell count played. The median entry CD4 cell count in this study was well over 600/mm3, but there was a range at baseline and a count of 525/mm3 is not the same as 925/mm3. Other factors could also contribute to having higher levels of these markers such as duration of HIV infection and an assortment of co-morbid conditions. The important message from this analysis is less that relative elevation of these markers predicted poor outcomes, and more that we need to figure out why they were elevated.
Protease Inhibitor Pluses and Minuses
The D:A:D Cohort Study first reported an association between protease inhibitor-containing antiretroviral therapy (ART) and CVD well over a decade ago. At the time, protease inhibitors were widely used to treat HIV infection, allowing for investigation of earlier drugs in this antiretroviral class for links to CVD incidence. As more patients have received darunavir and atazanavir, still the newest kids on the protease inhibitor block, they can now also be similarly scrutinized. In doing so, the D:A:D team found a significant but small association between darunavir and CVD (~59% increased risk for every 5 years of exposure) – on par with that seen with the older protease inhibitors (7). However, such an association was not seen with atazanavir. Interesting, the darunavir-CVD association did not seem to be explained by dyslipidemia. The study did not collect data on dosing and some of the darunavir-receiving patients could have been taking the higher twice daily dosing.
A clue as to why atazanavir may be an outlier when it comes to protease inhibitors and risk of CVD can be found in by separate study from the Veterans Aging Cohort Study (VACS), also presented at CROI. This analysis examined the relationship between total bilirubin levels in the blood and the risk of CVD, as determined by diagnosis codes, in tens of thousands of HIV-infected and -uninfected patients (8) (it is known that those with Gilbert’s Syndrome, a common genetic disorder in which unconjugated bilirubin levels are elevated, have a lower risk of CVD). A clear bilirubin-CVD risk relationship was seen with a decline in CVD (and heart failure and acute myocardial infarction) risk at total bilirubin levels above 0.6 mg/dL; this was the case for HIV-positive and -negative patients. There were too few CVD events among those on atazanavir to tease out whether this protease inhibitor was in any way protective. (from Jules: taking atazanavir increases bilirubin).
The Bottom Line: Fewer people living with HIV in the US are being treated with protease inhibitors now that once-a-day integrase inhibitors have popped on to the scene. Therefore, the impact of the D:A:D finding of an association between CVD and cumulative use of darunavir and the failure to find a similar link with exposure to atazanavir, is diminished compared to a few years ago. That said, some patients do need to be on protease inhibitors for one reason or another and these data may influence selection of their therapy. The observation that darunavir acts like older protease inhibitors is less surprising than the observation that atazanavir doesn’t. Although the D:A:D analysis did not find bilirubin to be explanatory, it is hard to ignore the inverse relationship between bilirubin and CVD seen in the VACS cohort and previously reported data from the AIDS Clinical Trials Group (ACTG) and others demonstrating positive changes in inflammatory markers and carotid intimal thickness with atazanavir compared to darunavir. It is important to recognize that of the 35,711 patients included in the D:A:D analysis, only 1,157 (3.2%) had a CVD event over a median 7 years of follow-up. Reassuringly, the absolute number of patients on darunavir who experienced a CVD event was low, especially among those on the drug longer term (18 patients with 5-6 years of exposure and 27 patients with >6 years of exposure). Therefore, very, very few people on the protease inhibitor experienced CVD.
Certainly, these findings may tip the balance a smidge back in favor of atazanavir but there remain important differences between these two effective protease inhibitors, including side effect profiles and drug-drug interactions, that will likely lead to little change in provider (and guideline) preferences. As described above, more cardiovascular protective juice can be had from a different sort of squeeze.
Not every co-morbidity that strikes those living with HIV infection can be prevented or reversed with good primary care. Brains, kidneys, and arteries damaged by the long-term immunosuppression of CD4 cell count depletion, cannot always be fixed. However, the preponderance of data point out where gains can be made.
HIV medicine has transitioned from an oncological mode created to manage a progressive and complicated fatal disease to a model that more closely resembles a diabetes clinic, where lab metrics are used to plot a long-term course that avoids complications. For our patients to not only survive but thrive we need a new way to support them that recognizes their outsized risk for physical and psychological co-morbidities and the entrenched toxic social and emotional challenges that feed these conditions and, also, make addressing them difficult. The next leap forward in HIV management could be the development of a comprehensive approach to co-morbidity detection and intervention – one that can be readily implemented across HIV clinics, be they in Birmingham or Boston. Designing and implementing such a program, with input from experts in prevention and geriatric medicine, can be yet another example of HIV care leading the way.
Subject: NATAP/CROI: Frailty/Muscle Loss in HIV Increases Mortality & is CommonNATAP 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
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
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
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*1,2, 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+
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 =
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
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.
Today was the start of the first international workshop on Aging and HIV in Baltimore.
The program was started by Dr L. Ferrucci who gave the first presentation on frailty. He works in geriatrics and presented general data from previous studies in the general aging HIV negative population. He presented compelling data that showed that people lose lean body mass (via a syndrome. called age related sarcopenia) and strength in people as they age, and those decreases are correlated to higher mortality. Also, inflammation markers like interleukin 6 increase with age, and levels of over 2.5 pg/ml in the blood have been linked to disability due to loss of muscle strength and mass. He also added that aging related inflammation can decrease brain volume and may be implicated in depression and other health issues.
Dr Joseph Margolick from the MACS Cohort presented previously published frailty data from this cohort that followed 4959 men who have sex with men since 1984 until 2006. Some of these men got infected with HIV and have been followed up before and after infection. A total of 1045 patients with HIV were followed. 75% of them had undetectable HIV viral load.
The frailty related phenotype (FRP) (i.e., the physical characteristics of frailty) was identified using 1 item selected from the questionnaires for each of the following 4 components: weight loss (answer yes to since your last visit, have you had unintentional weight loss of at least 10 pounds), exhaustion [answer yes to during the past 4 weeks, as a result of your physical health, have you had difficulty performing your work or other activities (for example, it took extra effort)?], slowness (answer yes, limited a lot to does your health now limit you in walking several blocks?), and low physical activity level (answer yes, limited a lot to does your health now limit you in vigorous activities, such as running, lifting heavy objects, participating in strenuous sports?). The assessment of weakness (ie, grip strength) was not incorporated into the MACS protocol until October 2005 and therefore could not be used in defining the FRP. A participant was considered as having the FRP at the visit if at least 3 of the 4 components were present. The FRP thus defined had a prevalence of 4.4% among MACS HIV-uninfected men aged 65 years and older, which was similar to the prevalence of frailty observed in the Cardiovascular Health Study for men of similar ages.
Frailty improved with the introduction of HAART. However, after adjusting for most important factors, frailty was still higher in HIV+ men compared to HIV- men. In fact, frailty of a 55 year old HIV+ man may be similar to that of a 65 year old HIV negative man.
Basal metabolic rate has also been found to be higher in HIV+ men compared to HIV- ones.
No therapeutic intervention data was presented to review the effect of exercise, testosterone replacement, and other factors on frailty in HIV+ men.
Strive To Thrive While Growing Older With HIV
|By Dennis McMillan
Published: February 11, 2010
Positive Force will present “Survivor Health Wisdom: Strive to Thrive While Growing Older with HIV” on Wednesday, Feb. 17, 6:30-9:30 p.m. at the San Francisco LGBT Community Center, 1800 Market and Octavia Streets. Join Nelson Vergel, author of Built to Survive, for the latest information on lipoatrophy, combating premature aging, and much more. A light dinner will be provided. To take advantage of the fact that Vergel will be in the Bay Area for a conference, Positive Force scheduled this event on the third Wednesday of the month. Twice annually, Positive Force produces a community health forum on a hot button issue. “Survivor Health Wisdom…” is a Positive Force community health forum.In this instance, they decided to do a forum on HIV and aging. The face of HIV changes with each passing day. For example, thanks to treatment advances, many people living with HIV today are living longer lives. Along with longer lives come the usual health concerns: increased risks for heart disease, non-HIV related cancers, bone loss, decreased mental function, etc.
I bet this could compete with Theratecnologies/Serono’s Tesamorelin eventually. But Merck is smart going after baby aging boomers
An Anti-frailty Pill For Seniors? New Drug Increases Muscle Mass In Arms And Legs Of Older Adults
ScienceDaily (Nov. 5, 2008) — Researchers at the University of Virginia Health System report that a daily single oral dose of an investigational drug, MK-677, increased muscle mass in the arms and legs of healthy older adults without serious side effects, suggesting that it may prove safe and effective in reducing age-related frailty.
Published in the November 4, 2008 issue of Annals of Internal Medicine, the study showed that levels of growth hormone (GH) and of insulin-like growth factor I (IGF- I) in seniors who took MK-677 increased to those found in healthy young adults. The drug restored 20 percent of muscle mass loss associated with normal aging.
“Our study opens the door to the possibility of developing treatments that avert the frailty of aging,” explains Dr. Michael O. Thorner, a nationally recognized researcher of growth hormone regulation and a professor of internal medicine and neurosurgery at UVA. “The search for anti-frailty medications has become increasingly important because the average American is expected to live into his or her 80s, and most seniors want to stay strong enough to remain independent as they age.”
Funded by the National Institutes of Health, the two-year, double-blind, placebo-controlled, modified-crossover study involved 65 men and women ranging in age from 60 to 81.
The study drug, MK-677, mimics the action of ghrelin, a peptide that stimulates the growth hormone secretagogue receptor (GHSR). Drug developers are focusing on GHSR because it plays an important role in the regulation of growth hormone and appetite. They think it may prove to be an excellent treatment target for metabolic disorders such as those related to body weight and body composition.
According to Dr. Thorner, the UVA research was a “proof-of-concept” study that sets the stage for a larger and longer clinical trial to determine whether MK-677 is effective in people who are frail and to assess its long term safety.
University of Virginia Health System (2008, November 5). An Anti-frailty Pill For Seniors? New Drug Increases Muscle Mass In Arms And Legs Of Older Adults. ScienceDaily. Retrieved November 10, 2008, from http://www.sciencedaily.com /releases/2008/11/081104132902.htm