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CROI 2014: Researchers Discuss HIV, Aging, and Frailty


People living with HIV are at greater risk of geriatric syndromes such as frailty and difficulty with daily activities than HIV negative people of the same age -- and this can have a significant effect upon their quality of life as they age, according to several studies presented at the 14th Conference on Retroviruses and Opportunistic Infections (CROI 2014) last month in Boston.

Some of the findings described how HIV-associated inflammation and immune activation may be partly responsible for early aging in people with HIV, while others reported on increased frailty risk associated with a number of other conditions that are common in HIV positive people, such as injection drug use.

The effects are not limited to outward physical signs of aging, but many people with HIV seem to have immune systems that are aging prematurely. Meanwhile, whether associated with HIV or its treatment, there are also increasing reports of bone weakness and osteoarthritis.

The message to HIV clinicians was loud and clear: "We need to start thinking about how to integrate geriatric principles into the clinical care of our newly aging population," said Meredith Greene from the Division of Geriatrics at the University of California at San Francisco, who presented one of the studies.

Fortunately, there may be partial remedies for frailty -- increased physical exercise seems to help at least somewhat.

Frailty and HIV

"Frailty is a syndrome of decreased physiological reserve or an accumulation of deficits or comorbidities that are associated with an increased susceptibility to undesirable outcomes such as loss of function, loss of independence, falls, worsening mobility, ending up in the hospital or an institution, and then, eventually, dying," said Kevin Yarashski from Washington University School of Medicine, who gave a brief overview on frailty at a themed poster discussion on Frailty and Functional Impairment, where the findings were presented.

Though most of the studies in the session focused on physical frailty -- including physical weakness, muscle wasting, and not being able to do activities of daily living -- Yarashski stressed that they often co-exist and interact with cognitive and immune frailty as well.

"We have to think about the cognitive domain -- the triple D's: dementia, depression, and poor disposition or mood, and how that affects physical frailty and a compromised immune system," he said.

Aging and frailty are complex, and there are a number of potentially confounding variables in people living with HIV. Studies suggest that how people age can be affected by their demographics, including sex, race/ethnicity, education, socioeconomic factors, and employment.

A number of HIV-related issues may increase frailty risk, such as how long a person has been HIV positive, when they started antiretroviral therapy (ART), their adherence to treatment, what drugs they are taking, their CD4 T-cell count now or at their lowest point (nadir) before starting treatment, their viral load both in plasma and in cerebrospinal fluid (CSF), and coinfections such as cytomegalovirus (CMV) or hepatitis C. Other medical and physiological factors can also increase risk, such as other medications being taken, cardiovascular health, liver and kidney function, cancer, body weight and composition, and lifestyle issues such as smoking, diet, and levels of physical activity.

Recent data suggest that all these factors probably work together to increase the risk of frailty for people living with HIV. An example includes a recent report from the Multicenter AIDS Cohort Study, following 1946 men who have sex with men. This analysis found a significantly higher prevalence of frailty among HIV positive compared to HIV negative individuals (about 12% versus 9%, respectively) that began to be apparent at the age of 50 and persists into later life.

Geriatric Syndromes

Greene’s presentation -- an analysis of aging HIV positive participants in the UCSF cohort -- lent support to the MACS conclusions and also looked at the effects of some of the variables associated with increased risk of geriatric syndromes in people living with HIV.

This was a cross-sectional study that enrolled 155 HIV positive people aged 50 or older (median age 57), all with an undetectable viral load on ART. Over half were Caucasian, 80% were men who have sex with men, the median CD4 count was 567 cells/mm3, the median length of HIV infection was 21 years, and they had a median of 4 comorbidities.

Frailty was observed in 9% of the participants, but "pre-frailty" was observed in 56% of the cohort -- higher than seen in the national HIV negative population. Other geriatric syndromes were also common: 26% were at risk of falls and 25% had urinary incontinence. 25% reported that they had difficulty with more than 1 basic activity of daily living (self-care tasks such as bathing, using the toilet, feeding or clothing oneself) and 47% reported difficulty with more than 1 instrumental daily activity (higher level tasks such as shopping, housekeeping, managing accounts, food preparation, taking medications, using the telephone, or transportation).

In multivariate analyses, non-white race, increasing number of comorbidities, and a lower nadir CD4 count were all associated with increased risk of geriatric syndromes.

Unexpectedly, the researchers saw that exposure to some of the earlier nucleoside analog or NRTI drugs -- AZT (zidovudine or Retrovir), d4T (stavudine or Zerit), ddC (zalcitabine or Hivid), or ddI (didanosine or Videx) -- was actually associated with decreased risk of geriatric syndromes. This could reflect the possibility that people who were earlier adopters of treatment availed themselves of a higher standard of treatment generally -- or perhaps they represent a cohort of survivors, while other people in the cross-sectional study could have had a very different trajectory.

Inflammation and Aging

Whether HIV itself or the comorbidities associated with it are most responsible for frailty and other geriatric symptoms is unclear, but it is widely agreed that inflammation related to HIV, other infections such as CMV, and chronic conditions or lifestyle factors plays a major role in driving more rapid aging and increased morbidity and mortality.

In particular, elevated levels of interleukin 6 (IL-6), an immune system cytokine, have been strongly associated with inflammation in people with HIV (as well as a number of other conditions). At CROI, a poster by Supriya Krishnan from Harvard and colleagues reported that increased age, increased central obesity, and smoking were risk factors for higher levels of soluble inflammatory markers such as IL-6 in HIV positive people on suppressive ART -- and likely play a significant role in the increased risk of non-AIDS events and death seen in people living with HIV.

HIV itself can have lasting effects on immune activation that persist despite virological suppression and CD4 cell normalization. One may be a persistent imbalance in CD4/CD8 ratios. For instance, Cristina Mussini and colleagues reported data from a large Italian cohort showing that HIV positive people with low CD4/CD8 ratios continue to be at higher risk of serious non-AIDS events and death regardless of CD4 count.

However, another poster reported that markers associated with monocyte activation phenotypes, and modestly with T-cell maturation, most strongly predicted clinical risk for non-AIDS morbidity, rather than CD8 T-cell activation or phenotypes.

Similarly, Katherine Erlandson of the University of Colorado gave a presentation on CMV-related inflammation and aging during the themed discussion. She and her colleagues found that CMV-specific humoral (antibody) immune responses were more strongly correlated with functional impairment and related inflammation, activation, and senescence, than cell-mediated immune responses.

But it may be a mistake to look at any of these factors in isolation, and many of these markers are already known to occur together in normal aging populations. For instance, Damani Piggott of Johns Hopkins University reported on the use of a simple inflammatory index (looking at IL-6 and tumor necrosis factor-alpha receptor-1) that has been validated to capture the effect of inflammation on mortality among adults age 65 and older.

Previously, Piggott and colleagues reported that HIV significantly increased frailty -- defined as fulfilling at least 3 of 5 standard criteria: weakness (grip strength), slow gait speed, weight loss, low physical activity, and exhaustion -- in people who inject drugs, who are already at greater risk of frailty than the general population.

In a further analysis, the researchers looked at whether the inflammatory index could be used to identify the patients with frailty. In fact, the inflammatory index was strongly associated with frailty and independently associated with mortality risk among aging HIV positive injection drug users, independent of HIV disease stage.

Similarly, Patricia Ndumbi and colleagues from McGill University in Montreal described another combination of biomarkers as being typically associated with an aged immune system (though this study did not look specifically at physical frailty). Her poster reported evidence that a significant proportion of people living with HIV may have "prematurely senescent immune systems" despite increases in CD4 cell counts on treatment.

The researchers looked for what they called an elderly immune risk phenotype (IRP) -- characterized by low CD4/CD8 T-cell ratio (<1), high CD28-negative T-cell percentages, and CMV IgG seropositivity -- in 126 successfully treated HIV positive people with undetectable viral load and in 21 age-matched HIV negative control subjects. They found a significantly higher prevalence (32%) of IRP among people living with HIV than in the control group, none of whom had the aging immune phenotype.

To see whether the immune system is literally aging, the researchers looked at the length of telomeres in a subset of participants. Telomeres are protective strings of nucleotides at the end of chromosomes that tend to wear down a bit each time a cell divides -- getting shorter and shorter as a cell line ages -- and exposing the chromosomes to deterioration. They found that HIV positive people with an immune risk phenotype were much more likely to have shorter telomeres in their immune cells than those with more normal immune systems.

What exactly this means has yet to be determined. As Ndumbi and colleagues wrote, "larger studies will be needed to substantiate this finding and to determine whether the IRP may also represent a risk profile associated with higher mortality/morbidity in the HIV population."

While research looking at the immunological mechanisms behind frailty, morbidity, and mortality is important from a pathological perspective, some of the doctors at the themed discussion asked how useful it was clinically.

"Do we need to add another cost to the panel of tests that we get on our patients if anemia is a decent marker of inflammation and frailty?" asked Julie Justice, one of the researchers on the Veterans Aging Cohort Study project team. The physical performance test developed by that project -- the VACS Index -- which was developed for people with HIV but has been found to be useful in other populations as well -- has also been shown to be correlated with inflammation, frailty, and fragility fractures.

Fracture Risk and Osteoarthritis

It is unclear to what extent HIV is directly responsible for bone fragility in people living with HIV, or to what extent this is due to the effects of certain antiretroviral drugs. One poster by Bonnie Wandera of Makerere University School of Public Health and colleaguesreported decreased bone mineral density among patients starting second-line ART in Uganda, at least some of which may have been associated with use of tenofovir (Viread, also in the Truvada, Atripla, Complera, and Stribild coformulations).

Other antiretroviral drugs may have an effect as well. A study by Todd Brown of Johns Hopkins and colleagues suggested that when looking at the total hip and lumbar spine, bone mineral density losses were less pronounced among people taking raltegravir (Isentress) than those on ritonavir-boosted atazanavir (Reyataz) or boosted darunavir (Prezista). When looking at total bone density, losses were greater on atazanavir than on darunavir. Nevertheless, baseline markers of inflammation and immune activation were associated with increased bone loss at the hip independent of CD4 cell count and viral load.

Weakened bones can lead to fractures, which increase the frailty experienced by people living with HIV and reduce their functional capacity. Again, the causes may be multifactorial.

Linda Battalora from the Colorado School of Mines and colleagues reported on a study of 2 cohorts including more than 1000 people with HIV, mostly men. In an unadjusted analysis, age, current or prior tobacco smoking, hepatitis C coinfection, history of fracture, and low bone mineral density (osteopenia or osteoporosis) were significantly associated with increased risk of a new fracture. In a multivariate analysis, however, only low baseline bone density and increasing age were strongly associated with elevated risk of incident fractures.

Another frailty-associated condition that may be associated with chronic inflammation in people with HIV is osteoarthritis. One visually disturbing poster from a team of French researchers led by Anne-Laurence Tomi reported that HIV positive people have a higher risk of hand osteoarthritis than the general population of the same age. People with HIV are also at risk of more severe osteoarthritis, particularly in the case of those with metabolic syndrome (associated with trunk obesity, elevated triglycerides, and other metabolic abnormalities).

Functional Impairment and Quality of Life

In the end, all of these frailty-associated conditions can make day-to-day living more difficult for people living with HIV. And perhaps not surprisingly, reductions in frailty-associated functional capacity are associated with a lower quality of life, according to another study using the VACS Index that Erlandson presented during the themed discussion.

This was a cross-sectional study of people with HIV, aged 45-65, on ART for more than 6 months with undetectable viral load (<48 copies/mL). The researchers assessed participants' medical history, administered a quality-of-life questionnaire (SF-36), and performed objective physical function assessments for walk speed (m/sec), power (chair rises/sec), and grip strength (kg).

They found that decreases in functional performance (which signify frailty on the VACS Index) were also associated with lower quality of life. Among aging people with well-controlled HIV, better performance on the 400-meter walk, faster chair rise, and greater physical activity were associated with both higher physical and mental quality-of-life scores, independent of HIV-related mortality risk as estimated by the VACS Index.

Erlandson concluded that targeted exercise programs to increase physical activity and improve speed and power should be evaluated as interventions to improve quality of life for HIV positive people on ART.

Consequently, the themed discussion session concluded with a study looking at the effects of brisk walking on inflammatory markers associated with frailty, presented by Valeria Longo of the San Raffaele Scientific Institute in Milan.

The study enrolled 50 HIV positive people on ART with less active lifestyles into a 12-week exercise program which consisted of 3 x 60 minute walks per week at 65%-75% of maximum heart rate, either with or without 30 minutes of circuit training (the "walk" and "strength-walk" groups).

35 of the 50 participants completed the 12-week program: 21 in the "walk" group and 14 in the "strength-walk" group. After 12 weeks, participants showed significant improvement in performance and in all strength exercises, as well as in body mass index, waist and hip circumferences, and total and LDL cholesterol levels. There were also significant reductions in the inflammation biomarkers D-dimer, IL-18, IL-6, and myostatin.

Programs incorporating moderate exercise may be beneficial, at least for less active people with HIV. But as Yarashki noted, "we certainly need an awful lot more information on what types of exercise, how much, how little, and how long."



M Greene, V Valcour, Y Miao, et al. Geriatric Syndromes Are Common Among Older HIV-Infected Adults. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 766.

S Krishnan, R Bosch, B Rodriguez, et al. Correlates of Inflammatory Markers After One Year of Suppressive Antiretroviral Treatment (ART). 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 757.

C Mussini, P Lorenzini, A Cozzi-Lepri, et al. Incidence of CD4/CD8 Ratio Normalization and Its Role in the 
Onset of Non-AIDS-Related Events. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 753.

E Wilson, A Singh, K Huppler Hullsiek, et al. Inflammatory Biomarkers in Chronic HIV Disease Predominantly 
Associate With Monocyte Activation. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 755.

K Erlandson, A Allshouse, R Rapaport, et al. Cell-Mediated CMV Responses in HIV-Infected Persons With Impaired Physical Function. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 764.

D Piggott, R Varadhan, S Mehta, et al. Frailty, Inflammation and Mortality Among Aging HIV-Infected and At-Risk Injection Drug Users. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 762.

P Ndumbi, J Falutz, J Szabo, et al. Presence of the Immune Risk Phenotype and Telomere Shortening Among HIV Treated Patients. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 765.

B Wandera, F Ssemitala, A Kiragga, et al. Low Bone Mineral Density (BMD) Among Ugandan HIV-Infected Patients on Failing First-Line ART. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 784.

T Brown, C Moser, J Currier, et al. Bone Density Changes After Antiretroviral Initiation With Protease Inhibitors or Raltegravir. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 779LB.

L Battalora, K Buchacz, C Armon, et al. Low Bone Mineral Density Is Associated with Increased Risk of Incident Fracture in HIV+ Adults. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 781.

K Erlandson, A Allshouse, C Jankowski, et al. Physical Function Impairment On Quality of Life AmongPersons Aging With HIV Infection. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 767.

V Longo, M Bonato, S Bossolasco, et al. Brisk Walking Improves Inflammatory Markers in cART-Treated Patients. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 763.