Frailty Syndrome in Patients With HIV Infection
Frailty syndrome is frequently encountered in elderly populations. Frailty has been defined as a geriatric syndrome of increased vulnerability to environmental factors.1-3 This syndrome is characterized by reduced physiologic reserve affecting multiple organ systems, is considered synonymous with disability and comorbidity, is highly prevalent in old age, and is associated with increased risk of falls, hospitalization, morbidity, and mortality.2,3 Geriatric frailty is found in 20% to 30% of elderly persons over age 75 years, and the risk increases with advancing age.4 Many molecular, physiologic, and clinical pathways have been hypothesized that increase vulnerability to this syndrome.5
There is an increasing number of individuals surviving with HIV and AIDS; in fact, the Centers for Disease Control and Prevention (CDC) reported a fivefold increase in cases of HIV infection in persons over the age of 50 from 1990 to 2001.6,7 A report from Karpiak and Shippy8 showed that there were more than 100,000 persons over age 50 years with AIDS in the United States in 2004. In 2006, approximately 27% of people with AIDS in the United States were over age 50.8 Another review reported that approximately 25% of new HIV infections occur in the over-50 age group.9 It is estimated that in a few years, these percentages will increase rapidly.
Frailty syndrome has not been comprehensively explored in patients with HIV infection. It appears that persons with HIV might be particularly prone to developing frailty syndrome because of the aging process and the influence of HIV. This article reviews the current evidence on frailty syndrome in persons with HIV infection, the applicability of general frailty indices to individuals who are HIV-positive, and future research involving frailty syndrome and HIV patients.
Frailty Syndrome in the General Elderly Population
Fried and colleagues10 constructed an index to help define frailty that is comprised of 5 physical features, all of which are able to predict an adverse outcome early11: unintentional weight loss (≥ 10 lb in the past year); weakness (low grip strength); poor endurance and energy (self-reported exhaustion); low physical activity level; and slow walking speed. This index stratifies elderly persons into “non-frail,” “intermediate” or “prefrail,” and “frail.” Frailty is defined by the presence of 3 or more of these criteria, and prefrailty is defined as the presence of one or 2 of these criteria.10 Many leading experts in the field of frailty syndrome have recommended using the definition suggested by Fried et al.
The median survival of a person with frailty is under 2 years.11 Frailty is an extreme phenotype of aging.10 Numerous authors have studied the factors that are associated with frailty syndrome. Blaum et al12 examined 543 participants (age 70-79 years) in the Women’s Health and Aging Studies I and II and found that a hemoglobin A1c (HbA1c) level of 6.5% or higher was associated with a greater prevalence of prefrail and frail status. The effect of other factors, such as comorbidities, body mass index, and inflammation, on frailty status was independent of the effect of hyperglycemia and could not explain the association of HbA1c and frailty status.12
A study published in 2007 reviewed a subcohort of 3141 community-dwelling elderly participants in the Cardiovascular Health Study from 1989-1990 through 1998-1999.13 Subjects were age 69 to 74 years and were observed to be without frailty or any other illness that mimics frailty or increases inflammation markers. The authors found that insulin resistance and C-reactive protein levels were associated with frailty.13
In 2003, Vanitallie14 reported that sarcopenia contributes significantly to the development of frailty syndrome in elderly patients. Sarcopenia is measured through total body protein and visceral protein depletion, which, in turn, is measured through transthyretin, retinol-binding protein, and albumin; visceral protein depletion is indicative of protein-calorie malnutrition.14
An Italian study published in 2006 evaluated 923 participants age 65 years or older who were enrolled in the Invecchiare in Chianti study in an effort to validate the measurement of muscle density and ratios of muscle and fat areas through the use of peripheral quantitative computed tomography measures, and to validate these results with Fried’s scale of frailty.15 The authors found that individuals with frailty have lower muscle density and muscle mass and higher fat mass than nonfrail individuals.15
The search for serologic markers that could define frailty in elderly persons is under way. High levels of interleukin (IL)-6 and white blood cell counts predict future disability in elderly people.11,16 Somatic and mitochondrial DNA mutations have also been proposed to play a role in the development of frailty. These mutations accumulated in postmitotic cells could lead to senescence, low testosterone levels, or low cholesterol levels.17
HIV Infection in the Elderly
There are numerous reviews about the relationship of aging and HIV infection, most of which reported on the differences in the epidemiology of HIV in older persons, influence of highly active antiretroviral therapy (HAART), T-cell count, comorbidities, morbidity, and mortality of older persons with this disease.18-21
In a critical review of the available literature, Martin et al9 stated that approximately 25% of HIV infections occur in the over-50 age group.22 The authors posit that the treatment of HIV is more complex in elderly patients than in younger patients due to the increased prevalence of comorbidities in the elderly, the lack of clear guidelines for treatment in the elderly, a paucity of studies examining the interactions between antiretrovirals and other medications taken by this age group, and the presence of age-related or geriatric syndromes.9
Nogueras et al20compared the epidemiologic and clinical characteristics of HIV infection in 36 patients age 50 years or older with 419 patients age 13 to 40 years in a city in Spain. They found that in the older age group, sexual contact was the main means of HIV transmission; in the younger group, intravenous drug use was the main means of transmission. The older and younger groups showed similar immunologic and virologic response to HAART, but the CD4 T-cell count response in the older age group was not as optimal as that of the younger age group, partly due to a delay between the time of their first presentation and care. In addition, researchers found that HIV infection progressed to AIDS faster and that there was a shorter survival time in the older patients as compared with the younger patients. Based on these findings, the authors recommended rapid treatment upon the diagnosis of HIV in elderly individuals.20
In 2 studies of patients age 50 years and older, Gebo et al23,24 suggested that even though the virologic response to HAART might be equal or better in older persons with HIV patients as compared with younger persons with HIV, the effectiveness of the immune response may be reduced in older patients as compared with younger patients. The authors concluded that immunologic response in older patients (> 50 years) may not be optimal even though viral load suppression is as effective as in younger patients.
Frailty and HIV Infection
It has been suggested that the phenotype of frailty is remarkably similar to the wasting syndrome that occurs in HIV infection.14,25 Wasting syndrome, or cachexia, is a debilitating and potentially life-threatening complication of HIV and is associated with reduced strength and functional ability, reduced capacity to withstand HIV-related complications, and a significant increase in morbidity and mortality.15 Its etiology seems to be multifactorial, and its pathogenesis is not well understood. A very intense proinflammatory response and endocrine abnormalities such as low testosterone levels and growth hormone resistance have also been proposed as pathogenetic mechanisms. Elevated levels of IL-1, IL-2, IL-6, and interferon gamma and/or tumor necrosis factor (TNF) have been observed in patients with wasting syndrome.25
An interesting prospective study evaluating 445 persons (71% men, 63% African American) with a mean age of 41.7 years and who had received their HIV diagnosis a mean of 8.4 years earlier found a frailty prevalence of 9% when using Fried et al’s frailty scale.26 The authors concluded that unemployment, more comorbid conditions and past opportunistic illnesses, higher depression severity score, use of antidepressants, and lower serum albumin levels were independent predictors of frailty. In addition, it was found that HIV infection was associated with a premature presentation of frailty.26
Desquilbet et al27 investigated the relationship between HIV infection and the prevalence of frailty-related phenotype (FRP). The authors defined FRP based on the definition proposed in Fried et al’s frailty index. Subsequently, they assessed the prevalence of frailty among men without HIV infection who participated in the Multicenter AIDS Cohort Study (MACS) between 1994 and 2004 (a total of 1905 individuals contributing 12,155 visits). Finally, the association between FRP and HIV infection before the era of HAART was evaluated in 245 men with HIV infection during 691 visits. The authors found that HIV infection was strongly associated with FRP prevalence and that the FRP prevalence for 55-year-old men infected with HIV for 4 years or less was similar to that of men age 65 years or older without HIV infection.27
The relationship between FRP and progressive deterioration of the immune system in 1046 men with HIV infection who participated in the MACS trial before and after the development of HAART was studied from 1994 to 2005.28 CD4 T-cell count and plasma HIV-RNA viral load were evaluated as predictors of FRP. The authors found that the adjusted prevalence of FRP remained low for CD4 T-cell counts of greater than 400 cells/mm3. After 1996, CD4 T-cell count was the only factor that was independently associated with FRP. The authors concluded that CD4 T-cell count predicted the development of FRP in men with HIV infection, independent of HAART use. The study also suggests that the deterioration of the immune system in individuals with HIV contributes to the systemic physiologic dysfunction of frailty.28 These findings might have interesting implications for the prevention of frailty syndrome in HIV populations. Theoretically speaking, HAART may contribute to a delay in the development of frailty syndrome in HIV-infected patients.
General Frailty Indexes: Are They Suitable for Patients With HIV Infection?
The few studies involving patients with HIV and frailty syndrome considered the general frailty index definition suggested by Fried and colleagues. One of the potential uncertainties regarding a general frailty index is whether it is applicable to patients with HIV infection in view of the many other issues that frequently affect HIV populations, such as cognitive dysfunction, bone density, immunosuppression, and vitamin D deficiency. These parameters might be important in the development of frailty indices for HIV populations.
In a 4-year, longitudinal study of 6030 community-dwelling persons age 65 to 95 years, Avila-Funes et al29 showed that, because cognitive impairment increases the risk of adverse health outcomes in this population, it improves the predictive validity of the operational definition of frailty. Cognitive impairment was present in 10% of nonfrail subjects, 12% of prefrail subjects, and 22% of frail subjects, respectively. After adjustment, disability in activities of daily living and instrumental activities of daily living were more likely to develop, and the risk of incident mobility disability and hospitalization was marginally greater, in persons with cognitive impairment who were classified as frail.29
Bone loss is another parameter that should be taken into account, as there are reports indicating that bone loss is common in patients with HIV and in patients with frailty.30-33 In fact, the use of certain antiretroviral therapies has been associated with the development of osteoporosis.31
Immunosuppression is another common pathway between HIV populations and individuals with frailty. Decreased CD4 T-cell count (< 200 cells/mm3) and high CD8 T-cell count (average, 563 cells/mm3) associated with poor proliferation of lymphocytes have been associated with high mortality in elderly individuals with frailty syndrome and in patients with HIV infection.34-37
Vitamin D deficiency has been associated with frailty syndrome. In a study of 444 male and 561 female subjects age 65 years and older, from the Invecchiare in Chianti study, Shardell et al38 found an association between vitamin D insufficiency and frailty only in men. Recent reports show that patients with HIV frequently present with vitamin D deficiency.39 In a study of 57 subjects with HIV infection in an outpatient clinic, moderate and severe 25-hydroxyvitamin D deficiency was found in 36.8% and 10.5% of participants, respectively.39 This deficiency might place HIV populations at higher risk for falls, fractures, and frailty status.
Toward the Development of an HIV-Related Frailty Index
The need for a specific HIV-related frailty index is imperative. The frequency of frailty syndrome might be underrepresented in patients with HIV infection if general frailty indices are used. In an interesting article, Searle et al40 suggested a step-by-step procedure for the construction of a frailty index based on an accumulation of health deficits. The process includes an initial selection of health variables, combination of these variables in an index, testing, and validation of results.
In a cross-sectional analysis, Cigolle et al41 compared 3 models of frailty (deficiencies in function, index of health burden, and biological syndrome) based on the Health and Retirement Study. A total of 11,113 adults age 65 years and older were studied. Interestingly, approximately 30.2% of respondents were frail according to at least 1 model, whereas 3.1% were frail according to all 3 models. The authors concluded that different models of frailty might capture different groups.41
Prognostic scores for frailty outcomes have been developed. In a prospective population-based study that included 1007 subjects age 65 years and older, Ravaglia et al42 identified 9 predictors associated with frailty: age 80 years or older; male gender; physical inactivity; use of 3 or more drugs; sensory deficits; calf circumference of less than 31 cm; disabilities in instrumental activities of daily living; Tinetti gait and balance test score of ≤ 24, which has been recommended and widely used in the elderly to assess mobility, balance, and gait, and to predict falls (a score of > 24 indicates low probability for falls); and pessimism about one’s health.
We suggest the construction of an index with the inclusion of Fried et al’s general frailty criteria (the aforementioned 5 physical measures)10 and HIV-related issues (cognitive dysfunction/dementia, bone loss, severe immunosuppression [CD4 T-cell count < 200 cells/mm3], and vitamin D deficiency). This index needs to be validated with other frailty indices in further studies. The definition of frailty, prefrailty, and nonfrailty status in persons with HIV infection will be influenced by further validation studies.
Conclusion and Future Research
Frailty syndrome is frequently encountered in elderly populations. It has been suggested that the phenotype of frailty is remarkably similar to the wasting syndrome that occurs in HIV infection. Factors such as hyperglycemia, insulin resistance and inflammation, sarcopenia, high levels of IL-6, IL-1, IL-2, and interferon gamma and/or TNF have been related to frailty in elderly patients. In patients with HIV infection, other factors, such as cognitive dysfunction/dementia, bone loss, severe immunosuppression (CD4 T-cell count < 200/ cells/mm3), and vitamin D deficiency, have been connected to frailty.
A dedicated HIV-frailty index proposed in this article needs to be validated with trials of frail patients with HIV infection age 50 years and older. A study comparing this scale with traditional frailty indices is necessary to ensure that this index reflects the real frequency of frailty in patients with HIV infection. The dynamics of frailty in aging HIV populations also needs to be studied. Whether HIV infection and aging interact together to cause early senescence and an increased prevalence of frailty is unknown. More studies are required to elucidate the role of HIV infection, the aging process, and frailty. Finally, treatment trials and preventive measures used in general elderly patients with frailty need to be studied in aging patients with HIV, as the effectiveness of these measures in patients with HIV is unknown.
The authors report no relevant financial relationships.
Dr. Ruiz is Assistant Professor of Clinical Medicine and Associate Director, and Dr. Cefalu is Professor of Medicine, Chief, Geriatric Medicine Section, and Director, Louisiana State University Geriatric Medicine Fellowship Program, Louisiana State University Health Sciences Center, New Orleans.
1. Afilalo J, Karunananthan S, Eisenberg MJ, Alexander KP, Bergman H. Role of frailty in patients with cardiovascular disease. Am J Cardiol 2009;103(11):1616-1621.
2. Srinivas-Shankar U, Wu FC. Frailty and muscle function: Role for testosterone? Front Horm Res 2009;37:133-149.
3. Rodin MB, Mohile SG. A practical approach to geriatric assessment in oncology. J Clin Oncol 2007;25(14):1939-1944.
4. Topinková E. Aging, disability and frailty. Ann Nutr Metab 2008;52(suppl 1):6-11.
5. Walston J, Hadley EC, Ferruci L, et al. Research agenda for frailty in older adults: Toward a better understanding of physiology and etiology: Summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc 2006;54(6):991-1001.
6. Mack KA, Ory MG. AIDS and older Americans at the end of the Twentieth Century. J Acquir Immune Defic Syndr 2003;33(suppl 2):S68-S75.
7. Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report, 2005, Volume 17, Revised Edition, June 2007. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2007. www.cdc.gov. Accessed February 3, 2011.
8. Karpiak SE, Shippy RA. Research on older adults with HIV/AIDS. AIDS Community Research Initiative of America; 2006. http://acria.org/clinical/roah_final_sept06.pdf. Accessed January 17, 2011.
9. Martin CP, Fain MJ, Klotz SA. The older HIV-positive adult: A critical review of the medical literature. Am J Med 2008;121(12):1032-1037.
10. Fried LP, Tangen CM, Walston J, et al; Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: Evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56A(3):M146-M156.
11. Repetto L, Venturino A, Fratino L, et al. Geriatric oncology: A clinical approach to the older patient with cancer. Eur J Cancer 2003;39(7):870-880.
12. Blaum CS, Xue QL, Tian J, Semba RD, Fried LP, Walston J. Is hyperglycemia associated with frailty status in older women? J Am Geriatr Soc 2009;57(5):840-847.
13. Barzilay JI, Blaum C, Moore T, et al. Insulin resistance and inflammation as precursors of frailty: The Cardiovascular Health Study. Arch Intern Med 2007;167(7):635-641.
14. Vanitallie TB. Frailty in the elderly: Contributions of sarcopenia and visceral protein depletion. Metabolism 2003;52(10 suppl 2):22-26.
15. Cesari M, Leeuwenburgh C, Laurentani F, et al. Frailty syndrome and skeletal muscle: Results from the Invecchiare in Chianti study. Am J Clin Nutr2006;83(5):1142-1148.
16. Leng SX, Xue QL, Tian J, Walston JD, Fried LP. Inflammation and frailty in older women. J Am Geriatr Soc 2007;55(6):864-887.
17. Kirkwood TB. Understanding ageing from an evolutionary perspective. J Intern Med 2008;263(2):117-127.
18. Grabar S, Weiss L, Costagliola D. HIV infection in older patients in the HAART era. J Antimicrobial Chemother 2006;57(1):4-7.
19. Navarro G, Nogueras MM, Segura F, et al; PISCIS Study Group. HIV-1 infected patients older than 50 years. PISCIS cohort study. J Infect 2008;57(1):64-71.
20. Nogueras M, Navarro G, Antón E, et al. Epidemiological and clinical features, response to HAART, and survival in HIV-infected patients diagnosed at the age of 50 or more. BMC Infect Dis 2006;6:159.
21. Gebo KA. HIV and aging: Implications for patient management. Drugs Aging 2006;23(11):897-913.
22. Operskalski EA, Mosley JW, Busch MP, Stram DO. Influences of age, viral load and CD4+ count on the rate of progression of HIV-1 infection to AIDS. Transfusion Safety Study Group. J Acquir Immune Defic Syndr Hum Retrovirol 1997;15(3):243-244.
23. Gebo KA, Justice A. HIV infection in the elderly. Curr Infect Dis Rep 2009;11(3):246-254.
24. Gebo KA. Epidemiology of HIV and response to antiretroviral therapy in the middle aged and elderly. Aging Health 2008;4(6):615-627.
25. Walston J, McBurnie MA, Newman A, et al; Cardiovascular Health Study. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: Results from the Cardiovascular Health Study. Arch Intern Med 2002;162(20):2333-2341.
26. Onen NF, Agbebi A, Shacham E, Stamn KE, Onen AR, Overton ET. Frailty among HIV-infected persons in an urban outpatient care setting. J Infect 2009;59(5):1-7.
27. Desquilbet L, Jacobson LP, Fried LP, et al; Multicenter AIDS Cohort Study. HIV-infection is associated with an earlier occurrence of a phenotype related to frailty. J Gerontol A Biol Sci Med Sci 2007;62(11):1279-1286.
28. Desquilbet L, Margolick JB, Fried LP, et al; Multicenter AIDS Cohort Study. Relationship between a frailty-related phenotype and progressive deterioration of the immune system in HIV-infected men. J Acquir Immune Defic Syndr 2009;50(3):299-306.
29. Avila-Funes JA, Amieva H, Barberger-Gateau P, et al. Cognitive impairment improves the predictive validity of the phenotype of frailty for adverse health outcomes: The Three-City Study. J Am Geriatr Soc 2009;57(3):453-461.
30. Paganelli R, Di Iorio A, Cherubini A, et al. Frailty in older age: The role of the endocrine-immune interaction. Curr Pharm Des 2006;12(24):3147-3159.
31. Brown TT, McComsey GA, King MS, Qaquish RB, Bernstein BM, da Silva BA. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. J Acquir Immune Defic Syndr 2009;51(5):554-561.
32. Huang J, Meixner L, Fernandez S, McCutchan JM. A double-blind, randomized, controlled trial of zolendronate therapy for HIV-associated osteopenia and osteoporosis. AIDS 2009;23(1):51-57.
33. Amorosa V, Tebas P. Bone disease and HIV infection. Clin Infect Dis 2006;42(1):108-114.
34. Semba RD, Margolick JB, Leng S, Walston J, Ricks MO, Fried LP. T cell subsets and mortality in older community-dwelling women. Exp Gerontol 2005;40(1-2):81-87.
35. Vrisekoop N, van Gent R, de Boer AB, et al. Restoration of the CD4 T cell compartment alters long-term highly active antiretroviral therapy without phenotypical signs of accelerated immunological aging. J Immunol 2008;181(2):1573-1581.
36. Leng SX, Hung W, Cappola AR, Yu Q, Xue QL, Fried LP. White blood cell counts, insulinlike growth-factor-1 levels, and frailty in community-dwelling older women. J Gerontol A Biol Sci Med Sci 2009;64(4):499-502.
37. Leng SX, Xue QL, Huang Y, Ferrucci L, Fried LP, Walston JD. Baseline total and specific differential white blood cell counts and 5-year all-cause mortality in community-dwelling older women. Exp Gerontol 2005;40(12):982-987.
38. Shardell M, Hicks GE, Miller RR, et al. Association of low vitamin D levels with frailty syndrome in men and women. J Gerontol A Biol Sci Med Sci 2009;64(1):69-75.
39. Rodriguez M, Daniels B, Gunawardene S, Robbins GK. High frequency of vitamin D deficiency in ambulatory HIV-positive patients. AIDS Res Hum Retroviruses 2009;25(1):9-14.
40. Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K. A standard procedure for creating a frailty index. BMC Geriatr 2008;8:24.
41. Cigolle CT, Ofstedal MB, Tian Z, Blaum CS. Comparing models of frailty: The Health and Retirement Study. J Am Geriatr Soc 2009;57(5):830-839.
42. Ravaglia G, Forti P, Lucicesare A, Pisacane N, Rietti E, Patterson C. Development of an easy prognostic score for frailty outcomes in the aged. Age Ageing 2008;37(2):161-166.