Multimorbidity and depression in HIV-infected older adults

Mental health practitioners should be alert to the physical conditions and changes experienced by older people with HIV and address these in treatment.

By Richard J. Havlik, MD

The U.S. population is aging as a result of the “baby-boom” generation living longer and entering advanced age. Persons with HIV are aging largely because of anti-retroviral therapy (ART). For most of us, aging results in thinning and graying of hair, wrinkles and loose skin, loss of muscle mass and strength, and other such manifestations. But there are other changes occurring below the surface, such as distortion or loss of an effective immune system (immune senescence) and increases in irritating proteins in the blood, such as interleukin-6 and tumor necrosis factor (chronic inflammation; Bhatia, Ryscavage & Taiwo, 2011).

A similar process of immune dysregulation and chronic inflammation occurs in HIV-infected older adults, even those who are well-treated with ART. Inflammatory responses may continue because of the presence of low levels of virus or other bacteria or viruses (Aberg, 2012). Normally, inflammation in the body occurs in response to an injury or successful limitation of an infection; in an HIV-infected older adult, a smoldering condition is hypothesized to lead to an increase in disease burden (Bhatia et al., 2011). For HIV-infected older adults, diseases and conditions such as heart attacks (indicating cardiovascular disease) and low bone density (indicative of osteoporosis) are more frequent than would be expected with normal aging (Havlik, 2009). With more than one additional disease or condition (comorbidity) added to the presence of HIV, the use of the term “multi-morbidity” is more appropriate in this situation (Justice, 2010).  

Depression may also complicate the lives of HIV-infected older adults. Population-based numbers from the HIV Cost and Services Utilization Study (HCSUS; Bing et al. 2001) suggest that the estimated prevalence of major depression and dysthymic disorder is higher in people living with HIV than among non-infected individuals. In persons without HIV, chronic depression can inhibit immune response to certain vaccines, such herpes zoster vaccine (Irwin et al., 2013). Depression may also be associated with increases in inflammatory markers, such as interleukin 6 and tumor necrosis factor further adding to disease burden. In addition, inflammation may be causal for the onset of depression (Messay, Lim, & Marland, 2012); chronic inflammation may be an underlying mechanism for the associations among age, HIV, depression and multi-morbidity.

The conceptual model in Figure 1 shows various interrelationships among depression and other factors, with connections going in almost every direction. For example, depression can adversely affect adherence to ART and other treatments. Interferon used for treatment of hepatitis C can cause depression in up to one-third of those receiving therapy, especially in those with a history of depression. The realities of a new HIV diagnosis can contribute to the onset of a reactive depression in addition to the stigma, loneliness and lack of social support that are common in older persons living with HIV/AIDS. Of course, HIV can also have direct effects on multi-morbidity. The focus of this article is on the arrows between depression and multi-morbidity and the inter-relationships with age and HIV.

 Figure 1 Conceptualization of Multi-morbidity and Depression. Adapted from Havlik, R. J., Brennan, M. & and Karpiak, S. E. (2011). Comorbidities and depression in older adults with HIV. Sexual Health, 8, 551-559.

Figure 1 Conceptualization of Multi-morbidity and Depression. Adapted from Havlik, R. J., Brennan, M. & and Karpiak, S. E. (2011). Comorbidities and depression in older adults with HIV. Sexual Health, 8, 551-559.


HIV-Associated Diseases and Conditions in ROAH 

To systematically investigate HIV and multi-morbidity, “Research on Older Adults with HIV” (ROAH) was conducted in 2005-2006 in New York City with almost 1,000 HIV-positive older adults who completed self-administered surveys (Karpiak, Shippy & Cantor, 2006). The mean age of the sample was 55.5 years; two-thirds of the sample were persons of color and one-quarter were women. Over half had graduated high school, 25 percent had some college, 13 percent were college graduates, and 9 percent had graduate degrees. Most were not working (20 percent unemployed 54 percent on disability, 7 percent retired). Half had been diagnosed with AIDS; 13 percent had CD4 counts of less than 200.

The presence of diseases and conditions was collected using a list of 24 self-reported illnesses experienced during the previous year with a “yes” or “no” response option. The mean number of comorbidities reported by respondents was 3.3 per person. A comparison of this value to a group of much older persons in a national sample (National Health Interview Survey) is consistent with an interpretation of more diseases and conditions in HIV-infected older adults than would be expected (Havlik, 2009). 

Figure 2 shows the most prevalent comorbid health conditions reported by HIV-infected older adults in the ROAH Project. The reported rates of arthritis, hypertension and diabetes were similar to those found in the general population (Cheng, Hootman, Murphy, Langmaid, & Helmick, 2010; National Center for Health Statistics, 2013; CDC, 2013). Although reported diabetes was consistent with national trends, research suggests that certain antiretroviral medications may increase risk for diabetes in people with HIV (Butt et al., 2009; De Wit et al, 2008).

Figure 2 Chronic Diseases from ROAH Study. Adapted from Havlik, R. J., Brennan, M. & and Karpiak, S. E. (2011). Comorbidities and depression in older adults with HIV. Sexual Health, 8, 551-559.

Figure 2 Chronic Diseases from ROAH Study. Adapted from Havlik, R. J., Brennan, M. & and Karpiak, S. E. (2011). Comorbidities and depression in older adults with HIV.  Sexual Health, 8, 551-559.


Although self-reported heart conditions were slightly lower than reported national trends (National Center for Health Statistics, 2013), heart conditions may be somewhat elevated in older adults with HIV. HIV may contribute directly to this increased comorbidity (SMART Study Group, 2006) and certain antiretroviral treatments may contribute to increased cardiovascular risk (Islam, Wu, Jansson & Wilson, 2012; DAD Study Group, 2008).

Older persons with HIV have higher fracture rates (broken bones, see Figure 2) than the general population (Triant, Brown, Lee, & Grinspoon, 2008), consistent with findings of greater than expected bone loss in bone density testing in older men with HIV (Arnsten et al., 2007). Chronic inflammation is associated with increased osteoporosis and cardiovascular disease and may underlie bone disease in HIV infection (Aberg, 2012); alternatively, the combination of HIV infection, typical osteoporosis risk factors, and antiretroviral treatment may contribute to bone disease in HIV infection (McComsey et al., 2011).  

Whatever the cause of these various physical maladies, medical and mental health professionals should be aware of their risk among persons with HIV and be prepared to address them in the context of treatment.

Depression in HIV-infected Older Adults in ROAH

Depression was one of the most frequently endorsed conditions in HIV-infected older adults in ROAH, with 52 percent being depressed in the past year (Havlik, 2009) compared to a CDC estimate of 9.1 percent of the general population reporting any depression (Gonzales et al., 2010). The prevalence of depression appears lower at older ages in the general population: Kessler et al (2003) reported that adults ≥ 60 years of age reported less current depression than adults less than 45 years old. Using the Center for Epidemiologic Studies Depression Scale (CES-D, Radloff, 1977), ROAH investigators found that 38 percent of participants endorsed symptoms indicative of moderate depression and another 26 percent endorsed symptoms indicative of severe depression (Karpiak, Shippy & Cantor, 2006). Rabkin and McElhiney (2007) suggested that, in older adults with HIV, there is some plateauing of depressive symptoms with increasing age, but that they do not achieve the lower levels of non-HIV infected older adults in the general population. Suicide rates remain high and there is no doubt that depression is a major issue that requires attention in HIV-infected older adults (Keiser et al, 2010). 

Depression is also related to physical comorbidities. In the ROAH Project, a significant and positive correlation (r=.27) existed between the number of diseases/conditions and CES-D scores (Havlik, Brennan, & Karpiak, 2011). This correlation remained significant, even after controlling for relevant demographic characteristics, drug and alcohol use, and self-rated health. Correlations between CES-D scores and individual comorbid health conditions were modest (range ~ .10 to .15) but statistically significant. In general, participants with more depressive symptoms tended to have a greater likelihood of having vision and hearing loss, dermatological problems, heart and respiratory conditions, diabetes, impotence and broken bones (Havlik, Brennan, & Karpiak, 2011). 

Although ROAH’s cross-sectional design precludes causal inferences or determining the directionality of relationships involving depressive symptoms and the presence of other diseases and conditions, data from other sources suggest strong and possibly causal relationships. For example, low bone mass has been found in premenopausal women with depression (Eskandari et al., 2007), suggesting that depression may exert an independent effect on osteoporosis and fractures through depression-related inflammation. Additional research on the impact of depression on HIV-infected older adults is urgently needed; available data suggest that elevated levels of depression may adversely affect the health of people aging with HIV. 

Conclusions

  • The combination of HIV and aging may result in more diseases and conditions in HIV-infected older adults than in non-HIV-infected older adults.
  • More diseases and conditions in older persons with HIV may result from a combination of immune senescence and inflammation.
  • Depression can suppress immune responses and is associated with an increased inflammatory response.
  • Depression can be linked to multi-morbidity in HIV-infected older adults through similar mechanisms of immune suppression and inflammation.

Future Research and Implications

  • Further research, using appropriate comparison groups, is required to quantify and understand the possible effects of HIV and aging on multi-morbidity.  
  • To address causality, longitudinal studies examining interrelationships among various diseases and conditions, particularly depression and multi-morbidity in HIV-infected older adults, are needed. 
  • More assertive screening for certain diseases and conditions during HIV treatment visits, especially screening for the presence of depressive symptoms, will identify treatment opportunities.  
  • Psychologists working with HIV-infected older adults should be aware of the elevated prevalence of depressive symptoms in this population, screen for their presence and provide appropriate treatment, either directly or through referral.  
  • Treatment of other diseases and conditions by using established guidelines, whether developed in HIV-infected or uninfected individuals, is warranted. Emphasis should be placed on using knowledge gained by geriatricians and gerontologists in dealing with these issues in older patients to address the range of interrelated problems in HIV-infected older adults and reduce multi-morbidity in this vulnerable group. 

References

Aberg, J.A. (2012). Aging, inflammation, and HIV infection. Topics in Antiviral Medicine, 20, 101-105.

Arnsten, J.,H., Freeman, R., Howard, A. A., Floris-Moore, M., Lo, Y., Klein, R.S. (2007).  Decreased bone mineral density and increased fracture risk in aging men with or at risk for HIV infection. AIDS, 21, 617-623.  

Bhatia, R., Ryscavage, P., and Taiwo, B. (2012). Accelerated aging and human immunodeficiency virus infection: Emerging challenges of growing older in the era of successful antiretroviral therapy. Journal of Neurovirology,18, 247-55. doi: 10.1007/s13365-011-0073-y. Epub 2011 Dec 29. 

Bing, E.G., Burnam, M.A., Longshore, D., Fleishman, J.A., Sherbourne, D.C., London, A.S.,  … & Shapiro, M. (2001) Psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the United States. Archives of General Psychiatry, 58, 721-28. 

Butt, A.A., McGinnis, K., Rodriguez-Barradas, M.C., Crystal, S., Simberkoff, M., Goetz, M.,B.,  … & Veterans Aging Cohort Study (2009). HIV infection and risk of diabetes. AIDS, 23, 1227-1234.  doi: 10.1097/QAD.0b013e32832bd7af.

Centers for Disease Control and Prevention (2013). Percentage of Civilian, Noninstitutionalized Population with Diagnosed Diabetes, by Age, United States, 1980–2011. June 7, 2013. 

Cheng, Y. J., Hootman, J. M., Murphy, L. B., Langmaid, C. G. & Helmick, M. D. (2010). Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation—United States, 2007-2009 (PDF, 1.61MB). Morbidity and Mortality Weekly Report, 59, 1261-1265. June 7, 2013. 

Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group (2008).  Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: A multi-cohort collaboration. Lancet, 37, 1417-1426. 

De Wit, S., Sabin, C. A., Weber, R., Worm, S. W., Reiss, P., Cazanave, D.,  … &  & Data Collection on Adverse Events of Anti-HIV Drugs (DAD Study) (2008). Incidence and risk factors for new-onset diabetes in HIV-infected patients: The data collection on Adverse Events of Anti-HIV Drugs (DAD) Study. Diabetes Care, 31, 1224-1229. June 7, 2013.

Eskandari, F., Martinez, P.E., Torvik, S., Phillips, T.M., Sternberg, E.M., Mistry, S.  … & Premenopausal Osteoporosis Women Alendronate Depression (POWER) Study Group. (2007). Low bone mass in premenopausal women with depression. Archives of Internal Medicine. 167, 2329-2336.  

Gonzalez, O., Berry, J. T., McKnight, L. R., Strine, T., Edwards, V. J., Lu, H., & Croft, J. B. (2010). Current depression among adults—United Sates, 2006 and 2008. Morbidity and Mortality Weekly Report, 59, 1229-1235. 

Havlik, R.J., (2009). Health status, comorbidities, and health-related quality of life. In: Brennan, M., Karpiak, S. E., Cantor, M. H. & Shippy, R. A. (Eds.). Research on older adults with HIV: An in-depth examination of an emerging population. New York: Nova Science, pp. 13-25.  

Havlik, R.J., Brennan, M., Karpiak, S.E., (2011).  Comorbidities and depression in older adults with HIV. Sexual Health, 8, 551-559.  

Irwin, M.,R., Levin, M.,J., Laudenslager, M.,L., Olmstead, R., Lucko, A., Lang, N. … & Oxman, M. N.  (2013).  Varicella zoster virus-specific immune response to a herpes zoster vaccine in elderly recipients with major depression and impact of antidepressant mediations. Clinical Infectious Disease. doi: 10.1093/cid/cis 1208. First published on line: Feb. 13, 2013.  

Islam, F. M., Wu, J., Jansson, J., & Wilson, D. P. (2012).  Relative risk of cardiovascular disease among people living with HIV: A systematic review and meta-analysis. HIV Medicine, 13, 451 – 468. 

Justice, A.C., (2010). HIV and aging: Time for a new paradigm. Current  HIV/AIDS Reports, 7, 69-76. 

Karpiak, S. E., Shippy, R. A., & Cantor, M. (2006). Research on older adults with HIV. New York: AIDS Community Research Initiative of America.  

Keiser, O., Spoerri, A., Brinkhof, M., W., G., Hasse, B., Gayet-Ageron, A., Tissot, F. …  & Wang, P. S. (2010). Suicide in HIV-infected individuals and the General population in Switzerland, 1988-2008. American Journal of Psychiatry, 167, 143-150. 

Kessler, R.C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K.R… & Wang, P. S. (2003) The epidemiology of major depressive disorder – Results from the National Comorbidity Survey Replication (NCS-R). JAMA, 289, 3095-3105. 

McComsey, G. A., Kitch, D., Daar, E. S., Tierney, C., Jahed, N. C., Tebas, P., … & Sax, P. E. (2011).  Bone mineral density and fractures in antiretroviral-naïve persons randomized to receive abacavir - lamivudine or tenofovir disoproxil fumarate - emtricitabine along with efavirenz or atazanavir - ritonavir: AIDS Clinical Trials Group A522s, a substudy of ACTG A5202. Journal of Infectious Disease, 203, 1791 – 1801. 

Messay, B., Lim, A., Marsland, A.L. (2012). Current understanding of the bi-directional relationship of major depression with inflammation. Biology of Mood & Anxiety Disorders, 2, 1-4. 

National Center for Health Statistics (2013). Health, United States, 2012: With special feature on emergency care (PDF, 9.64MB). Hyattsville, MD. June 7, 2013.  

Rabkin, J.G.,& McElhiney, M.  (2007). Depression and distress in older HIV+ adults. GMHC Treatment Issues 3, 3-5. 

Radloff, L.S., (1977). The CES-D scale: A self-report depression scale for research in the general population. Applied Psychological Measurement, 1, 385-401. 

The Strategies for Management of Antiretroviral therapy (SMART) Study Group. (2006) CD4+ Count-guided interruption of antiretroviral treatment. New England Journal of Medicine, 355, 2283-2296. 

Triant, V.A., Brown, T. T., Lee, H., Grinspoon, S. K. (2008). Fracture prevalence among Human Immunodeficiency Virus (HIV)-infected versus non-infected patients in a large U.S. healthcare system. Journal of Clinical Endocrinology Metabolism, 93, 3499-3504.

About the Author

Richard J. Havlik, MD, MPH, has been a consultant to the AIDS Community Research Initiative of America since his retirement from the National Institute on Aging (NIA), part of the National Institutes of Health, Bethesda, Md. From 1990 to 2004, Havlik was associate director for epidemiology, demography and biometry and subsequently chief of the Laboratory of Epidemiology, Demography, and Biometry in the intramural research program at NIA. He directed a comprehensive program of research into the determinants and correlates of aging and age-associated diseases. His own research has covered a wide range of topics, including cardiovascular disease, cancer, cognitive functioning, dementia and genetic epidemiology. Since 1968, he also held various positions at the National Heart, Lung, and Blood Institute and the National Center for Health Statistics. He is the author of about 100 peer-reviewed publications as well as other chapters, articles and letters. Havlik has developed a current interest in the comorbidities associated with aging in HIV patients over 50 years of age.