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HIV and aging

Open AccessPublished:October 15, 2016DOI:https://doi.org/10.1016/j.ijid.2016.10.004

      Highlights

      • The world's HIV population is aging; in developed countries, 50% of patients are over the age of 50 years.
      • In the effective antiretroviral era, mortality has fallen and life expectancy has increased for HIV patients.
      • HIV increases systemic inflammation, but whether HIV accelerates aging is controversial.
      • HIV-positive people are at increased risk of co-morbidities.
      • The management of HIV patients will increasingly focus on geriatric issues.

      Abstract

      With the wider availability of antiretrovirals, the world's HIV population is aging. More than 10% of the 34.5 million HIV-positive individuals worldwide are over the age of 50 years and the average age continues to increase. In the USA more than 50% of the 1.3 million people with HIV are over 50 years old and by the year 2030 it is estimated that 70% will be over the age of 50 years. Although the life expectancy of HIV-positive people has increased dramatically, it still lags behind that of HIV-negative individuals. There is controversy about whether HIV itself accelerates the aging process. Elevated rates of inflammation seen in people with HIV, even if their viral loads are suppressed and their CD4 counts are preserved, are associated with greater rates of cardiovascular, renal, neurocognitive, oncological, and osteoporotic disease. These conditions increase exponentially in the elderly and will represent a major challenge for HIV patients. In addition, conditions such as geriatric syndromes including frailty are also seen at higher rates. Management of the aging HIV patient includes an emphasis on early diagnosis and treatment, preventative measures for co-morbidities, and avoiding polypharmacy. Finally, the issue of quality of life, prioritization of medical issues, and end of life care become increasingly important as the patient grows older.

      Keywords

      1. Introduction

      The epidemic caused by the human immunodeficiency virus (HIV) was first recognized in the USA in the early 1980s and shortly afterwards throughout the world. It affected younger populations with devastating effects. Before effective combination antiretroviral therapy (cART) became available in the 1990s, most patients with HIV infection had an inexorable down-hill course dominated by infections, tumors, wasting, and death. Now, in most instances, patients with HIV treated with cART live with their disease successfully.
      As people living with HIV age, they face a variety of new challenges including possible accelerated aging and higher rates of co-morbidities such as cardiovascular disease. They also develop geriatric syndromes and frailty earlier than uninfected people. Thus patients with HIV on cART have far less life-threatening acute illnesses, but must confront issues related to the aging process.
      The problem of aging in the HIV-positive population has been recognized in high-income countries where the percentage of people over the age of 50 years has increased rapidly, in many cases to over 50%. Because much of the information on aging and HIV has come from these countries, this review will concentrate on reports from the USA and Western Europe. The same trends and the same issues will become important in middle- and low-income countries in the future. This review, therefore, will be increasingly relevant to the care of HIV-positive patients throughout the world.
      This article is directed towards the general infectious diseases community, as well as physicians and other practitioners directly caring for patients with HIV. Issues covered include the epidemiology of aging, the question of accelerated aging, co-morbidities, geriatric syndromes and frailty, management, and the unique psychosocial issues facing HIV patients.

      2. History

      HIV was first recognized in the USA in 1981 as a fatal disease of young gay men and intravenous (IV) drug users. The virus was identified as the cause of HIV in 1983, and by 1985 there was a serum test to identify infected individuals. The early history is tragically outlined in the The Band Played On by Randy Shilts, published in 1987. By 1996 in the USA and Western Europe, there was widespread use of effective combinations of antiretroviral drugs initially termed highly active antiretroviral therapy or HAART and now referred to as cART. The death rate from HIV began to fall in 1996 in the USA, and the further availability of cART worldwide saw a global decline in new cases for the first time in 2012. This remarkable reversal of the prognosis of HIV caused a dramatic shift in the demographics of people living with HIV.

      3. Epidemiology of aging in people living with HIV

      The age of people living with HIV has been rising steadily, largely due to the success of cART. An estimated 3.6 million of the 35.6 million people worldwide living with HIV are over the age of 50 years and this trend is increasing steadily.
      HIV and aging: a special supplement to the UNAIDS report on the global AIDS epidemic 2013. Joint United Nations Programme on HIV/AIDS (UNAIDS).
      In countries where the epidemic was recognized earlier and effective therapy was available in the mid-1990s, the age of people living with HIV has increased dramatically. For example, in the USA approximately 40% of people living with HIV in 2012 were over the age of 50 years and 11% were over the age of 60 years.
      HIV and aging: a special supplement to the UNAIDS report on the global AIDS epidemic 2013. Joint United Nations Programme on HIV/AIDS (UNAIDS).
      By 2015 it was estimated that 50% of people were over the age of 50 years. Less appreciated are data indicating that 18% of newly diagnosed patients are over the age of 50 years.
      Centers for Disease Control and Prevention
      Both of these factors, aging and new acquisition later in life, have pushed up the average age of people living with HIV.
      A geographically specific example of this rise is demonstrated by data from San Francisco, one of the epicenters of the epidemic in the 1980s and 1990s. In 1990, the percentage of people living with HIV in San Francisco who were over the age of 50 years was 10%. By 2010 it had reached 50%.
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      • Scheer S.
      • Chen M.J.
      • Hughes A.J.
      • Pipkin S.
      People fifty years or older now account for the majority of AIDS cases in San Francisco, California, 2010.
      Similar data have been reported from New York City (New York City HIV/AIDS Annual Surveillance Statistics 2013) and France.
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      • Abgrall S.
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      • et al.
      Cohort profile: French hospital database on HIV (FHDH-ANRS CO4).
      The same trends, although delayed, have also been documented in low- and middle-income countries.
      HIV and aging: a special supplement to the UNAIDS report on the global AIDS epidemic 2013. Joint United Nations Programme on HIV/AIDS (UNAIDS).

      4. Mortality and lifespan

      There is great heterogeneity in the mortality figures and life expectancy of people with HIV, driven by factors such as patient virological suppression, CD4 nadir, time of diagnosis, and IV drug use. Nonetheless, the overall mortality rate has fallen dramatically.
      • Weber R.
      • Ruppik M.
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      • Battegay M.
      • et al.
      Decreasing mortality and changing patterns of causes of death in the Swiss HIV Cohort Study.
      Despite these advances, mortality rates in selected HIV-infected populations range from 1.7- to 7.0-times those of HIV-uninfected populations.
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      • Lodwick R.
      • Schechter M.
      • Deeks S.
      • Amin J.
      • Gilson R.
      • et al.
      Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population.
      • Antiretroviral Therapy Cohort C
      Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies.
      • Lewden C.
      • Chene G.
      • Morlat P.
      • Raffi F.
      • Dupon M.
      • Dellamonica P.
      • et al.
      HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population.
      • Legarth R.A.
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      • et al.
      Long-term mortality in HIV-infected individuals 50 years or older: a nationwide, population-based cohort study.
      • Collaboration of Observational H.I.V.E.R.E.i.E.
      • Lewden C.
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      • De Wit S.
      • Sabin C.
      • Mocroft A.
      • et al.
      All-cause mortality in treated HIV-infected adults with CD4 ≥500/mm3 compared with the general population: evidence from a large European observational cohort collaboration.
      Of great interest, subgroup analyses indicate that mortality approaches the uninfected population if the diagnosis of HIV is made early in the course of the disease, the CD4 count is maintained at >350–500 cells/μl, and the viral load is suppressed.
      • Rodger A.J.
      • Lodwick R.
      • Schechter M.
      • Deeks S.
      • Amin J.
      • Gilson R.
      • et al.
      Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population.
      Similarly, calculated life expectancy, which is based on mortality data, has risen since the late 1990s, but it is still only two-thirds that of the general population.
      • Antiretroviral Therapy Cohort C
      Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies.
      • Samji H.
      • Cescon A.
      • Hogg R.S.
      • Modur S.P.
      • Althoff K.N.
      • Buchacz K.
      • et al.
      Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada.
      • Lohse N.
      • Hansen A.B.
      • Pedersen G.
      • Kronborg G.
      • Gerstoft J.
      • Sorensen H.T.
      • et al.
      Survival of persons with and without HIV infection in Denmark, 1995-2005.
      • Losina E.
      • Schackman B.R.
      • Sadownik S.N.
      • Gebo K.A.
      • Walensky R.P.
      • Chiosi J.J.
      • et al.
      Racial and sex disparities in life expectancy losses among HIV-infected persons in the United States: impact of risk behavior, late initiation, and early discontinuation of antiretroviral therapy.
      • Sabin C.A.
      Do people with HIV infection have a normal life expectancy in the era of combination antiretroviral therapy?.
      • May M.
      • Gompels M.
      • Delpech V.
      • Porter K.
      • Post F.
      • Johnson M.
      • et al.
      Impact of late diagnosis and treatment on life expectancy in people with HIV-1: UK Collaborative HIV Cohort (UK CHIC) Study.
      • May M.T.
      • Gompels M.
      • Delpech V.
      • Porter K.
      • Orkin C.
      • Kegg S.
      • et al.
      Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy.
      As with mortality data, subgroup analyses indicate that those who achieve a CD4 count of above 350 cells/μl and viral suppression in the absence of other risk factors have a life expectancy that is similar to the general population.
      • May M.T.
      • Gompels M.
      • Delpech V.
      • Porter K.
      • Orkin C.
      • Kegg S.
      • et al.
      Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy.
      Caution regarding these studies, particularly the subgroup analyses, is warranted. Patients in some cohort analyses are not representative of the overall HIV-positive population, appropriate HIV-uninfected controls are difficult to identify, and data on aging are still preliminary for the HIV epidemic. In particular, it is difficult to control for differences in lifestyle factors, socio-economic status, risk factors for co-morbidities, nutrition, safe environment, ethnicity, social isolation, and chronic infections such as those caused by hepatitis and herpes viruses. The issues in identifying appropriate non-HIV-infected control populations has been reviewed recently.
      • Wong C.
      • Althoff K.
      • Gange S.J.
      Identifying the appropriate comparison group for HIV-infected individuals.
      A recent article compared life expectancy of HIV-positive and matched HIV-negative individuals (rather than the general population) cared for in the Kaiser Permanente Health System in California from 1996 (at the beginning of widespread cART in the USA) to 2011.
      • Marcus J.L.
      • Chao C.R.
      • Leyden W.A.
      • Xu L.
      • Quesenberry Jr., C.P.
      • Klein D.B.
      • et al.
      Narrowing the gap in life expectancy between HIV-infected and HIV-uninfected individuals with access to care.
      The life expectancy at age 20 years of an HIV-positive individual rose from 19.1 years to 53.1 years by 2011, but was still less than that of HIV-negative individuals (64.9 years). After controlling for risk factors including cART therapy, smoking, substance abuse, and hepatitis virus infection, a gap between HIV-positive and HIV-negative individuals of almost 6 years of life expectancy was still demonstrated. Thus the best data, i.e. HIV-positive individuals compared to matched HIV-negative individuals rather than the general population, indicate a continuing gap in life expectancy for HIV-positive individuals compared to those who are uninfected.

      5. Changing causes of death

      Data on cause of death from six different cohorts in developed countries after 1996 have demonstrated a dramatic fall in the rate of AIDS-related infections and malignancies. The rate of non-AIDS-related causes of death has fallen as well, but not as dramatically.
      • Weber R.
      • Ruppik M.
      • Rickenbach M.
      • Spoerri A.
      • Furrer H.
      • Battegay M.
      • et al.
      Decreasing mortality and changing patterns of causes of death in the Swiss HIV Cohort Study.
      • The Antiretroviral Therapy Cohort Collaboration
      • Gill J.
      • May M.
      • et al.
      Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies.
      • French A.L.
      • Gawel S.H.
      • Hershow R.
      • Benning L.
      • Hessol N.A.
      • Levine A.M.
      • et al.
      Trends in mortality and causes of death among women with HIV in the United States: a 10-year study.
      • Lewden C.
      • Salmon D.
      • Morlat P.
      • Bevilacqua S.
      • Jougla E.
      • Bonnet F.
      • et al.
      Causes of death among human immunodeficiency virus (HIV)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS.
      • Morlat P.
      • Roussillon C.
      • Henard S.
      • Salmon D.
      • Bonnet F.
      • Cacoub P.
      • et al.
      Causes of death among HIV-infected patients in France in 2010 (national survey): trends since 2000.
      • Smith C.J.
      • Ryom L.
      • Weber R.
      • Morlat P.
      • Pradier C.
      • Reiss P.
      • et al.
      Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration.
      These studies show widely varying causes of death depending on the characteristics of each cohort, but some important trends are clear. In the cART era, HIV-related causes of death remain important, but occur primarily in patients with delayed or ineffective treatment (non-adherence, drug resistance, poor CD4 recovery). The rates of liver disease, cardiovascular disease, and non-HIV-related infection have either fallen slightly or remained the same in the cART era. In contrast, the rate of death caused by non-HIV-related malignancies has increased.
      • The Antiretroviral Therapy Cohort Collaboration
      • Gill J.
      • May M.
      • et al.
      Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies.
      • Smith C.J.
      • Ryom L.
      • Weber R.
      • Morlat P.
      • Pradier C.
      • Reiss P.
      • et al.
      Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration.
      Other causes of death in the cART era include non-AIDS-related infections, renal disease, substance abuse, violence, and suicide.
      • Rodger A.J.
      • Lodwick R.
      • Schechter M.
      • Deeks S.
      • Amin J.
      • Gilson R.
      • et al.
      Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population.
      • French A.L.
      • Gawel S.H.
      • Hershow R.
      • Benning L.
      • Hessol N.A.
      • Levine A.M.
      • et al.
      Trends in mortality and causes of death among women with HIV in the United States: a 10-year study.

      6. Does HIV accelerate aging?

      The data quoted above suggest that HIV itself may accelerate the aging process. Aging has been broadly defined as “the time-dependent functional decline that affects most living organisms.”
      • Lopez-Otin C.
      • Blasco M.A.
      • Partridge L.
      • Serrano M.
      • Kroemer G.
      The hallmarks of aging.
      Multiple biological mechanisms for aging have been described, some of which may affect HIV-positive individuals at higher rates.
      • Lopez-Otin C.
      • Blasco M.A.
      • Partridge L.
      • Serrano M.
      • Kroemer G.
      The hallmarks of aging.
      • Horvath S.
      • Levine A.J.
      HIV-1 infection accelerates age according to the epigenetic clock.
      These mechanisms are discussed in detail by Lopez-Otin et al.
      • Lopez-Otin C.
      • Blasco M.A.
      • Partridge L.
      • Serrano M.
      • Kroemer G.
      The hallmarks of aging.
      and include genetic instability, telomere shortening, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The latter includes abnormal endocrine and neuroendocrine signaling, as well as immune dysregulation. Immune dysregulation, immune cell senescence, and chronic inflammation found even in HIV-positive patients virally suppressed on cART appear to be most important. For example HIV-positive individuals have increased serum levels of interleukin (IL)-6, a marker of inflammation that is associated with chronic illnesses including cancer and cardiovascular disease, with overall fitness, as well as with increased mortality.
      • Nordell A.D.
      • McKenna M.
      • Borges A.H.
      • Duprez D.
      • Neuhaus J.
      • Neaton J.D.
      • et al.
      Severity of cardiovascular disease outcomes among patients with HIV is related to markers of inflammation and coagulation.
      • Borges A.H.
      • O’Connor J.L.
      • Phillips A.N.
      • Ronsholt F.F.
      • Pett S.
      • Vjecha M.J.
      • et al.
      Factors associated with plasma IL-6 levels during HIV infection.
      • Nixon D.E.
      • Landay A.L.
      Biomarkers of immune dysfunction in HIV.
      • So-Armah K.A.
      • Tate J.P.
      • Chang C.C.
      • Butt A.A.
      • Gerschenson M.
      • Gibert C.L.
      • et al.
      Do biomarkers of inflammation, monocyte activation, and altered coagulation explain excess mortality between HIV infected and uninfected people?.
      Other biomarkers have also been shown to be increased in HIV-positive patients, including D-dimer, a prothrombotic protein.
      • Kamat A.
      • Misra V.
      • Cassol E.
      • Ancuta P.
      • Yan Z.
      • Li C.
      • et al.
      A plasma biomarker signature of immune activation in HIV patients on antiretroviral therapy.
      • Freiberg M.S.
      • Bebu I.
      • Tracy R.
      • So-Armah K.
      • Okulicz J.
      • Ganesan A.
      • et al.
      D-dimer levels before HIV seroconversion remain elevated even after viral suppression and are associated with an increased risk of non-AIDS events.
      There are probably multiple mechanisms accounting for increased inflammation in HIV-positive individuals, as outlined below.
      • 1.
        Low-level tissue viral infection with HIV, even in patients treated with effective cART who have undetectable serum virus. While controversial, recent evidence based on both tissue and peripheral blood of patients on cART indicates ongoing tissue viral replication.
        • Dampier W.
        • Nonnemacher M.R.
        • Mell J.
        • Earl J.
        • Ehrlich G.D.
        • Pirrone V.
        • et al.
        HIV-1 genetic variation resulting in the development of new quasispecies continues to be encountered in the peripheral blood of well-suppressed patients.
        • Lorenzo-Redondo R.
        • Fryer H.R.
        • Bedford T.
        • Kim E.Y.
        • Archer J.
        • Kosakovsky Pond S.L.
        • et al.
        Persistent HIV-1 replication maintains the tissue reservoir during therapy.
        • Martinez-Picado J.
        • Deeks S.G.
        Persistent HIV-1 replication during antiretroviral therapy.
        Both studies used genetic analysis to estimate viral evolution and mutation over time . In spite of cART, viral evolution continued for 6 months in one study and for 6 years in the other, suggesting ongoing tissue replication despite cART. It is important to note that viral evolution is not a direct measure of tissue viral replication. Analysis of the data from these studies required sophisticated statistical methods to infer tissue viral replication. Thus, further studies including more direct methods will be required to confirm these findings.
      • 2.
        Chronic viral reactivation of herpes viruses, particularly cytomegalovirus, in HIV.
        • Naeger D.M.
        • Martin J.N.
        • Sinclair E.
        • Hunt P.W.
        • Bangsberg D.R.
        • Hecht F.
        • et al.
        Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease.
      • 3.
        Microbial translocation, i.e. penetration of gut microbes and their products into the systemic circulation due to abnormal gut immunity despite effective cART.
        • Dinh D.M.
        • Volpe G.E.
        • Duffalo C.
        • Bhalchandra S.
        • Tai A.K.
        • Kane A.V.
        • et al.
        Intestinal microbiota, microbial translocation, and systemic inflammation in chronic HIV infection.
      • 4.
        Immune dysregulation and senescence with depletion of CD4+ T cells, increased numbers of senescent CD8 T cells (CD57 + CD28 − ) that secrete cytokines, and increased monocyte activation.
        • Angelovich T.A.
        • Hearps A.C.
        • Maisa A.
        • Martin G.E.
        • Lichtfuss G.F.
        • Cheng W.J.
        • et al.
        Viremic and virologically suppressed HIV infection increases age-related changes to monocyte activation equivalent to 12 and 4 years of aging, respectively.
        Immune senescence occurs at a younger age in HIV-infected patients than in elderly non-HIV-infected persons. Functionally, this results in a decreased ability to respond immunologically to new antigens, pathogens, and vaccines, as well as an increased inflammatory state.
      Interestingly, each of these mechanisms has also been described in elderly HIV-negative individuals as part of the normal aging process.
      • Pathai S.
      • Bajillan H.
      • Landay A.L.
      • High K.P.
      Is HIV a model of accelerated or accentuated aging?.
      Other biological mechanisms of aging have also been described in HIV-positive persons at higher rates, including mitochondrial dysfunction, dysfunction of the growth hormone/insulin-like growth factor/insulin pathway that regulates cell growth and metabolism, telomere shortening, and epigenetic changes.
      • Lopez-Otin C.
      • Blasco M.A.
      • Partridge L.
      • Serrano M.
      • Kroemer G.
      The hallmarks of aging.
      Whether these inflammatory and immune changes translate into accelerated aging is controversial.
      • Pathai S.
      • Bajillan H.
      • Landay A.L.
      • High K.P.
      Is HIV a model of accelerated or accentuated aging?.
      • Justice A.
      • Falutz J.
      Aging and HIV: an evolving understanding.
      It is important to emphasize that changes in inflammation, immune dysfunction, physical functional changes, e.g. geriatric syndromes and frailty (see below), and co-morbidities have not always been correlated. While each of these has been identified in HIV-positive populations, it is not clear that they cause accelerated aging.
      Arguments supporting accelerated aging processes in HIV patients include the presence at younger ages of the following changes: (1) increased rates of chronic co-morbidities, (2) increased rates of geriatric syndromes and frailty, (3) senescent immune changes, and (4) persistent increased inflammatory markers termed inflamm-aging.
      • Franceschi C.
      • Bonafe M.
      • Valensin S.
      • Olivieri F.
      • De Luca M.
      • Ottaviani E.
      • et al.
      Inflamm-aging. An evolutionary perspective on immunosenescence.
      Consistent with these findings are the increased mortality and reduced lifespan of HIV-positive populations compared to the general population.
      However, arguments against accelerated aging in HIV-positive patients include the fact that the life expectancy of HIV-positive patients with CD4 counts >500 cells/μl and suppressed viral loads on cART in some cohorts is no different to that of the general population.
      • Antiretroviral Therapy Cohort C
      Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies.
      • May M.
      • Gompels M.
      • Delpech V.
      • Porter K.
      • Post F.
      • Johnson M.
      • et al.
      Impact of late diagnosis and treatment on life expectancy in people with HIV-1: UK Collaborative HIV Cohort (UK CHIC) Study.
      • May M.T.
      • Gompels M.
      • Delpech V.
      • Porter K.
      • Orkin C.
      • Kegg S.
      • et al.
      Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy.
      In addition while co-morbidities occur at higher rates in the HIV population for any given age, the rate of co-morbidities does not increase with the length of time a person is infected with HIV. HIV may be a risk factor for co-morbidities, but does not appear to accelerate their occurrence over time.
      • Althoff K.N.
      • McGinnis K.A.
      • Wyatt C.M.
      • et al.
      Comparison of risk and age at diagnosis of myocardial infarction, end-stage renal disease, and non-AIDS-defining cancer in HIV-infected versus uninfected adults.
      • Rasmussen L.D.
      • May M.T.
      • Kronborg G.
      • et al.
      Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study.
      Further mechanistic and epidemiological data will be needed to clarify this ongoing controversy.

      7. Increased risk of chronic non-AIDS diseases in HIV-positive patients

      Patients with HIV have an increased number of co-morbidities compared to those without HIV.
      • Smit M.
      • Brinkman K.
      • Geerlings S.
      • Smit C.
      • Thyagarajan K.
      • Sighem A.
      • et al.
      Future challenges for clinical care of an ageing population infected with HIV: a modelling study.
      These co-morbidities occur at high rates at all ages in HIV-positive patients, but will become increasingly important as this population ages. The following sections review data indicating increased risk in HIV-positive people for certain co-morbidities.

      7.1 Cardiovascular disease and stroke

      In the pre-cART era, HIV-positive patients were at risk of myocarditis and dilated cardiomyopathy, usually associated with a low CD4 count.
      • Barbaro G.
      • Di Lorenzo G.
      • Grisorio B.
      • Barbarini G.
      Incidence of dilated cardiomyopathy and detection of HIV in myocardial cells of HIV-positive patients. Gruppo Italiano per lo Studio Cardiologico dei Pazienti Affetti da AIDS.
      With the advent of effective cART, these conditions have faded, and HIV-positive patients are recognized to be at increased risk of chronic cardiovascular disease including coronary artery disease, myocardial fibrosis, congestive heart failure, and ischemic stroke.
      • Thiara D.K.
      • Liu C.Y.
      • Raman F.
      • Mangat S.
      • Purdy J.B.
      • Duarte H.A.
      • et al.
      Abnormal myocardial function is related to myocardial steatosis and diffuse myocardial fibrosis in HIV-infected adults.
      • Feinstein M.J.
      • Bahiru E.
      • Achenbach C.
      • Longenecker C.T.
      • Hsue P.
      • So-Armah K.
      • et al.
      Patterns of cardiovascular mortality for HIV-infected adults in the United States: 1999 to 2013.
      • Martin-Iguacel R.
      • Llibre J.M.
      • Friis-Moller N.
      Risk of cardiovascular disease in an aging HIV population: where are we now?.
      For example, data from the Veteran Aging Cohort Study in HIV-positive individuals showed a 1.5-times increased risk of acute myocardial infection and a 1.17-times increased risk of stroke at all ages, even in those with suppressed viral loads.
      • Freiberg M.S.
      • Chang C.C.
      • Kuller L.H.
      • Skanderson M.
      • Lowy E.
      • Kraemer K.L.
      • et al.
      HIV infection and the risk of acute myocardial infarction.
      • Sico J.J.
      • Chang C.C.
      • So-Armah K.
      • Justice A.C.
      • Hylek E.
      • Skanderson M.
      • et al.
      HIV status and the risk of ischemic stroke among men.
      Similar increased risks have been noted in other cohort studies, although the risk seems to have decreased in recent years, perhaps due to improved risk reduction through the use of statins.
      • Obel N.
      • Thomsen H.F.
      • Kronborg G.
      • Larsen C.S.
      • Hildebrandt P.R.
      • Sorensen H.T.
      • et al.
      Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study.
      • Klein D.B.
      • Leyden W.A.
      • Xu L.
      • Chao C.R.
      • Horberg M.A.
      • Towner W.J.
      • et al.
      Declining relative risk for myocardial infarction among HIV-positive compared with HIV-negative individuals with access to care.
      Certain antiretroviral drugs may increase cardiovascular risk, including protease inhibitors, which induce a poor metabolic profile including hyperlipidemia compared to other drugs such as integrase inhibitors. The association of abacavir with cardiovascular disease noted in early studies has not been confirmed in all studies and remains controversial.
      • Martin-Iguacel R.
      • Llibre J.M.
      • Friis-Moller N.
      Risk of cardiovascular disease in an aging HIV population: where are we now?.
      Other cardiovascular risk factors seen commonly in HIV-positive populations include smoking, hypertension, insulin resistance, increased inflammatory and thrombotic markers, and more recently obesity.

      7.2 Osteoporosis and fracture

      Osteopenia and osteoporosis in HIV patients are increased compared to the general population; the cause is likely multifactorial. Risk factors such as substance abuse (particularly alcohol), smoking, low body weight, and vitamin D deficiency contribute to the increased risk in HIV-positive patients.
      • Kooij K.W.
      • Wit F.W.
      • Bisschop P.H.
      • Schouten J.
      • Stolte I.G.
      • Prins M.
      • et al.
      Low bone mineral density in patients with well-suppressed HIV infection: association with body weight, smoking, and prior advanced HIV disease.
      In addition, the direct effects of cART, particularly those due to protease inhibitor-based and tenofovir-based regimens, predispose to loss of bone density.
      • Walker Harris V.
      • Brown T.T.
      Bone loss in the HIV-infected patient: evidence, clinical implications, and treatment strategies.
      Chronic HIV infection itself is also a contributor, as HIV infection appears to confer an increased risk of osteoporosis in cross-sectional cohort-based studies. The risk of fracture in HIV-infected individuals has been found to be increased almost three-fold.
      • Rasmussen L.D.
      • May M.T.
      • Kronborg G.
      • et al.
      Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study.
      • Prieto-Alhambra D.
      • Guerri-Fernandez R.
      • De Vries F.
      • Lalmohamed A.
      • Bazelier M.
      • Starup-Linde J.
      • et al.
      HIV infection and its association with an excess risk of clinical fractures: a nationwide case–control study.

      7.3 Metabolic syndrome and diabetes mellitus

      The metabolic syndrome has been characterized by central obesity, hypertension, and metabolic abnormalities such as high fasting blood glucose and low high density lipoprotein levels, which confer a significant risk for cardiovascular disease and diabetes.
      • Alberti K.G.
      • Eckel R.H.
      • Grundy S.M.
      • Zimmet P.Z.
      • Cleeman J.I.
      • Donato K.A.
      • et al.
      Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.
      • Jarrett O.D.
      • Wanke C.A.
      • Ruthazer R.
      • Bica I.
      • Isaac R.
      • Knox T.A.
      Metabolic syndrome predicts all-cause mortality in persons with human immunodeficiency virus.
      The risk of metabolic syndrome in HIV patients, relative to non-HIV patients, has been found to be increased in some studies and decreased in others.
      • Jarrett O.D.
      • Wanke C.A.
      • Ruthazer R.
      • Bica I.
      • Isaac R.
      • Knox T.A.
      Metabolic syndrome predicts all-cause mortality in persons with human immunodeficiency virus.
      • Ford E.S.
      • Li C.
      • Zhao G.
      Prevalence and correlates of metabolic syndrome based on a harmonious definition among adults in the US.
      Similarly, the risk of developing diabetes mellitus in HIV populations is not well established.
      • Monroe A.K.
      • Glesby M.J.
      • Brown T.T.
      Diagnosing and managing diabetes in HIV-infected patients: current concepts.
      Studies earlier in the epidemic, when early cART regimens predominated, demonstrated an increased risk of diabetes mellitus in HIV-positive patients, whereas later studies have not consistently shown this relationship.
      • Rasmussen L.D.
      • Mathiesen E.R.
      • Kronborg G.
      • Pedersen C.
      • Gerstoft J.
      • Obel N.
      Risk of diabetes mellitus in persons with and without HIV: a Danish nationwide population-based cohort study.

      7.4 Renal disease

      Early in the HIV epidemic, a unique form of progressive renal disease was recognized primarily in African Americans, termed HIV nephropathy.
      • Mallipattu S.K.
      • Salem F.
      • Wyatt C.M.
      The changing epidemiology of HIV-related chronic kidney disease in the era of antiretroviral therapy.
      With the introduction of effective cART in the 1990s, the incidence of HIV nephropathy decreased markedly. However, the current prevalence of chronic renal disease remains increased at all ages in HIV-positive individuals compared to uninfected individuals.
      • Rasmussen L.D.
      • May M.T.
      • Kronborg G.
      • et al.
      Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study.
      • Ando M.
      • Tsuchiya K.
      • Nitta K.
      How to manage HIV-infected patients with chronic kidney disease in the HAART era.
      The prevalence of chronic kidney disease stage ≥3 (glomerular filtration rate of 30–59 ml/min) has ranged from 3.5% to 9.7%.
      • Ando M.
      • Tsuchiya K.
      • Nitta K.
      How to manage HIV-infected patients with chronic kidney disease in the HAART era.
      Risk factors for renal disease in HIV-positive individuals include age, black race, diabetes mellitus, hypertension, low CD4 counts, high viral loads, inflammatory markers, and certain cART drugs such as tenofovir.
      • Abraham A.G.
      • Althoff K.N.
      • Jing Y.
      • Estrella M.M.
      • Kitahata M.M.
      • Wester C.W.
      • et al.
      End-stage renal disease among HIV-infected adults in North America.

      7.5 Chronic neurological complications

      In the pre-cART era, neurological disease in AIDS patients was dominated by infectious complications of AIDS (CD4 <200 cells/μl), as well as HIV-associated dementia, myelopathy, and peripheral neuropathy.
      • d’Arminio Monforte A.
      • Duca P.G.
      • Vago L.
      • Grassi M.P.
      • Moroni M.
      Decreasing incidence of CNS AIDS-defining events associated with antiretroviral therapy.
      Despite a dramatic decrease in these conditions in the era of cART, HIV infection continues to be associated with neurocognitive disease termed HIV-associated neurocognitive disorders or HAND.
      • Heaton R.K.
      • Clifford D.B.
      • Franklin Jr., D.R.
      • Woods S.P.
      • Ake C.
      • Vaida F.
      • et al.
      HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study.
      Approximately 50% of all HIV-positive individuals have some degree of neuropsychological impairment. Most are asymptomatic, but up to 12% may have mild and 2% severe disorders.
      • Rasmussen L.D.
      • May M.T.
      • Kronborg G.
      • et al.
      Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study.
      • Heaton R.K.
      • Clifford D.B.
      • Franklin Jr., D.R.
      • Woods S.P.
      • Ake C.
      • Vaida F.
      • et al.
      HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study.
      The risk of dementia in one cohort was increased for older HIV-infected patients (>50 years old) compared to younger HIV-infected patients (20–39 years old) by more than three-fold.
      • Valcour V.
      • Shikuma C.
      • Shiramizu B.
      • Watters M.
      • Poff P.
      • Selnes O.
      • et al.
      Higher frequency of dementia in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort.
      Changes seem to correspond to changes in brain volume.
      • Becker J.T.
      • Maruca V.
      • Kingsley L.A.
      • Sanders J.M.
      • Alger J.R.
      • Barker P.B.
      • et al.
      Factors affecting brain structure in men with HIV disease in the post-HAART era.
      Risk factors for HAND include age, history of immune suppression, other co-morbidities and disease indicators, psychiatric disorders, IQ, previous brain trauma, and infection, as well as co-infection with hepatitis C virus (HCV).
      • Heaton R.K.
      • Franklin Jr., D.R.
      • Deutsch R.
      • Letendre S.
      • Ellis R.J.
      • Casaletto K.
      • et al.
      Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study.
      • Schuster R.M.
      • Gonzalez R.
      Substance abuse, hepatitis C, and aging in HIV: common cofactors that contribute to neurobehavioral disturbances.
      Unlike Alzheimer's disease, HAND is not necessarily progressive.
      • Heaton R.K.
      • Franklin Jr., D.R.
      • Deutsch R.
      • Letendre S.
      • Ellis R.J.
      • Casaletto K.
      • et al.
      Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study.
      • Cysique L.A.
      • Franklin Jr., D.
      • Abramson I.
      • Ellis R.J.
      • Letendre S.
      • Collier A.
      • et al.
      Normative data and validation of a regression based summary score for assessing meaningful neuropsychological change.
      Treatment with both pharmacological and non-pharmacological approaches is an area of active research.
      • Mothobi N.Z.
      • Brew B.J.
      Neurocognitive dysfunction in the highly active antiretroviral therapy era.
      • Weber E.
      • Blackstone K.
      • Woods S.P.
      Cognitive neurorehabilitation of HIV-associated neurocognitive disorders: a qualitative review and call to action.
      As the HIV-positive population ages, the intersection of HAND with age-related neurological conditions including dementia and Alzheimer's disease will be of great importance.

      7.6 Malignancies

      Increased rates of Kaposi's sarcoma and non-Hodgkin B cell lymphoma were recognized early in the HIV epidemic. Kaposi's sarcoma had rates of 1000 times and non-Hodgkin B cell lymphoma had rates 100 times those in non-HIV populations.
      • Patel P.
      • Hanson D.L.
      • Sullivan P.S.
      • Novak R.M.
      • Moorman A.C.
      • Tong T.C.
      • et al.
      Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003.
      Subsequently other malignancies were noted to occur more frequently in HIV patients, including primary central nervous system lymphoma, invasive squamous cell carcinoma of the cervix, lung cancer, anal cancer, Hodgkin lymphoma, liver cancer, and head and neck squamous cell cancer. With the advent of effective cART in the mid-1990s, a dramatic fall in the incidence of many malignancies, particularly Kaposi's sarcoma and non-Hodgkin B cell lymphoma, was noted.
      • Franceschi S.
      • Lise M.
      • Clifford G.M.
      • Rickenbach M.
      • Levi F.
      • Maspoli M.
      • et al.
      Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study.
      • Simard E.P.
      • Pfeiffer R.M.
      • Engels E.A.
      Cumulative incidence of cancer among individuals with acquired immunodeficiency syndrome in the United States.
      • Park L.S.
      • Tate J.P.
      • Sigel K.
      • Rimland D.
      • Crothers K.
      • Gibert C.
      • et al.
      Time trends in cancer incidence in persons living with HIV/AIDS in the antiretroviral therapy era: 1997-2012.
      The incidence of other virally related cancers, however, has either remained the same or has increased somewhat.
      • Rasmussen L.D.
      • May M.T.
      • Kronborg G.
      • et al.
      Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study.
      Rates of skin and lung cancer remain high, but the rates of breast, colon, and prostate cancers are not increased when compared to the general population.
      • Silverberg M.J.
      • Lau B.
      • Achenbach C.J.
      • Jing Y.
      • Althoff K.N.
      • D'Souza G.
      • et al.
      Cumulative incidence of cancer among persons with HIV in North America: a cohort study.
      • Yanik E.L.
      • Katki H.A.
      • Engels E.A.
      Cancer risk among the HIV-infected elderly in the United States.
      As the HIV-positive population ages, the rates of all cancers, particularly lung, prostate, colorectal, and breast, will increase.
      • Shepherd L.
      • Borges A.
      • Ledergerber B.
      • Domingo P.
      • Castagna A.
      • Rockstroh J.
      • et al.
      Infection-related and -unrelated malignancies, HIV and the aging population.
      The estimated cumulative incidence of cancer by the age of 75 years for HIV-positive patients is increased for Kaposi's sarcoma, non-Hodgkin B cell lymphoma, lung cancer, anal cancer, liver cancer, and Hodgkin lymphoma, in HIV-positive individuals.
      • Silverberg M.J.
      • Lau B.
      • Achenbach C.J.
      • Jing Y.
      • Althoff K.N.
      • D'Souza G.
      • et al.
      Cumulative incidence of cancer among persons with HIV in North America: a cohort study.
      Furthermore, cancer-related mortality rates for HIV-positive patients remain high for many cancers.
      • Coghill A.E.
      • Shiels M.S.
      • Suneja G.
      • Engels E.A.
      Elevated cancer-specific mortality among HIV-infected patients in the United States.

      7.7 Quality of life in older patients with HIV

      Older patients with HIV face a number of factors that affect their quality of life, including increasing physical disabilities and morbidities, psychiatric illnesses, losses of partners and friends, social isolation, and stigma. Added to this are additional stressors often experienced by older HIV patients, including unemployment, poverty, and crime. In a poignant qualitative study, the changes experienced by aging HIV-positive patients were categorized as physical challenges, internal changes, stigma, and in particular, a sense of lost community and social support described by one participant as “a shrinking kind of life”.
      • Masten J.
      A shrinking kind of life”: gay men's experience of aging with HIV.
      In a case-controlled study from San Diego, older HIV-positive patients were found to have worse physical and mental functioning and greater psychosocial stress than HIV-negative patients.
      • Moore R.C.
      • Moore D.J.
      • Thompson W.K.
      • Vahia I.V.
      • Grant I.
      • Jeste D.V.
      A case-controlled study of successful aging in older HIV-infected adults.
      Interestingly, however, there were no differences in measures of optimism, personal mastery, and social support. In a separate study, HIV patients with strong resilience measures seemed to manage the stress of aging, including physical and emotional challenges, better than those who had weak resilience measures.
      • Fang X.
      • Vincent W.
      • Calabrese S.K.
      • Heckman T.G.
      • Sikkema K.J.
      • Humphries D.L.
      • et al.
      Resilience, stress, and life quality in older adults living with HIV/AIDS.
      Interventions focusing on improving factors such as social support and resilience may improve the quality of life of HIV-positive patients who are aging.

      7.8 Geriatric syndromes and frailty

      The term ‘geriatric syndromes’ has been used to describe a wide variety of conditions associated with aging that predict adverse clinical outcomes.
      • Inouye S.K.
      • Studenski S.
      • Tinetti M.E.
      • Kuchel G.A.
      Geriatric syndromes: clinical, research, and policy implications of a core geriatric concept.
      For HIV patients, geriatric syndromes generally include the following: falls, urinary incontinence, difficulty with activities of daily living, slow gait, sensory deficits such as hearing and sight loss, and neurocognitive impairment.
      • Greene M.
      • Covinsky K.E.
      • Valcour V.
      • Miao Y.
      • Madamba J.
      • Lampiris H.
      • et al.
      Geriatric syndromes in older HIV-infected adults.
      Studies have demonstrated a high incidence of geriatric syndromes in HIV-positive individuals over the age of 50 years.
      • Greene M.
      • Covinsky K.E.
      • Valcour V.
      • Miao Y.
      • Madamba J.
      • Lampiris H.
      • et al.
      Geriatric syndromes in older HIV-infected adults.
      In one study, more than half (53%) of the individuals had two or more geriatric syndromes, with the most frequent conditions being prefrailty (modified Fried criteria–see below), difficulty with activities of daily living (ADLs), and neurocognitive impairment.
      Geriatric syndromes include frailty, which by itself confers a risk of morbidity, hospitalization, and mortality. The Fried criteria, which represent the most commonly accepted definition of frailty, are based on the assessment of weight loss, strength, endurance, walking speed, and activity level.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • Newman A.B.
      • Hirsch C.
      • Gottdiener J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      Multiple studies have demonstrated that patients with HIV are more susceptible to developing frailty at earlier ages than the general population,
      • Brothers T.D.
      • Kirkland S.
      • Guaraldi G.
      • Falutz J.
      • Theou O.
      • Johnston B.L.
      • et al.
      Frailty in people aging with human immunodeficiency virus (HIV) infection.
      • Levett T.J.
      • Cresswell F.V.
      • Malik M.A.
      • Fisher M.
      • Wright J.
      Systematic review of prevalence and predictors of frailty in individuals with human immunodeficiency virus.
      and thus are more susceptible to adverse outcomes.
      • Desquilbet L.
      • Jacobson L.P.
      • Fried L.P.
      • Phair J.P.
      • Jamieson B.D.
      • Holloway M.
      • et al.
      HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty.
      Risk factors for frailty include low current CD4 and low nadir CD4 counts, other co-morbidities such as hepatitis C, central obesity, and other geriatric syndromes, as well as social factors including lower education.
      • Brothers T.D.
      • Kirkland S.
      • Guaraldi G.
      • Falutz J.
      • Theou O.
      • Johnston B.L.
      • et al.
      Frailty in people aging with human immunodeficiency virus (HIV) infection.
      As the HIV-positive population ages, the rates of frailty will increase and will represent an important challenge for clinicians. Although few data exist on the prevention or treatment of frailty, potential strategies include early diagnosis and treatment of HIV, identifying and treating co-morbidities, and exercise.
      • Brothers T.D.
      • Kirkland S.
      • Guaraldi G.
      • Falutz J.
      • Theou O.
      • Johnston B.L.
      • et al.
      Frailty in people aging with human immunodeficiency virus (HIV) infection.
      • Pahor M.
      • Guralnik J.M.
      • Ambrosius W.T.
      • Blair S.
      • Bonds D.E.
      • Church T.S.
      • et al.
      Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial.

      8. Care of the patient

      Recommended guidelines for the treatment of older patients with HIV can be found in the executive summary of the HIV and Aging Consensus Project, a joint project between the American Academy of HIV Medicine, the American Geriatrics Society, and the AIDS Community Research Initiative of America,
      • Work Group for HIV, Aging Consensus Project
      • Abrass C.K.
      • Appelbaum J.S.
      • et al.
      Summary report from the Human Immunodeficiency Virus and Aging Consensus Project: treatment strategies for clinicians managing older individuals with the human immunodeficiency virus.
      and in the guidelines for the treatment of HIV-positive individuals available from the Department of Health and Human Services (DHHS) (http://aidsinfo.nih.gov). An overall approach to the care of the older patient with HIV can be found in the article by Greene et al.
      • Greene M.
      • Justice A.C.
      • Lampiris H.W.
      • Valcour V.
      Management of human immunodeficiency virus infection in advanced age.
      Also important for the care of the elderly patient are the Primary Care Guidelines for the Management of Persons Infected with HIV: 2013 Update by the HIV Medicine Association of the Infectious Diseases Society of America (IDSA).
      • Aberg J.A.
      • Gallant J.E.
      • Ghanem K.G.
      • Emmanuel P.
      • Zingman B.S.
      • Horberg M.A.
      • et al.
      Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America.
      The following are brief comments regarding the above guidelines for diagnosis and treatment, behavioral risks, screening and prevention, and prioritization of elderly HIV-positive patients. Table 1 summarizes suggested management guidelines for newly diagnosed HIV patients over 50 years of age.
      Table 1Suggested management guidelines for newly diagnosed HIV patients over 50 years of age
      Guidelines are based on Aberg et al.92 and the Department of Health and Human Services guidelines (http://aidsinfo.nih.gov/guidelines for the care of patients with HIV).
      RecommendationsComments
      1.Comprehensive history, including sexual history and physical examinationInclude screening for hypertension, obesity, depression (e.g., Geriatric Depression Scale), smoking and substance abuse
      2.Complete blood and chemistry panel
      3.Plasma HIV RNA (viral load)Once stable on cART every 6 months
      4.Blood CD4 count and percentageOnce stable on cART every 6–12 months
      5.HIV resistance testingInitially and for elevated viral load
      6.Treatment with cART for all patients by August 1, 2016 guidelinesFollow DHHS guidelines http://aidsinfo.nih.gov/guidlines
      7.Screening for syphilis, chlamydia, gonorrheaRepeat periodically if indicated
      8.Fasting lipids and cardiovascular riskLipids initially and 3 months after starting cART; base treatment on ACC/AHA guidelines (http://www.nhlb.nih.gov)
      9.Urinalysis, creatinine clearance, and urine proteinAnnually
      10.Hepatitis A, B, C screeningVaccination (A, B) and treatment (C)
      11.Tuberculosis screeningRepeat if indicated
      12.Vaccination for influenzaAnnually
      13.Vaccination for pneumococcal infection
      14.Cervical Pap and HPV screenInitially; if negative every 3 years; http://aidsinfo.nih.gov/guidelines
      15Baseline DEXA screen for men and women >50 years of age
      16.Fasting blood glucose and HbA1c for diabetesInitially, 1–3 months following initiation of cART, and then annually
      17.Mammography for women >50 yearsAnnually
      18.ColonoscopyAge 50–75 years
      19.Low resolution lung CT cancer screening>30 pack/year smoking history who smoke or quit in the last 15 years; age >55–80 years; annually
      20.Ultrasound for abdominal aortic aneurysmMen age 65–75 years who have ever smoked
      21.Chest X-rayIf positive TB test or presence of other pre-existing lung condition
      cART, combination antiretroviral therapy; DHHS, Department of Health and Human Services; ACC/AHA, American College of Cardiology/American Heart Association; HPV, human papillomavirus; DEXA, dual-energy X-ray absorptiometry; HbA1c, glycated hemoglobin; CT, computed tomography; TB, tuberculosis.
      a Guidelines are based on Aberg et al.
      • Aberg J.A.
      • Gallant J.E.
      • Ghanem K.G.
      • Emmanuel P.
      • Zingman B.S.
      • Horberg M.A.
      • et al.
      Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America.
      and the Department of Health and Human Services guidelines (http://aidsinfo.nih.gov/guidelines for the care of patients with HIV).

      8.1 Diagnosis and treatment of HIV

      The diagnosis of HIV remains a problem in older patients, as screening and diagnosis of older patients for HIV has not been emphasized and is frequently overlooked by both physicians and patients. Data indicate that 18% of newly diagnosed patients are over the age of 50 years.
      Centers for Disease Control and Prevention
      Screening for HIV should be considered for all older adults.
      • Work Group for HIV, Aging Consensus Project
      • Abrass C.K.
      • Appelbaum J.S.
      • et al.
      Summary report from the Human Immunodeficiency Virus and Aging Consensus Project: treatment strategies for clinicians managing older individuals with the human immunodeficiency virus.
      Treatment with cART should be offered to all HIV-positive patients unless there is a medical or pharmacological contraindication. A recent study indicated that patients in the age range 45–60 years have a higher mortality than younger patients if antiretroviral treatment is delayed.
      • Edwards J.K.
      • Cole S.R.
      • Westreich D.
      • Mugavero M.J.
      • Eron J.J.
      • Moore R.D.
      • et al.
      Age at entry into care, timing of antiretroviral therapy initiation, and 10-year mortality among HIV-seropositive adults in the United States.
      Key considerations include the following:
      • 1.
        All patients over age 50 years should be offered cART treatment for HIV. Guidelines are available at http://aidsinfo.nih.gov/guidelines.
      • 2.
        The choice of cART will be influenced by underlying co-morbidities (e.g., renal disease).
      • 3.
        Resistance testing should be performed at the time of initiation of cART.
      • 4.
        cART side effects including bone, kidney, metabolic, cardiovascular, and liver are more common in the elderly, and side effects should be monitored carefully. Newer drug options, such as tenofovir alafenamide in place of tenofovir disoproxil fumarate, may reduce side effects such as bone and renal toxicity.
        • Mills A.
        • Arribas J.R.
        • Andrade-Villanueva J.
        • DiPerri G.
        • Van Lunzen J.
        • Koenig E.
        • et al.
        Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study.
      • 5.
        Routine monitoring of CD4 count and HIV RNA levels should be done according to guidelines. CD4 responses to cART are reduced in older patients compared to younger patients, and this poor response may be related to greater clinical progression.
        • Althoff K.N.
        • Justice A.C.
        • Gange S.J.
        • Deeks S.G.
        • Saag M.S.
        • Silverberg M.J.
        • et al.
        Virologic and immunologic response to HAART, by age and regimen class.
        • Grabar S.
        • Kousignian I.
        • Sobel A.
        • Le Bras P.
        • Gasnault J.
        • Enel P.
        • et al.
        Immunologic and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV.
        There are no differences in virological responses between older and younger patients.
      • 6.
        Because of polypharmacy, older patients are more prone to drug–drug interactions. Drug–drug interactions have been reviewed recently.
        • Burgess M.J.
        • Zeuli J.D.
        • Kasten M.J.
        Management of HIV/AIDS in older patients—drug/drug interactions and adherence to antiretroviral therapy.
      • 7.
        Although adherence by older adults may be better than younger ones,
        • Ghidei L.
        • Simone M.J.
        • Salow M.J.
        • Zimmerman K.M.
        • Paquin A.M.
        • Skarf L.M.
        • et al.
        Aging, antiretrovirals, and adherence: a meta analysis of adherence among older HIV-infected individuals.
        a recent study using Medicaid data on over 5000 patients indicated that only 32% of participants had optimal adherence.
        • Abara W.E.
        • Adekeye O.A.
        • Xu J.
        • Heiman H.J.
        • Rust G.
        Correlates of combination antiretroviral adherence among recently diagnosed older HIV-infected adults between 50 and 64 years.
        An increased number of co-morbidities and living in rural areas and small metropolitan areas were risk factors for lower adherence.

      8.2 Behavioral risk factors for HIV

      Many people with HIV have higher rates of smoking,
      • Kariuki W.
      • Manuel J.I.
      • Kariuki N.
      • Tuchman E.
      • O’Neal J.
      • Lalanne G.A.
      HIV and smoking: associated risks and prevention strategies.
      substance abuse including alcohol,
      • Edelman E.J.
      • Tetrault J.M.
      • Fiellin D.A.
      Substance use in older HIV-infected patients.
      and low fitness and physical activity levels.
      • Shah K.N.
      • Majeed Z.
      • Yoruk Y.B.
      • Yang H.
      • Hilton T.N.
      • McMahon J.M.
      • et al.
      Enhancing physical function in HIV-infected older adults: a randomized controlled clinical trial.
      Each of these behaviors should be assessed at the initiation of care, and strategies to address these issues should be discussed with the patient. Smoking in particular has been shown to increase the risk of cardiovascular disease, chronic lung disease, and malignancy in HIV-positive individuals. With the rise in obesity, HIV individuals will be at risk of diabetes mellitus and hypertension. Nutritional advice and weight reduction programs should be offered.
      A sexual history should be taken at each visit. As with other HIV-positive populations, and consistent with primary care guidelines, patients should be screened for high-risk sexual behavior and evidence of sexually transmitted infections at each visit. Prevention including behavioral and pharmacological approaches (pre-exposure prophylaxis or PrEP) should also be emphasized with this population if appropriate.

      8.3 Screening and prevention for co-morbidities

      Standard guidelines for HIV-negative individuals should be followed for the screening, risk assessment, and treatment of both cardiovascular disease and dyslipidemia for HIV-positive patients (for example the American College of Cardiology/American Heart Association risk calculator). Screening hyperlipidemia should be performed before and 1–3 months after starting cART. Drug–drug interactions of hydroxymethylglutaryl coenzyme A (HMG co-A) reductase inhibitors with cART are a concern in HIV-positive individuals with indications for statins.
      • Burgess M.J.
      • Zeuli J.D.
      • Kasten M.J.
      Management of HIV/AIDS in older patients—drug/drug interactions and adherence to antiretroviral therapy.
      These can be minimized by using pravastatin, pitavastatin, and to some extent, low-dose atorvastatin and rosuvastatin.
      Older patients with HIV are particularly prone to renal disease secondary to drugs (e.g., tenofovir), HIV itself (HIV nephropathy(HIVN)), hypertension, or diabetes. All HIV-positive patients should have annual measurements of serum creatinine and urinary protein excretion.
      All HIV patients should be screened for hepatitis A, B, and C initially, and appropriate vaccinations should be given if the patients are not immune to hepatitis A virus or hepatitis B virus. Identification of hepatitis C has become particularly important, because patients co-infected with HIV and HCV have an increased risk of developing progressive cirrhosis as well as hepatocellular carcinoma. Because of the truly remarkable advances using oral treatment for hepatitis C, most patients co-infected with HIV and HCV should be considered for treatment.
      • Feeney E.R.
      • Chung R.T.
      • Yazdanpanah Y.
      Current guidelines and prioritizing treatment of hepatitis C virus in HIV-infected patients.
      Individuals co-infected with HIV and HCV have been listed as ‘high priority’ for treatment in the latest American Association for the Study of Liver Disease (AASLD) guidelines.
      Other immunizations, including yearly influenza vaccination and appropriate vaccination for pneumococcal disease, are important preventative measures.
      Cancer screening by current guidelines is important because of the increased risk of cancer as patients age (see above). DHHS guidelines recommend that HIV-infected women should have a cervical Pap test and human papillomavirus (HPV) testing initially, and if negative repeated every 3 years (DHHS guidelines at http://aidsinfo.nih.gov/guideliness). Although controversial, many practitioners recommend that HIV-infected men, HIV-infected women practicing receptive anal intercourse, and those with anal warts should have an annual anal Pap test.
      Screening for osteoporosis by bone density scanning and assessment of the risk of fracture should be performed (e.g., FRAX calculator) in older patients, and treatment should be offered when appropriate.
      • Brown T.T.
      • Hoy J.
      • Borderi M.
      • Guaraldi G.
      • Renjifo B.
      • Vescini F.
      • et al.
      Recommendations for evaluation and management of bone disease in HIV.
      IDSA guidelines recommend screening for osteoporosis at age 50 years for HIV-positive individuals, rather than age 65 years as recommended for the general population. Preventative therapy with vitamin D (HIV patients are often vitamin D deficient) and calcium should be routine in older HIV-positive patients.
      • Overton E.T.
      • Chan E.S.
      • Brown T.T.
      • Tebas P.
      • McComsey G.A.
      • Melbourne K.M.
      • et al.
      Vitamin D and calcium attenuate bone loss with antiretroviral therapy initiation: a randomized trial.
      Dysregulation of endocrine pathways may occur in HIV individuals. Screening for diabetes mellitus consisting of a fasting blood glucose and glycated hemoglobin (HbA1c) should be obtained prior to and within 1–2 months after starting cART. Similarly, screening for hyperlipidemia should be performed before and 1–3 months after starting cART. Hypogonadism hallmarked by decreased libido and erectile dysfunction is common in elderly HIV-positive men, and, if indicated, should be screened for with a morning serum testosterone level. Androgen replacement therapy may be indicated if testosterone levels are low. Although controversial, hormone replacement therapy for menopausal women in those with severe menopausal symptoms can be considered.
      • Aberg J.A.
      • Gallant J.E.
      • Ghanem K.G.
      • Emmanuel P.
      • Zingman B.S.
      • Horberg M.A.
      • et al.
      Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America.
      Older patients should be screened for depression (with tools such as the Geriatric Depression Scale), and, if present, treatment with selective serotonin reuptake inhibitors (SSRIs) or cognitive and behavior therapy should be considered as first-line therapy.
      • Pinquart M.
      • Duberstein P.R.
      • Lyness J.M.
      Effects of psychotherapy and other behavioral interventions on clinically depressed older adults: a meta-analysis.
      Non-benzodiazepine agents are preferred for the long-term treatment of anxiety, particularly because of concern for drug–drug interactions with benzodiazepine agents (especially diazepam, alprazolam, and midazolam). In addition, patients should be screened for neurocognitive impairment and referred for treatment if appropriate. A widely used although imperfect tool to determine neurocognitive impairment is the Montreal Cognitive Assessment.
      • Brouillette M.J.
      • Mayo N.
      • Fellows L.K.
      • Lebedeva E.
      • Higgins J.
      • Overton E.T.
      • et al.
      A better screening tool for HIV-associated neurocognitive disorders: is it what clinicians need?.
      Polypharmacy is a major risk for HIV-positive patients because cART consists of at least three drugs and the treatment of co-morbidities often brings the total to 10 or more drugs. Data from non-HIV geriatric populations indicate that taking five or more drugs increases the risk of adverse drug events, drug interactions, inappropriate medication use, delirium, falls, fractures, and poor adherence. Medication interactions between cART and other medications are a major consideration, particularly the cytochrome p450 inhibition that occurs with protease inhibitors (e.g., darunavir) and non-nucleoside reverse transcription inhibitors (e.g., efavirenz). Regular review of all medications prescribed to a patient with regard to drug interactions, toxicity, and necessity is important.

      8.4 Prioritization

      Perhaps most important is to recognize that HIV-positive patients develop an increasing number of co-morbidities as they age. Stages of aging, priority driven care for co-morbidities, and issues of social isolation in the aging are discussed in more detail in the article by Greene et al.
      • Greene M.
      • Justice A.C.
      • Lampiris H.W.
      • Valcour V.
      Management of human immunodeficiency virus infection in advanced age.
      The expectations of aging patients and the appropriate therapy for these patients will be different than those of younger patients and will evolve over time. For example, aggressive therapy of an advanced medical condition may be inappropriate for an older patient whose quality of life may be far more important than the potential benefit of treatment with risks and side effects. Communication between care givers and the patient becomes essential in establishing agreed-upon goals of treatment. Finally, advance directives are frequently overlooked in the care of HIV-positive patients, but take on increased importance for the elderly patients.
      The prognosis of people living with HIV has improved dramatically over the past 20 years, but increased rates of co-morbidities as well as frailty and neurocognitive changes as they age pose challenges to patients and their caregivers. Early diagnosis, appropriate treatment and prevention, as well as appropriate geriatric care, will be essential to the wellbeing of this important patient population.
      Funding: None.
      Conflict of interest: Dr Wing does not have any conflicts.

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