Introduction

The HIV/AIDS epidemic continues to affect millions of people throughout the world more than 30 years after it was first described.¹ Acquired immunodeficiency syndrome (AIDS) refers to a complex of often fatal infectious and malignant conditions occurring as a result of the severe and progressive immunodeficiency caused by infection with a novel retrovirus, human immunodeficiency virus (HIV). The median time from HIV infection to the development of AIDS is 10 years. Most people are relatively asymptomatic during this clinically latent phase and, unless specifically tested for HIV, are unaware of being infected. During the first 10 to 15 years of the epidemic, effective anti-HIV therapy was unavailable, and most patients died within 2 to 3 years after their first AIDS-defining illness.² During this early period, rapid advances occurred in understanding the biology of HIV infection. This led to the development of effective antiretroviral (ARV) drugs. Their use has transformed AIDS into a mostly manageable chronic disease, so that now few effectively treated patients develop AIDS-related complications.³ However, for various sociopolitical and economic reasons, these benefits are only available to a minority of infected persons worldwide.

Treated patients are living longer, and overall survival has increased.⁴ This has had a significant impact on the age distribution of the infected population. Most people were infected as young adults during the early phase of the disease. Currently, about 50% of infected persons in high-income countries are older than 50 years,⁵ and similar proportionate increases have occurred in low- and middle-income countries. At present, older HIV patients are generally not considered as being elderly, because this term is understood by most health care providers working within the traditional confines of geriatric medicine.

This chapter will summarize the biologic and clinical principles relevant to the effective management of older HIV patients. It will focus on the evolving clinical parameters related to the complex interrelationship between the current paradigm of HIV infection and those aging with HIV. The underlying biologic and psychosocial similarities between the traditional older adult population and aging HIV population will be considered.

HIV Infection: Evolution of Clinical Profile and Management

In 1981, reports appeared of usually rare and severe opportunistic infections and malignancies occurring in previously healthy gay men living in high-income countries. All patients had a significant loss of cellular immunity, denoted by very low levels of CD4⁺ T-helper cells (normal level > 600 to 800/µL) and disruption of normal immune homeostasis parameters. By 1983, it was shown that AIDS was caused by infection with HIV,⁶ which caused immunodeficiency by specifically targeting CD4⁺ cells.

HIV originated as a benign chimpanzee virus (simian immunodeficiency virus [SIV]) within a localized area of sub-Saharan Africa, the Congo River Basin. SIV crossed species barriers early during the twentieth century because of increased rates of hunting and eating chimpanzee meat. SIV mutated to the much more pathogenic HIV, which then spread slowly but efficiently via sexual, bloodborne, and perinatal transmission through the increasingly urban population. Clinical disease was not recognized as a distinct entity because of its generally nonspecific manifestations. Dissemination then occurred progressively from sub-Saharan Africa to industrialized countries in the late 1960s and 1970s.⁶

Approximately 75 million people have been infected worldwide, and more than 50% of them have died. Since HIV has been identified as the cause of AIDS, effective HIV risk prevention and education programs have significantly reduced new infection rates, although new infections clearly occur. Older adults remain at particular risk for exposure to HIV and other sexually transmitted infections. Health care workers infrequently discuss sexual issues, including HIV, with older patients.⁷ This is associated with a perception of low personal HIV risk among older adults.

Soon after the cause of AIDS was discovered, the HIV life cycle and pathogenesis of the ensuing immunodeficiency were characterized.⁸ This facilitated the development of effective ARVs, which disrupt HIV replication by acting at multiple points in its life cycle.⁹ Zidovudine, a nucleoside reverse transcriptase inhibitor, the first ARV, was approved in 1987. Since then, drugs of different classes continue to be produced; more than 30 ARV drugs are now licensed. Since 1996, these drugs have been used in various combinations, referred to by the acronym HAART (highly active antiretroviral therapy). Currently available ARVs have minimal toxicity, resulting in improved adherence compared to that associated with the large number of drugs required to be taken in the 1990s. Several ARVs are now co-formulated, allowing for the daily use of a single pill.¹⁰ This allows the drug’s potent and durable antiviral effects to be exerted fully. These regimens are increasingly available to many people worldwide through innovative programs involving close collaboration among the pharmaceutical industry, government and public organizations, and affected communities. At present, there is no consensus that specific HAART regimens are better tolerated and more effective in older compared to younger patients.

Untreated HIV infection results in very high plasma HIV viral loads (HIV-VL), often greater than 1 million copies/mL. There is an inverse relationship between the concentration of HIV-VL and extent of CD4⁺ cell reduction. All HAART regimens effectively reduce HIV viral replication to below the level of detection of current assays (<40 copies/mL) resulting in a slow and variable but progressive immune recovery.⁶ This reduces the risk of AIDS-related complications; the higher the CD4⁺ recovery, particularly to levels more than 500/mL, the lower the risk of AIDS. This relationship informs the clinical scenarios faced by aging HIV patients.

AIDS-related morbidity and mortality in treated patients declined dramatically following the introduction of HAART. Overall long-term survival has improved significantly in adherent patients with reliable access to ARVs but remains at only 75% to 85% of that of the general population.¹¹ Importantly, patients who maintain an undetectable HIV-VL and CD4⁺ count more than 500/mcL for over 5 years are predicted to achieve normal long-term survival.¹² The major burden associated with taking HAART is the need for strict adherence to prescribed regimens. Poor adherence leads to the rapid emergence of drug resistance, with resulting recurrence of viral replication.¹³ The main predictor of the extent of immune recovery is the nadir CD4⁺ count, referring to the lowest CD4⁺ count that a patient had prior to starting HAART. Counts less than 200 CD4⁺cells/mL are associated with poor immune recovery,¹⁴ which is especially relevant to understanding older patients’ ability to respond to treatment.

The age of 50 years has been used in HIV infection as a transition point separating older from younger patients, recognizing that there is no specific biologic rationale for this age to represent older patients. Its use likely stems from the fact that during the first decade of the epidemic, only 10% of affected patients in industrialized countries were older than 50 years,¹⁵ a proportion that has progressively increased to 50%.

The term long-term survivors refers to patients infected early in the epidemic who did not develop AIDS or who survived those complications to benefit from the first HAART regimens. Their survival is the main explanation for the overall increasing age of infected persons.⁵ In addition, the mean age at the time of HIV seroconversion has also increased.¹⁶ Older adults are more likely to have become exposed to HIV heterosexually than younger people; this is partially related to increased divorce rates and longevity, maintaining an active functional status, including sexual activity,¹⁷ availability of effective drugs for erectile dysfunction, and infrequent use of condoms between nonmonogamous partners.¹⁸

As AIDS-related complications have decreased, the spectrum of illness occurring in treated patients has evolved and now consists generally of otherwise common medical conditions. These include cardiovascular disease, bone demineralization, metabolic disorders and associated body composition changes, several malignancies, certain hepatorenal diseases, and nondementing cognitive dysfunction.¹⁹ In general, their clinical presentation, course, and response to treatment are broadly similar to that occurring in non-HIV infected persons. However, the risk of developing these complications, referred to by various acronyms, such as serious non-AIDS related events (SNAREs), is variable and related to a post-HAART plateau CD4⁺ count less than 500 copies/mL.²⁰ This immune outcome is more likely to occur in older HIV patients.⁵

Older HIV patients are more likely to present initially with advanced immunosuppression or AIDS-related complications, likely because HIV is less often considered in the differential diagnosis of otherwise common HIV-related symptoms. Older patients’ baseline CD4⁺ counts are often lower at the initial clinical presentation, possibly because age-related immunosenescence may be accelerated in HIV patients, leading to a lower CD4⁺ count.²¹

Although consensus remains elusive, older patients are generally less likely to attain the same degree of post-HAART immune recovery than younger patients, and their plateau CD4⁺ counts are also lower.²² They therefore remain at a higher risk of developing AIDS-related complications. Older patients’ survival after developing AIDS is also less than that of younger patients.²³ However, plausible data has suggested that after starting HAART, older patients achieve an undetectable HIV-VL as often as younger patients.²² Furthermore, they are more likely than younger patients to maintain an undetectable HIV-VL, likely due to better adherence to drug therapy.²⁴

Immune Activation and Chronic Inflammation

Patients with untreated HIV infection have laboratory features consistent with an activated immune state, even in the absence of concurrent infectious or malignant complications.⁶ This refers to processes involving immune cell activation and proliferation, as demonstrated by increased levels of inflammatory cytokines, monocytes, activated T cells, and coagulation parameters.²⁵ HAART reduces increased activation markers but generally not to pre-HIV infection levels.²⁶ Several factors predispose to chronic immune activation. Treated patients with undetectable HIV-VL continue to have ongoing low-level HIV replication,²⁵ itself a strong stimulus to chronic immune activation. Other contributors include thymic dysfunction leading to impaired T cell maturation²⁷ and co-infection with specific viruses, including hepatitis B and C virus, human papillomavirus (HPV), and cytomegalovirus (CMV).²⁵ Immune activation is also related to microbial translocation, which refers to the passage of intestinal microbial products to the systemic circulation. This occurs because of incomplete HAART-associated restoration of the severe initial HIV-related disruption of gut-associated lymphatic tissue (GALT), which causes epithelial injury and loss of CD4⁺ cells. Incomplete restoration of GALT allows passage of biologically active products, including lipopolysaccharide (LPS), to the bloodstream, which activate monocytes and macrophages, B and T cells, plus coagulation factors, and contribute to immune activation.²⁸ Microbial translocation occurs in normal aging,²⁹ also considered to be a state of chronic immune activation, although to a much more limited extent than HIV. Persistent immune activation contributes to incomplete CD4⁺ recovery,³⁰ a risk factor for developing SNAREs. Although older HIV patients generally have lower nadir and plateau CD4⁺ cell counts, it is unknown if they have an increased risk of developing SNAREs compared to younger patients with a similar CD4⁺ count.

Markers of chronic inflammation include cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), IL-1β, and acute-phase reactants, which attract further immune system components. Physiologic aging itself is accompanied by such a state of low-grade inflammation, leading to a chronic increase in inflammatory mediators.³¹ These may contribute to an increase in age-related diseases such as atherosclerosis, dementia, diabetes, cancer, and sarcopenia. This proinflammatory state may also occur if the normal mechanisms that turn off the otherwise effective immune response are defective or inefficient. In treated HIV infection, ongoing low-grade HIV viremia and the resulting chronic immune response plays an important pathogenic role in the development of the major non-AIDS complications. These include atherosclerosis, osteoporosis, neurocognitive decline, and the increasingly recognized geriatric frailty syndrome.³²

The term inflamm-ageing was coined almost 15 years ago to describe the tripartite interaction among the upregulated inflammatory response, subsequent low-grade chronic inflammation, and increase in inflammation-driven chronic illnesses that are seen in older adults.³³ This process incorporates neuroendocrine activation via a chronically stimulated hypothalamic-pituitary-adrenal axis, so that glucocorticoid hypersecretion functions as the major counteractive response; this has its own long-term toxicities.³⁴ A similar scenario may be active in treated HIV disease.³⁵

Immunosenescence and HIV

Chronic immune activation and related chronic inflammation also contribute to the development of immunosenescence, a term describing the quantitative and functional changes in immune parameters that occur in normal aging.³⁶ These have been mostly studied in persons older than 80 years who have an increased vulnerability to infections, decreased effectiveness in responding to recommended vaccines, and increased risk of disorders in which chronic inflammation plays a pathogenic role.³⁷ Genetic signals also affect several factors, including gender, diet, and age-related thymic involution, which affect immune parameters.³⁶

Immunosenescence affects all aspects of immune function, including innate immunity components such as neutrophils, natural killer (NK) cells, monocytes and macrophages, dendritic cells, and T cell and B cell lymphocyte senescence markers.^37–39 These are described in the chapter on the clinical immunology of aging (see Chapter 93). Many of the immune dysfunction changes occurring in response to chronic untreated HIV infection and, to a lesser extent, in those on HAART, are similar to those occurring in normal aging. Treated HIV has therefore been described as a state of accelerated immunosenescence.⁴⁰

Age-related changes in immune parameters are related to chronic simulation of the immune system and genetically determined rates of telomere shortening,³⁹ possibly modifiable by lifestyle factors. Chronic immune stimulation is associated with lifelong exposure to environmental antigenic stresses, persistence of noncurable infections (e.g., CMV, herpesviruses), increase in age-related microbial translocation via the gut, and thymic atrophy resulting in decreased thymic hormone levels. These stimuli cause the following: (1) expansion of the pool of terminally differentiated senescent memory CD28⁻ T cells, which then release the proinflammatory cytokines IL-6 and TNF-α, further contributing to chronic inflammation; (2) reduction of the pool of naive T cells capable of responding to new antigenic stimuli; and (3) an inverted T helper–to–T suppressor cell ratio, which is normally greater than 1 to 1.5.^37,39 The inverted T cell ratio is a key feature that was shown to predict short-term morbidity and mortality in the Swedish OCTO and NONA studies of community-dwelling octogenarians and nonagenarians.⁴¹ These studies have also shown that CMV seropositivity contributes to expansion of the CD8⁺ and CD28⁻ T cells.⁴²

Similar immune changes occur to a variable degree in untreated and treated HIV patients, including a low CD4⁺/CD8⁺ ratio, low numbers of naive T cells, low T cell proliferation potential, expanded CD8⁺/CD28⁻ numbers, reduced T cell repertoire, increased IL-6 production, reduced thymus function, reduced T cell telomere lengths, expanded CMV-specific CD8⁺ T cells, and reduced vaccine responses.^43–45 This similarity between immunosenescence-related changes in people with HIV and in older adults is further supported by the finding that young HIV patients with severe immunosuppression have naive T cell numbers comparable to those of healthy seronegative persons older than 80 years.⁴¹ Rates of telomere shortening in terminally differentiated CD8⁺ and CD28⁻ cells of young HIV patients are also comparable to those in healthy seronegative centenarians.⁴⁶ Levels of a known biomarker of aging, CDKN2A, a cell senescence mediator, are increased in treated younger patients, suggesting that increased biologic aging may occur in these patients.⁴⁷

Chronic CMV infection also contributes to overall immune dysfunction in HIV and older patients. In the very old, CMV seropositivity contributes to expansion of the CD8⁺ and CD28⁻ T cells and to an inverted CD4⁺/CD8⁺ T cell ratio, referred to as the immune risk phenotype (IRP), which is associated with poor health-related outcomes.⁴⁸ The overall T cell response to latent herpesvirus infections in older adults is important and represents up to 20% of the total memory T cell compartment.⁴⁹ Treated HIV patients with good immune recovery have a strong anti-CMV response.⁵⁰ They also have an inverse association between strong anti-CMV T cell responses and lower total and naive CD4⁺ T cell numbers.⁵¹ Treated CMV-negative HIV patients have higher CD4⁺/CD8⁺ T cell ratios, are more likely to achieve normalization of their CD4⁺/CD8⁺ T cell ratios (>1.0), and are less likely to have immunosenescence-related markers.⁵² Although CMV seropositivity in treated HIV patients represents a latent infection, the anti-CMV drug valganciclovir may decrease CD8⁺ T cell activation markers in treated patients.⁵³

HIV, Aging, and Selected Age-Related Comorbidities

Treated HIV patients develop age-related, non-AIDS complications at a younger age compared to controls (Box 113-1), which is one of the reasons proposed for why HIV represents a state of accelerated aging. Careful epidemiologic comparisons do not, however, consistently support the conclusion that HIV and HAART increase a true aging phenotype.⁵⁴ The increase in comorbidities may alternatively represent a state of accentuated aging, in which HIV and HAART increase the risk of chronic conditions occurring at all ages.⁵⁵ Nevertheless, of treated HIV patients 50 to 60 years old, 35% have at least two non-HIV related comorbidities, and 20% have three, whereas in patients older than 60 years, 15% have three comorbidities, and 5% have four. This age-controlled prevalence is higher than in controls.⁵⁶

Malignancies

The use of HAART has caused a significant decrease in the incidence of AIDS-defining cancers (ADCs), such as Kaposi sarcoma, primary central nervous system (CNS) lymphoma, and invasive endometrial cancer. However, as with the increase in CVD and other SNAREs, there is an increased risk of other non–AIDS-defining cancers (NADCs), which are now a leading cause of death in treated HIV patients. These include certain head and neck tumors, anal carcinoma, hepatocellular carcinoma in patients with hepatitis B or C (HBV or HCV) co-infection, and non-Hodgkin lymphoma.⁷⁸ Increasing age is a major risk for NADCs, as is duration of HIV, a low CD4⁺ T cell count (<200/µL), and possibly the use of HAART, although this may be a surrogate for increased survival.⁷⁹ Other contributing causes of NADCs include a decrease in competitive causes of death, a possible oncogenic effect of the HIV tat gene,⁸⁰ and impaired tumor surveillance related to HIV immunosuppression in treated patients. A common thread among these malignancies is their confirmed or strongly supported association with an underlying infectious cause—HPV with head and neck, endometrial, and anal cancers, Epstein-Barr virus with lymphomas, HBV and HCV with hepatocellular carcinoma.

The incidence of cancers not associated with an infectious cause, such as lung cancer (the higher incidence is more than can be attributed to the expected tobacco-associated risk⁸¹) and melanoma,⁸² has also increased in the post-HAART era. The risk of other age-related, non–infection-associated cancers, including colon, breast, and prostate cancers (whose risk may actually be decreased in HIV⁸³) has not increased.

HIV-associated immunosuppression, by causing impaired T cell immunity and chronic inflammation, even if reduced by effective HAART, may increase cancer risk via interaction with the oncogenic effects of the concurrently present infectious agents. These represent chronic co-infections capable of inducing host responses, with potentially deleterious immune consequences. This has been shown particularly for CMV. Micro­RNAs, particularly MiR-155, may serve as an intermediate between chronic inflammation and the associated cancer risk by causing a mutagenic effect.⁸⁴ The CD4⁺ T cell response to HAART has also been associated with virus-related NADCs.⁸⁵ Increasing age is the most consistently documented risk factor for ADCs and NADCs, and thus aging HIV patients are a particularly vulnerable population. Inconsistent evidence has suggested that NADCs, and lung cancer in particular, may present more aggressively and at more advanced stages in HIV patients.

Limiting the increased rates of certain cancers may be achieved by encouraging the timely diagnosis of HIV in older patients and the early initiation of HAART when substantial immune recovery is more likely. Aggressive cancer screening, based on accepted algorithms for the specific cancers, is indicated. Optimal screening strategies may differ in HIV patients, and further research is needed to determine how best to proceed.⁸⁶

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