All chromosomes of eukaryotic cells include a structure known as the telomere (from the Greek, telos, end, and meros, part), which is a marker of cellular division. Telomeres are a kind of “cap” that protect the ends of chromosomes and consist of proteins and noncoding DNA. Their function is to maintain the structural stability of chromosomes. Under normal aging conditions, the telomeres shorten at each cell division until the cell totally or partially loses its ability to divide, leading to disease and death. Telomeres play the role of a biological clock. The synthesis of telomeres occurs at the end of DNA replication by the action of the enzyme telomerase, which is a reverse transcriptase, and telomerase activity depends on the activation of a specific gene that is not activated (“turned on”) in all cells.

The role of telomeres in CD4+ T-cell depletion and in clonal replication of these cells during HIV infection was described in 1966.17 In HIV+ individuals, the length of telomeres is similar to that of non-infected elderly individuals, which might indicate a predisposition to premature aging. This finding might explain the presence of abnormalities common to the elderly in HIV+ younger individuals, such as low numbers of CD4+ T cells and decreased thymus activity. The physiopathology of aging in PLH with or without prolonged ART is still poorly understood. The use of thymidine analogs appears to induce telomere shortening.18

The oxidative stress that occurs in natural aging seems to favor the replication of HIV, and the presence of HIV, in turn, appears to accelerate the natural aging process. Factors involved in the progressive loss of the vital (reserve) capacity of the bodily systems in PLH, leading to organ failure, reduced cognitive functions, disease, and death include: the presence of comorbidities; viral hepatitis coinfection; alcohol abuse, tobacco, or other drugs; microbial translocation; and chronic immune dysfunction, in addition to the toxicity of ARV agents and other drugs used concomitantly.19

Aging and HIV infection can also affect immunological memory. HIV infection is associated with an increased activation of naïve B cells, which persists even during the use of HAART.21 Some examples of the B-cell dysfunction that occurs in both PLH and older adults include the increased risk of severe bacterial infections with pathogens such as Streptococcus pneumoniae and the reduced ability of polysaccharide antigens to activate B cells, demonstrated by a poor response to the pneumococcal vaccine in terms of the production of efficacious antibodies and clinical protection.22

The number of naïve T cells (CD4+ and CD8+) decreases with age and HIV infection, and this can also influence the effect of ART.22 The number of such cells is as low in PLH as in non-infected individuals aged 20–30 years older. The T cells become less responsive, are less able to proliferate, and exhibit alterations in the signaling receptors and surface markers, including a loss of CD28 expression.23 These changes result in an increase of the Th-2 cells and simultaneous decrease of the Th-1 cells. Consequently, the levels of interleukin-2 (IL-2), which is produced by Th-1 cells, decreases as a result of aging; this phenomenon represents one of the most common cytokine alterations observed in immunosenescence.

The number of cytotoxic CD8+ T lymphocytes (CTL) increases in HIV infection in both young and old individuals.24 The memory T cells express surface CD28, which stimulates cell division in the presence of antigens. “Old” memory cells tend to lose CD28 expression and thus multiply less than younger cells upon antigen exposure.25

During chronic HIV infection, the repeated expansion of the CD8+ T cell population leads to a loss of CD27 and CD28 by the T cells, resulting in a predominance of lymphocytes that lack the receptors needed for co-stimulation and efficient antigen presentation. Eventually, the cells attain replicative senescence (exhaustion), which is characterized by shorter telomeres, low telomerase activity, and increased production of pro-inflammatory cytokines. A high proportion of CD8+ CD28 CTL is predictive of early mortality19 and rapid progression to AIDS among PLH,23 although a causal relationship has not yet been established.

The immune function of the mucous membranes is severely impaired by HIV infection. Independently of the route of infection, HIV replicates more intensively and the CD4+ T cell population is exhausted much more quickly in the gut-associated lymphoid tissue (GALT) than in the peripheral blood. This reduction in the number of CD4+ T cells in the GALT does not recover after the onset of HAART as it does in the peripheral blood. The effects of aging on the GALT are still poorly understood. The consequences of T-cell senescence are profound, and the ability to control chronic viral infections is lost.

In general, the clinical manifestations of immunodeficiency appear late in the course of HIV infection. However, in most cases, diagnosis is established only after the immune system has been strongly affected and CD4+ T-cell count is less than 200cells/mm3. Older people are diagnosed at more advanced stages of HIV infection than younger individuals.34 This delayed diagnosis might partially explain some studies’ findings of poorer clinical outcomes, including shorter intervals between the identification of HIV, the AIDS diagnosis and reduced length of survival,7 in elderly patients than in younger patients. Healthcare professionals do not seem overly concerned with the possibility of HIV infection in older individuals, possibly because older people are less likely than younger people to be considered sexually active or intravenous drug users. In addition, many of the symptoms of HIV infection might be confused with signs of natural aging, such as weight loss, fatigue, and cognitive or visual problems.35 The older patients themselves also may not suspect of their HIV infection. Most individuals diagnosed with HIV after age 60 never suspected that they were infected before they were tested.36

Studies conducted in the pre-HAART era found an association between old age and the risk of death among HIV infected individuals.37 At the beginning of the HAART era, access to ART was identified as the only factor associated with survival in patients older than 50 years.38 Improvement of ART efficacy has been correlated with longer life expectancy among individuals with HIV infection, and it is estimated that 50% of the currently treated population will be aged ≥60 years in 2015.39

Early mortality risk after the HIV infection diagnosis increases with age. A CDC survey on 12-, 24-, and 36-month survival after diagnosis showed that mortality was substantially higher among older patients at all three time points assessed.40 A study comparing early mortality between the cities of Rio de Janeiro and Baltimore also found a higher risk of death among the elderly (hazard ratio (HR) 1.03; p=0.03).41

In terms of the CD4+ T cell count improvement and viral suppression at different age ranges, most studies found that older people can achieve success rates similar to younger individuals given adherence to HAART.42,43 Greenbaum et al. found that the average time to attain the first undetectable viral load (VL) was lower among patients aged ≥50 years than patients aged ≤40 years (3.2 vs. 4.4 months; p=0.001). This difference was more significant when HAART included one protease inhibitor (PI).44

Nevertheless, the immune recovery rate can be slower and less robust among older patients. Data from the NA-ACCORD cohort study showed that the probability of recovering the CD4+ T-cell count (an increase of at least 100cells/mm3 over the first two years of ART) decreased with age.45 Low treatment compliance does not seem to explain these outcomes because older patients exhibit better adherence than younger patients and have a lower risk of viral rebound.46

It is recommended that individual ART regimens take the patient's lifestyle, among other factors, into account. Age is also an important factor for the selection of ART. Nucleoside analogs are strongly associated with mitochondrial toxicity, and zidovudine (ZDV) causes bone marrow suppression. Older patients might exhibit reduced renal function and loss of bone mass in addition to depression and cognitive disorders. There is more information regarding aging patients with HIV infection that have been exposed to ART for long periods of time than information regarding how to treat an old HIV+ patient recently diagnosed. Moreover, the choice to start treatment for individuals who have a diagnosis in the age groups above 50–60 years is probably something new for most clinicians. As the proportion of older patients starting treatment increases, studies assessing the efficacy and tolerability of regimens for this particular population are needed.

Due to greater need for concomitant medications in older patients, elderly HIV+ patients are expected to have poorer tolerability to ART, higher toxicity, and more numerous drug interactions. However, there are currently few data regarding these aspects.47 In the Swiss cohort, older patients tended to use more concomitant medications than younger patients and also exhibited higher risks of drug interactions, which were mostly related to the effects of ART on the action of the concomitant medications. Toxic effects most commonly described are associated with gastrointestinal intolerance, followed by central nervous system disorders, hepatotoxicity, and dyslipidemia.48

There is little information regarding the reasons to change ART in the elderly population. Among 95 patients aged ≥50 years in the IPEC/Fiocruz cohort starting their first HAART regimen between January 1996 and December 2008, 59% modified or discontinued (MOD) the first regimen (28.1/100 individuals per year of follow-up); the mean time to MOD was 12 months, and the main reasons for MOD were therapeutic failure (14%), toxicity during the first year of HAART (11%), and long-term toxicity (6%). The incidence of MOD was significantly higher among patients who started HAART with CD4+ T-cell counts<100cells/mm3 (HR 1.97; 95% confidence interval (CI) 1.08–3.61).49 In a German cohort, a change of regimen was more common among patients aged ≥50 years.50

Some studies found higher adherence to ART among patients aged ≥50 years compared to younger patients.46,51

Data regarding the resistance profile in therapeutic failure among elderly patients are scarce, as are data on primary resistance and age. In a German cohort, no difference was found in transmission of resistance between older and younger patients.50 In an Italian cohort, increased age was independently associated with higher likelihood of primary resistance.52

Older patients tend to have more comorbidities, fall ill more often, and pharmacological intervention is frequently needed, with a consequent high risk of drug interactions. Older HIV+ patients use more medications for CVD, gastrointestinal, and hormonal problems than younger patients, whose use of these medications matches that of the general population.48 In the Swiss cohort, age was one of the risk factors associated with increased drug interactions.53

The higher incidence of malignancies in PLH is related to the chronic oncogenic effect of some viral infections but is not necessarily related to aging. Nevertheless, some important aspects related to HIV, age, and the incidence of neoplasias are still controversial, such as whether HIV leads to early occurrence of cancer, whether the high incidence of some malignancies among PLH is a consequence of accelerated aging, and whether all patients should be treated with HAART upon diagnosis of HIV infection to achieve steady viral suppression and maintain immunity close to its normal status. However, it is unclear whether avoiding severe immunodeficiency alone reduces the risk of HIV-related malignancies.56

Predictive factors of non-AIDS-defining malignancies include age (the risk rate doubles per ten years of age increase); the most recent low CD4+ T-cell count; a history of smoking, and hepatitis B (HBV) coinfection.57 HAART is protective against AIDS-defining malignancies but does not seem to protect against non-AIDS-defining malignancies.57 Some studies have shown that since HAART was introduced, non-AIDS-defining malignancies have been diagnosed earlier in HIV/AIDS patients.57,58 PLH might also be at a higher risk of cancer due to peculiarities of their lifestyle, particularly smoking and use of alcohol.56

As the HIV+ population ages while exhibiting persistent alterations of the immune system, an increasing number of malignancies can be expected over time. Lung, anal, and liver cancer, as well as Hodgkin's lymphoma, represent the main contributions to this increase. In the US, the incidence of breast, colon, and prostate cancer is lower among HIV+ individuals than among the general population; this may be because the HIV+ individuals had not reached a sufficient age to develop such malignancies or to some protective effect related to HIV.56

In any case, the prevention and early treatment of neoplasias in PLH must be included in public health follow-up strategies and therapeutic guidelines targeting the elderly population.

Frailty is a pathologic aging syndrome, the mechanism of which is unknown, that leads to unfavorable outcomes such as hospitalization, disability, and death.59 Increased free radical levels, mitochondrial dysfunction, and cytokines might activate inflammatory pathways, leading to this condition. The levels of C-reactive protein, d-dimer, fibrinogen, and IL-6 are increased in older individuals with the frailty phenotype.60 Similarly, HIV infection and ART toxicity activate the inflammatory mechanisms associated with frailty.59 There is no universal definition of “frailty” for patients with HIV/AIDS; in the general population, a frailty phenotype is established when at least three of the following traits are present: exhaustion, slow walking speed, low levels of physical activity, weakness, and weight loss.60 HIV infection seems to accelerate the development of frailty, even when the patient exhibits viral suppression under HAART. In addition to HIV, frailty has also been associated with age, the female gender, a low level of schooling, being single, abuse of non-prescription drugs, and depressive symptoms. Table 1 describes an algorithm for the calculation of frailty that can be applied to patients.

HIV infection is associated with a higher risk of metabolic disorders such as insulin resistance, pro-atherogenic lipid profiles, and alterations of the subcutaneous and visceral body fat distribution (lipodystrophy). Such disorders might contribute to the higher risk of CVD associated with HIV and ART.61 Some cross-sectional studies have found an increased risk of metabolic and hormonal disorders, including osteopenia, hypogonadism, diabetes mellitus, and dyslipidemia.62,63 In the Swiss cohort, a higher proportion of non-AIDS comorbidities and multiple morbidities such as diabetes mellitus and CVD were observed among older individuals.64

The earliest cohort studies associated HIV infection and exposure to ART with a risk of coronary disease and myocardial infarction (MI). Subsequently, Friis-Moller et al. found that the risk of MI was more strongly associated with pre-established risk factors such as advanced age.65 Nevertheless, the correlation among HIV infection, inflammation, and cardiovascular risk has not yet been fully elucidated.66 HIV infection, prolonged ART, and aging are known to contribute to lipoatrophy and metabolic disorders.67 In the American VACS cohort, the risk of MI was twice as high among the HIV+ than the non-infected individuals, even after adjusting for established risk factors such as age, race, hypertension, diabetes mellitus, hypercholesterolemia, smoking, infection with hepatitis C virus (HCV), kidney disease, body mass index (BMI), and history of cocaine and alcohol abuse. However, the age at which MI occurred did not differ significantly among the older individuals, regardless of HIV status.68

Renal function is reduced in both elderly and PLH, leading to an impaired elimination of drugs and an increased risk of toxicity and mortality associated with CVD.69 Although the survival of PLH with end-stage kidney disease has improved since the introduction of HAART, its incidence has not changed.69 The survival rates of elderly patients undergoing dialysis are low, and a delay in the initiation of dialysis is associated with even greater morbidity and mortality. It is not yet known whether the control of arterial pressure and glycemia might delay the progression of kidney disease in HIV+ patients as it does in the general population.69

Liver disease is an important cause of death among PLH, surpassed only by opportunistic infections. Morbidity and mortality due to liver disease are up to 4-fold higher among the elderly than among young adults. In addition, the liver volume, blood flow, drug metabolism, and regenerative capacity decrease with age. Age is also associated with greater risk of hepatocellular carcinoma. The progression of chronic hepatitis C into cirrhosis is accelerated in HIV+ patients.70

The natural history of HIV infection is changing, and factors associated with advanced age will become an important modulator of its clinical outcomes, particularly dementia. Historically, there was no need to consider the potential contribution of age-related neurodegenerative diseases such as Alzheimer's to cognitive disorders among PLH because HIV primarily affected young individuals, whose life expectancy was then low. With the advance of HAART, there is an increased likelihood that young and middle-aged HIV+ individuals will develop premature neurodegenerative disorders that could directly impact their ability to work and reduce their quality of life.71 Increased longevity under conditions of chronic HIV-mediated inflammation combined with the secondary effects of HAART might significantly contribute to the increased risk of early cerebral aging and cognitive loss. Although the incidence of HIV-related dementia decreased after HAART was introduced, several studies reported a correlation between old age and an increased risk of HIV-associated dementia as the initial AIDS-defining illness.32

The well-established risks of smoking are considered greater among PLH, as these risks may be enhanced by the chronic inflammation associated with HIV, even among individuals with appropriate viral suppression. Associated questions include whether PLH smokers are at a higher risk of lung cancer or other malignancies as well as cardiovascular complications compared to smokers in the general population. As PLH are aging, their risk for all age-related diseases, including malignancies, will increase. The impact of being a smoker among HIV+ individuals who are aging needs to be established, once the prevalence of smokers among PLH is high, ranging from 50 to 70%.72

Although the rate of vitamin D deficiency is high among PLH73,74 little is known about the benefits of vitamin D supplements in metabolic disorders other than those involving the bones. The available data are controversial and non-standardized. In addition, the ideal replacement and maintenance regimes for PLH are not known. It is also important to highlight that bone diseases, depression and cognitive impairments can be associated with both aging and vitamin D deficiency. Therefore, controlled trials assessing both the success of vitamin D replacement and its benefits are needed.

HIV causes chronic activation of T cells and increases the production of pro-inflammatory cytokines, which increase the activity of osteoclasts, and these alterations persist despite effective ART and viral suppression.75 The current understanding of bone metabolism in the aging HIV/AIDS population is limited, and the sparse longitudinal data available show conflicting results.76 Despite the currently limited understanding of the factors associated with bone mineral reduction, the assessment of risk factors for bone loss is needed to reduce the morbidity of osteopenia and osteoporosis in the HIV+ aging population.