Keywords

Elderly; HIV-AIDS; Acquired Immunodeficiency; Secondary Immunodeficiency

Introduction

The first time that the world heard about human immunodeficiency virus (HIV) was in the 80’s, in the United States of America (USA), San Francisco in homosexual men and intravenous (IV) drugs users. Only 10 years later, USA and Western Europe, had the first effective combination antiretroviral therapy (cART) or previously called highly active antiretroviral therapy (HAART). The paradigm of living with HIV has changed [1-20]. The mortality felt down in the USA starting in the year 1996, but only in 2012 with the widespread of cART, the death range worldwide also declined [1,2,4]. Similar patterns are reported in European countries, North America, Australia and Asia [6].

If in the 90’s people died very young with opportunist infections, tumours and undernutrition. Nowadays the reality is very different. With the adequate treatment, compliance and follow-up; they can live their disease in a successful way, allowing them to age [1-3]. There are a couple of challenges that appeared in the HIV aging people, such as accelerated aging, HIV associated non-AIDS conditions (HANA), geriatric syndromes and frailty [1,2]. In the general population, the “cut-off point” for old age is 60-75 years, but in the HIV, the limit falls to 50 years old [1-5].

Discussion

Epidemiology

The age of people infected with HIV-AIDS rose during the past 30 years [1,2]. It is estimated that 3,6 million of the 35,6 million people living worldwide with HIV are over the age de 50 years, and it is expected that this trend keeps rising. In the USA, in the year 2012 approximately 40% of the people living with HIV were over 50 years and 11% were 60 or more years [1,3,4]. Data shows that around 18% of new cases are diagnosed in patients with 50 years, also allowing to have older people with this syndrome [1] Early in the HIV epidemic, older patients acquired HIV from blood transfusions, but now they have the same risk factors as younger people–men who have sex with men (MSM), intravenous drugs users and women who have sex with infected men [3].

HIV and aging

Universally aging is defined as “the time-dependent functional decline that affects most living organisms”. Many factors are known in this process (genetic, lifestyle and environment exposures [1,7] and it is also known that they work more intensely in the HIV positive patients. Many mechanisms are described such as genetic instability, telomere shortening, epigenetic alterations, loss of proteostasis, dysregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem-cell exhaustion and altered intercellular communications (abnormal endocrine and neuroendocrine signalling–insulin, insulin-like growth factor, growth hormone [1] as well as immune dysregulation), chronic inflammation (“InflammAging”) with high markers such as interleukin (IL)-6, D-dimers, fibrinogen [1,4-7,9,11], C-reactive protein (CRP), tumour necrosis factor α (TNF-α) and high white blood cells count (WBC)–neutrophils, monocytes and CD8+ Tcells [2].

The literature shows that HIV positive, ART-treated women have a higher state of immune activation, exhaustion and senescence than uninfected age-matched controls. The simplest and safest intervention to reduce inflammation and grant health ageing is moderate exercise and low caloric intake, beyond disease control [5].

Inflammation in HIV may be increased by tissue and peripheral blood virus, chronic reactivation of herpes virus such as cytomegalovirus (CMV) [1,2], microbial translocation (more evident in the gut), immune dysregulation and senescence (with depletion of CD4+ cells and increased CD8+ and monocytes). Some of these mechanisms are also described in the HIV negative patients like part of the physiological process of aging [1,5,11].

Frailty and geriatric syndromes

Frailty, present in almost 25% of the patients with more than 85 years, is a clinical syndrome initially characterized in geriatric population with a hallmark of age-related declines in physiological reserve (and complexity in resting dynamics involving multiple physiological systems), function (with progressive decline) and increased vulnerability (due to maladaptive responses to everyday or acute stressors) to adverse health outcomes (like acute illness, falls, cognitive decline, hospitalization, disability, dependency and mortality) [1].

In the process of aging with HIV many mechanisms and cascades are involved, such as increased rates of chronic morbidities, increased rates of geriatric syndromes (conditions that associated with aging predict adverse outcomes, like falls, urinary incontinence, slow gait, sensory deficits and neurocognitive impairment, present in 25-56% of older patients) and frailty (evaluated frequently by the Fried criteria), senescent immune changes, persistent increased inflammatory markers [1,2,4-6,7,9,11,17-19,21]. Still is controversial, even though HIV may be a risk factor for morbidities, does not appear to accelerate their occurrence over time. Patients with the risk of frailty (low current and nadir of CD4+ cells, central obesity, Hepatitis C virus [HCV] coinfection, other geriatric syndrome and lower education) will increase and adequate strategies to slow down are needed, starting in the beginning of the disease [1].

Diagnosis, treatment and prevention of comorbilities

HIV is underdiagnosed in older patients. In 2011, 16% of the 1.1 million Americans living with HIV didn’t knew they had the disease. Around 18% of the patients had 50 years or older at the time of diagnosis [1,3-5]. Problems regarding to underdiagnosed infection are: provider and clinical recognition (frequently symptoms that may relate to an HIV infection or its progression may be misconstrued as relating to the aging process), insight and information about HIV prevention and transmission, lack of HIV-prevention education targeting older patients, disclosure because of the family/social stigma of HIV infection (3,4), lack of insurance or access to medical care [4].

The active screening may be considered in all older adults, as shown in the Table 1. Treatment should be offered to all, as early as possible, except if there is a pharmacological and/or medical contraindication [1,6].

Table 1: Screening in HIV.

HIV non-associated aids conditions

HIV patients have a higher number of comorbidities when comparing with the one HIV negative. They may appear in all ages, in high rates, but as expected are more frequent in older persons [1,3-9,11,15-18,21].

Cardiovascular Disease (CVD): Before HAART, it was more frequent myocarditis and dilated cardiomyopathy (especially with low CD4 nadir). Nowadays coronary artery disease (higher risk in 50%), interstice myocardial fibrosis, intracardiac fat infiltration, arrhythmic disorders, congestive heart failure and ischemic stroke are more frequent. Some drugs may enhance the cardiovascular risk such as the protease inhibitors. Other cardiovascular risk conditions are commonly seen such as insulin resistance and diabetes, obesity, hypertension, smoking. Therefore, there is an increased status of inflammation and thrombosis [1,3-5,7,9,12,13,21]. All together they make a mismatch between the chronological age and the vascular age. Note that traditional models for cardiovascular risk prediction may underestimate risk in HIV-infected patients, because atherosclerosis is driven mainly by the HIVHAART related risk factors. Drugs like lopinavir/ritonavir, indinavir and abacavir are also associated with higher cardiovascular risk [5].

Arterial hypertension: Regarding to arterial hypertension, a relationship between higher systolic blood pressure and duration of HIV has been reported, being greatest after 5 years or more of ART, especially with protease inhibitors and nonnucleoside reverse transcriptase inhibitor regimens [12].

Heart failure: HIV infection is associated with a 1,8-fold risk of developing heart failure (HF). A metanalysis showed that systolic dysfunction was present in 8,3% (secondary to chronic inflammation, tobacco smoking and history of myocardial infarction) and diastolic dysfunction in 43,4% (due to age and hypertension) [12].

Stroke: Stroke is a leading cause of death and disability worldwide. HIV patients have an increased risk of stroke, predominantly the ischemic type. Some mechanisms are being pointed as an explanation–vasculopathy, thrombophilia, cardioembolic events and opportunistic infections [12].

Pulmonary disease: Obstructive lung disease (OLD) has been reported in positive HIV populations since the pre-HAART era. Different types can occur - fixed airway obstruction, emphysema, diffusing capacity for carbon monoxide (DLCO) impairment, chronic bronchitis, bronchial hyperresponsiveness, and asthma. OLD is the most common type and the obstruction is more severe with a quicker progression in patients with higher HIV viral levels. Pulmonary Arterial Hypertension (PAH) is one of the most severe complications of HIV infection, carrying high mortality. Its incidence has not changed with HAART and Its severity doesn´t correlate consistently with the immunosuppression degree [12].

Insulin resistance and diabetes mellitus: Diabetes Mellitus (DM) is present in 3% of the HIV positive patients who have never received HAART, but glucose intolerance increases to the range of 10 to 25% in those who have started it. Lipodystrophy and hyperlipidaemia are also present in patients with a chronic use of protease inhibitor [3,4,7]. The incidence of diabetes is 4 times higher among HIV-infected men on HAART, especially with a ritonavir scheme [9]. In the diabetes mellitus treatment, besides metformin that causes lactic acidosis, there are no other significant interactions. Diet, exercise, eviction of smoking cannot as non-pharmacological measures cannot be forgotten [7,9,21].

Kidney disease: Kidney dysfunction is very frequent in ageing and more in HIV patients (around 3,5% to 9,7% in stage 3 or higher) [1,5]. HIV nephropathy (HIVAN) was initially described in the first years of the disease, especially in Afro- Americans. HAART has decreased its incidence and prevalence [1,9,21]. Risk factors known HIVAN are age, afro American, history of diabetes mellitus and hypertension, low CD4 counts, high viral loads, inflammatory markers and drugs like tenofovir [1] (with kidney lesion like proteinuria, renal tubular damage, interstitial nephritis, nephrolithiasis [9]) and hepatitis C virus infection (HCV) [4].

Neurological disease: At the beginning of the disease, in the 80s, both neurologic disease and dysfunction were secondary to opportunist or sexually transmitted infections (more frequent if CD4 ≤ 200 cells), leading to HIV associated dementia, myelopathy and peripheral neuropathy. Nowadays it is described HAND (HIV-associated neurocognitive disorders), that is present in around half of them [1,3,4,5,14,15,21]. It may be asymptomatic (in most cases, in 50%–Asymptomatic Neurocognitive Impairment [ANI]) but can me mild (minor neurocognitive disorder [MND], in 20%) or severe (in only 2% of the cases–HIV associated dementia [HIVD]) [3,14,15,21]. They can appear besides the good HIV control and it can be present among other comorbidities as CVD and sleep disturbances [3,14]. In the pre-HAART era, the HAND took the form of motor skill and cognitive deficits, but today patients have much less obvious decline in executive functioning or memory [4]. The risk of dementia is more than three-fold, with structural changes in the brain like decreased brain volume [1], blood brain barrier abnormalities and altered permeability [5]. Clinically is indolent and the first changes can be psychomotor, difficulty in multitasking and apathy. Bad control of the HIV disease may take to disorders like central nervous system toxoplasmosis, cryptococcal meningitides, progressive multifocal leukoencephalopathy and primary central system lymphoma [3].

Psychiatric disease: Depression is very common in older adults and no less so in patients’ HIV positive [4,5]. It may be initiated or worsened by social circumstances -isolation, loss of friends or loved ones, stigma or rejection or substance abuse. It may be subtle, and appear as sleeplessness, poor adherence to treatment regimens, poor hygiene, forgetfulness, weight loss or gain, sadness and anhedonia. Its treatment is multimodal and should be made by routine, with both social, psychological and pharmacological interventions [4,7].

Bone disease: Bone mineral density as measured by DXA (Bone densitometry) scans (each 2-3 year, from the 50 years), serves as a surrogate marker of fracture risk and provides data to categorize persons with osteoporosis. In fact, FRAX® (World Health Organization Fracture Risk Assessment Tool) has not been validated in HIV-infection and may underestimate the 10- year risk in these patients [17]. Dietary, lifestyle and HAART modifications allied to DXA screening is indicated in higher risk older patients [16].

Deterioration of the bone structure related with osteopenia and osteoporosis is often asymptomatic, multifactorial and increased in this population, due to substance abuse (alcohol), smoking, low body weight and vitamin D deficiency (present in 60 to 75% of the HIV-infected elderly) [1,4,5,16,17] hypogonadism [3,4,5], lactic acidaemia [7], post-menopause state [9]. Drugs like the protease inhibitors–tenofovir predispose to low bone density (bone mineral density decreases by 2 to 6% in the first two years starting this regimens) [1,7,9,17,18,21]. If there is severe osteoporosis an alternative is changing to regimens with raltegravir or abacavir associated with bisphosphonates [18]. The expected risk of fracture is around three-fold [1,3,5,7], more frequent in the vertebrae, forearms or hips (7) with severe medical, functional and economic consequences [16].

Neoplasms/malignancy: With aging, the risk of having cancer is higher. In both HIV-positive and HIV-negative, the incidence of lung, colorectal, prostate and breast cancers will increase. HIV patients are in higher risk for malignancy, at first with Kaposi’s sarcoma (1000 times), non-Hodgkin B cell lymphoma (100 times), invasive squamous cell carcinoma of the cervix (6 times higher), known as AIDS-defining cancers [1,3,19,21]. The last ones are reduced after the HAART era [19]. Several oncogenic viruses have been implicated in these cancers, such human herpesvirus 8 (HHV8), hepatitis B virus (HBV), HCV, HPV and Epstein-Barr virus (EBV) [4].

Mortality: Many factors contribute to the mortality in patients with HIV, such as the time of diagnosis, CD4+ nadir, virologic suppression and the use of drugs, especially the IV (but also the smoking and other substances abuse). Other contributors are also pointed like lifestyle factors, HAART therapy, socioeconomic status, risk factors for co-morbidities, nutritional status, safe environment, ethnicity, social isolation and other active infections like herpes viruses and hepatitis. The life expectancy in a HIV positive patient is around less 20 years than the HIV negative patient [1-3,7,8].

Besides all the improvement of care and refined treatments, the mortality in this group is 1,7 to 7,0 times higher than those who are not infected. The mortality may be near to the noninfected if the CD4+ nadir is persistently above 350-500 cells/μL and the viral load is suppressed [1]. Cancer is responsible for one third of the deaths in HIV patients [19] CVD is the second major cause of mortality among HIV infected patients, responsible for 15% of the deaths [7,9].

The literature shows that the causes of death in the HIV group has changed from infections and malignancy in the late 90’s to HANNA. This conditions still exist but in patients with delayed or ineffective treatment due to non-adherence, drug resistance, poor CD4 recovery.

Conclusion

The number of elderly people living with HIV reflect enormous treatment successes, and present new challenges related to aging. This increase is attributed to the effectiveness of HAART that increase longevity of life but also to the increased risk of acquiring HIV in this population. Comorbidities are more common because of aging and HIV status. This increase in age and comorbidities will increase the need for multiple professional competences, and the sharing of specialist medical skills. New screening test strategies for malignancies should be developed for older HIV-infected patients.

Near of forty years after the identification of HIV, a cure for HIV infection is still to be achieved. Advances of combined antiretroviral therapy in recent years transformed HIV infection into a chronic disease when treatment is available. Physiological changes associated with aging alter drug metabolism in these patients who in most cases experience polypharmacy exposing them to drug toxicities and drug to drug interactions. Special designed preventive measures and screening programs should be designed to target elderly individuals. Clinicians should also suspect HIV early in these patients to minimize late presentation and pay attention to the principles of geriatric prescribing recommendations to minimize complications from multiple medication use. As people with HIV live longer and with more complex health and social care needs, the concept of frailty could be useful for identifying vulnerable individuals, for organizing care and for comprehensively measuring the impact of illness and treatment on overall health status. As research for a cure for HIV infection continues, there is a vital need to examine the aging population, since any drug or vaccine must now work on an older population.

Conflict of Interest

The authors don’t have any conflict of interest.

References

1. Wing EJ (2016) HIV and aging. International Journal of Infectious Disease 53: 61-68.
2. LengSX,Margolick JB (2015) Understanding Frailty, Aging and Inflammation in the HIV infection.Curr HIV/AIDS Rep 12:25-32.
3. Blaylock JM, Wortmann G (2015) Care of the aging HIV patient. Cleveland Clinic Journal of Medicine 82:445-455.
4. Ball SC (2014) Increased Longevity in HIV: Caring for Older HIV-Infected Adults. Care Management Journal15:76-82.
5. Calcagno A,Nozza S, Muss C,Celesia BM, Carli F, et al (2015) Ageing with HIV: a multidisciplinary review. Infection43:509-22.
6. Winston A.Underwodd J (2015) Emerging concepts on the use of antiretroviral therapy in older adults living with HIV infection.CurrOpin Infect Dis28:17-22.
7. Libman H (2015) Will you still treat me when I’m 64? Care of Older Adult with HIV infection. Top Antivir Med23:97-103.
8. Short WR, Anderson JR (2014) Caring for women with HIV: Unique needs and challenges. Cleve Clin J Med 81:691-701.
9. Warriner AH, Burkholder GA, Overton ET(2014) HIV-related metabolic comorbidities in the Current ART Era. Infect Dis Clin N Am 28: 457-476.
10. Martinez DR,Permar SR,Fouda GG (2016) Contrasting Adult and Infant Immune Responses to HIV infection and Vaccination.Clin Vaccine Immunol 23: 84–94.
11. Appay V, Kelleher AD (2016) Immune activation and immune aging in HIV infection; CurrOpin HIV AIDS11:242-9.
12. Bloomfield GS,Khazanie P, Morris A,Rabadán-Diehl C, Benjamin LA, et al. (2014) HIV and Non-Communicable Cardiovascular and Pulmonary Diseases in Low- and Middle-Income Countries in the ART Era: What we Know and Best Directions for Future Research. J Acquir Immune DeficSyndr67: S40-S53.
13. Kaplan RC, Hanna DB,Kizer JR (2016) Recent Insights Into Cardiovascular Disease (CVD) Risk among HIV-Infected Adults.Curr HIV/AIDS Rep 13:44-52.
14. Tedaldi EM,Minniti NL, Fischer T (2015) HIV-Associated Neurocognitive Disorders: The Relationship of HIV Infection with Physical and Social Comorbidities. Biomed Res Int 641913.
15. Devaughn S, Muller-Oehring EM, Markey B, Bronte-Stewart HM (2015) Aging with HIV 1 Infection: Motor Functions, Cognition and Attention–A comparison with Parkinson’s Disease.Neuropsychol Rev 25:424-438.
16. Yin MT,Falutz J (2016) How to predict the risk of fracture in HIV? CurrOpin HIV AIDS 11:261-7.
17. Guerri-Fernández R,Villar-García J,Díez-Pérez A, Prieto-Alhambra D (2014) HIV infection, bone metabolism, and fractures.Arq Bras Endocrinol Metabol 58:478-83.
18. Hoy J (2015) Bone Disease in HIV: Recommendations for Screening and Management in Older Patients. Drugs Aging 32:549-558.
19. Goncalves PH, Montezuma-Rusca JM,Yarchoan R,Uldrick T (2016) Cancer Prevention in HIV-infected populations. Semin Oncol 43: 173-188.
20. Shorthill J, Demarco RF (2017) The Rellevance of Palliative Care in HIV and Aging; Interdiscip Top GerontolGeriatr42:222-233.
21. Battegay M, Lundgren JD,Ryom L (2017) European AIDS Clinical Society Guidelines. pp: 34-68.