F35 Ageing and HIV infection

The ageing population of PLWHA

With the availability of effective and durable highly active anti-retroviral therapy (HAART), people living with HIV/AIDS (PLWHA) are having life expectancy approaching that of the general population. With the scale-up of HAART, the average age of PLWHA is increasing in both high and middle/low-income countries. Moreover, there is also a significant number of people acquiring HIV infection at an older age.[1] As a result, we observe an increasingly larger proportion of older PLWHA. In many high-income countries and regions, more than 50% of the population of PLWHA are already above 50 years of age.[Further reading A]

Human ageing is a natural process, characterised by a progressive decline in the function of immune and organ systems, and is often associated with onset of adverse health outcomes, including disability, morbidity and mortality. Immune activation and chronic inflammation associated with HIV infection aggravates immune senescence in the natural ageing process.[2] The depletion of CD4+ T lymphocytes, increased senescent CD8+ T lymphocytes, increased monocyte activation, and thymic dysfunction cause immune dysregulation and senescence, leading to decreased ability in their response to new pathogens and vaccines.[2] Chronic inflammation is caused by several factors in the setting of HIV infection. Persistent low-level viral replication at the tissue level despite the use of antiretroviral therpay (ART) continues to activate pro-inflammatory biomarkers and promotes immune activation. Co-infections with other chronic viral infections like viral hepatitis and cytomegalovirus, as well as microbial translocation with circulating bacterial antigens, further stimulate the immune system. Lifestyle factors, such as smoking, alcohol, and substance use, are observed to be more prevalent in PLWHA, and further contribute to the ageing process.

Mitochondrial dysfunction, which correlates with multiple ageing outcomes, also plays an important role in the ageing process in PLWHA. Mitochondrial dysfunction is a result of both HIV infection and the use of antiretroviral drugs. A recent longitudinal study showed that mitochondrial DNA declined significantly in older PLWHA, including those receiving ART, while no decline was observed in demographically and behaviourally similar HIV-uninfected individuals.[3] These findings supported that HIV infection is associated with accentuated, or even accelerated, ageing in older individuals.

Premature ageing in PLWHA is reflected clinically by their increased risk of developing multiple age-related non-AIDS associated comorbidities. These comorbidities often occur approximately 10 years earlier than those who are not infected with HIV. For example, a study in Italy showed that PLWHA had higher prevalence of several age-related comorbidities, including cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure. Importantly, the prevalence of multimorbidity in PLWHA at age 40 years and above was similar to HIV-uninfected individuals who were 10 years older.[4]

In an Asian cohort of PLWHA with matched HIV-uninfected controls, a number of comorbidities, including multimorbidity, polypharmacy, neurocognitive impairment and depression, were more prevalent in PLWHA. The burden of multiple geriatric conditions was higher in PLWHA, and correlated with lower health-related quality of life, higher risk of healthcare utilization, and higher mortality risk in PLWHA.[5]

As we are seeing an increasing prevalence of these comorbidities in the ageing population of PLWHA, the interaction between HIV infection and these other chronic diseases potentiate chronic inflammation and immune activation, causing higher risk of end-organ dysfunction and mortality. Despite a great improvement in life expectancy of PLWHA in the HAART era, premature ageing and increased presence of these comorbidities likely account for the persistent gap in life expectancy between PLWHA and matched HIV-uninfected controls observed in recent studies.[Further Reading A] Moreover, the presence of these comorbidities adversely affects the quality of life of the ageing population of PLWH, and adds burden to the healthcare system. [Further reading B] Therefore, supporting PLWHA for healthy ageing is of paramount significance in this population. The goal of healthy ageing is regarded as the fourth “90” target in the HIV care continuum.[1]

Approach to healthy ageing in PLWHA

Healthy ageing is increasingly being recognised to be important in maintaining the well-being in the older general population. Healthy ageing is not merely the lack of diseases, but developing and maintaining the intrinsic capacity and functional ability that enables well-being. “Intrinsic capacity” is the combination of the individual’s physical, mental and psychological capacities, while “functional ability” is the combination and interaction of intrinsic capacity with the environment a person inhabits.[6] Therefore, intrinsic capacity should be monitored for ageing PLWHA and early reductions in physical and mental capacities, if detected early in the life course, could potentially allow timely intervention to prevent future disabilities.

Several conditions have been recommended by the WHO and geriatricians to characterise a person’s intrinsic capacity and functioning to maintain well-being. These conditions have been shown to be strong predictors of functional disability, care dependency, impaired quality of life, and mortality in the general older population. These conditions include mobility loss, malnutrition, visual impairment and hearing loss, neurocognitive impairment, depression, and several geriatric syndromes, such as multimorbidity, polypharmacy, frailty, sarcopaenia, falls and urinary incontinence.[6,7] More than half of PLWHA older than 50 have been shown to suffer from two or more geriatric syndromes.[8] Such conditions have also been shown to predict worse health outcomes in PLWHA. Early identification of individuals at risk of future functional decline and disability help to bring in timely intervention to prevent these poor outcomes. Assessments for these conditions systematically in an ageing population of PLWHA would also inform policy makers of the current and anticipated healthcare needs.[Algorithm 35]

Multimorbidity is often defined as the concurrent presence of two or more medical conditions, and its prevalence increases significantly in PLWHA aged 50 years and above. The most common medical conditions, or comorbidities, observed in PLWHA include hypertension, dyslipidaemia, diabetes, obesity, cardiovascular diseases, chronic obstructive pulmonary disease, cirrhosis, chronic kidney disease, osteoporosis, and cancers.[Further Reading B]

Multimorbidity very often leads to polypharmacy in PLWHA. Polypharmacy is often defined as concurrent use of 5 or more non-HIV medications, and was reported to be present in up to 55% of older PLWHA in cohort studies. Polypharmacy is increasingly prevalent among PLWHA over time due the ageing population, and is more common than in HIV-uninfected individuals.[9] Polypharmacy is associated with problems including increased risk of drug toxicity, drug-drug interactions (DDI), and altered pharmacokinetics.[Further Reading B]

Frailty is a distinct clinical syndrome, characterised by diminished strength, endurance, and physiologic function that increases an individual’s vulnerability for developing increased dependency and death. PLWHA have higher prevalence of frailty and more rapid progression to frailty at an earlier age, compared with age-matched HIV-uninfected controls. Risk factors for frailty include low nadir and current CD4 counts, hepatitis C and other comorbidities, and lower education level. Chronic inflammation possibly plays an important role, as markers of inflammation and immune activation, such as interleukin-6 and sCD163, correlated with frailty in PLWHA. Frailty identifies PLWHA with higher risk of adverse health outcomes, including falls, functional decline, disability, hospitalization, as well as development of multiple age-related chronic diseases (such as cardiovascular diseases and diabetes) and mortality.[8][10]

Sarcopaenia is a decline of both quantity and quality of muscle. It is recognised as an important problem in ageing in HIV-uninfected individuals, as ageing is associated with progressive loss of muscle mass. HIV infection and ART have long been recognised to have deleterious impact on muscles. In particular, nucleoside reverse transcriptase inhibitors (NRTIs) cause depletion and mutation of mitochondrial DNA, leading to oxidative stress and muscle fibrosis and dysfunction. Sarcopaenia therefore is an important problem in PLWHA, contributing to loss of muscle strength and impaired physical function.[11] Sarcopaenia is commonly defined as two standard deviation below the mean of appendicular skeletal mass index, which is the sum of lean mass of both upper and lower extremities, adjusted for body height. New definitions of sarcopaenia take into consideration both muscle mass and muscle function. The latter also include criteria like slow gait speed and weak handgrip strength.

In view of premature ageing and the presence of multiple health issues, older PLWHA are more prone to face challenges that affect their quality of life. Impaired quality of life is not only due to clinical diseases and physical and mental disabilities, but is also contributed by socio-environmental factors. They may experience new psychosocial issues as they age, such as unemployment as they approach retirement age, loneliness and lack of social support due to loss of partners and friends, and HIV-associated stigma, especially in those with suffered from care dependency. The chronic care of the ageing PLWHA in HIV services should take into consideration these psychosocial stressors, with an aim of preparing them for these changes associated with ageing, and improving or maintaining their overall quality of life as they age.

Management of ageing issues in PLWHA: assessment of problems associated with ageing and intervention for promotion of healthy ageing

In view of the ageing process and the associated problems in PLWHA, a multidimensional assessment should be performed for older PLWHA. Such assessment should include evaluation of an individual’s functional ability, physical performance, psychosocial factors affecting health, and assessment of various geriatric syndromes.[Further Reading B]

Assessment of the functional ability in general involves the assessment of activities of daily living (ADL), and instrumental activities of daily living (IADL). ADLs are daily self-care activities, e.g. eating, dressing, bathing, and using the toilet. IADL are activities that allow a person to live independently, e.g. doing household chore, preparing meals, handling finances, and taking medications.

Several assessment tools are used to determine a person’s physical performance. The Short Physical Performance Battery (SPPB) is an objective measure of lower limb physical function. It involves (i) standing balance tests, in which a person is asked to maintain a standing position with their feet side-by-side, and in semi-tandem and tandem positions for 10 seconds each, (ii) gait speed of doing a 4 metre-walk at normal pace, and (iii) chair-rise test, in which a person is asked to rise from a sitting to a standing position five times as quickly as possible. Another measure of muscle strength is the handgrip strength. Handgrip strength is measured by asking a person to use the strongest possible force to grip a dynamometer while in a standing position.

Frailty status should also be included in the multidimensional assessment of older PLWHA. Frailty is commonly measured using the frailty phenotype, or the frailty index.[12] The frailty phenotype is based on a set of five criteria, including unintentional weight loss, exhaustion, slow gait speed, weak handgrip strength, and low physical activity. The number of criteria is categorised into a 3-level variable depicting robustness (meets none of the criteria), pre-frailty (meets one or two criteria) and frailty (meets three or more criteria). Detection of frailty using the frailty phenotype alerts a clinician of possible underlying clinical problems, as it helps to predict disability independently of clinical diseases. On the other hand, frailty index is based on the accumulation of deficits. It usually consists of at least 30 to up to 70 variables, involving clinical diseases, ADL, and various results of clinical evaluation. Each variable is recorded with values of one when a deficit is present, and zero when absent. The number of deficits acquired by the individual is divided by the total number of variables, to produce a frailty index score ranging from 0 to 1. The frailty index is valuable in describing the health trajectory of an individual over time, and to assess effectiveness of an intervention aiming to improve health.

Several other geriatric syndromes should also be evaluated in older PLWHA.[8] Falls is commonly measured by a single question asking for fall in the past one year, with a fall being defined as an unexpected event in which a person comes to rest on the ground, floor, or a lower level. Urinary incontinence can be measured by validated questionnaires, such as the International Consultation on Incontinence Questionnaire. Hearing impairment can be measured by self-report of hearing loss, standardised questionnaires to assess the impact of hearing impairment on daily activities, and simple office-based screening test such as the whispered voice test. Visual impairment can be measured by self-report of difficulty seeing and measurement of visual acuity using a Snellen chart. Depression can be screened with standardized tool, such as the Center for Epidemiological Studies Depression Scale (CES-D). Older PLWHA should also be screened for neurocognitive impairment, e.g. using the Montreal Cognitive Assessment, and referred for further treatment if required. Identification of these geriatric syndromes allow clinicians to further work up for underlying causes accounting for these problems and arrange appropriate intervention.[Further reading C]

The physical and mental health problems of the ageing population of PLWHA also adversely affect their quality of life. Health-related quality of life should also be assessed, to allow clinicians to be aware of the general health status of PLWHA, and provide indicators to measure health outcomes in the aging population of PLWHA. Health-related quality of life can be assessed using a generic measure applicable to the general population, together with an HIV-specific instrument.[13] An example of a widely used generic tool is SF-36 (36 items Short Form Health Survey), which provides summary scores for both physical and mental health components. An increasingly applied HIV-specific measure is the WHOQOL (World Health Organization Quality of Life)-HIV survey, which covers six domains, including physical, psychological, level of independence, social relationships, environment, and spirituality/religious/personal beliefs.

As the population of PLWHA is ageing, incorporation of screening, diagnosing and managing comorbidities is essential in the delivery of care in HIV clinics.[1] Management of comorbidities can be more complex in PLWHA than in HIV-uninfected elderly populations. Comorbidities like chronic kidney disease, osteoporosis, and cardiovascular diseases may complicate the use and choice of antiretrovirals. Polypharmacy would imply higher risk of DDI between antiretrovirals and the therapeutic agents used to treat or prevent comorbidities. Cognitive impairment may impair adherence to HAART, which becomes a new issue in older PLWHA as they age.

For PLWHA who demonstrate frailty and impaired physical function, exercise has been shown to be beneficial. Aerobic and progressive resistance exercise have been shown to be safe and efficacious in improving physical function in older PLWHA with frailty.[14] Both moderate- and high-intensity exercise improve physical function, with high-intensity exercise showing more benefit. Exercise also improves cardiorespiratory fitness, endurance and ambulatory function in PLWHA.

Issues of special interest in the ageing PLWHA

As the rate of ageing differs significantly between individuals irrespective of HIV status, accurate measures to reflect an individual’s biological age are important to display the individual’s age-related changes in body composition and functional capacity, and predict the onset of adverse health outcomes. Several biomarkers have been evaluated for their role in describing biological age in PLWHA. These included markers of inflammation (e.g. C-reactive protein and interleukin-6), monocyte activation (e.g. soluble CD 163), leukocyte telomere length, mitochondrial DNA copy numbers and mutations, and DNA methylation.[3][15] A recent study showed that using a combination of established biomarkers of ageing may more accurately reflect the biological age than using single biomarkers.[15] Future research should be directed to determining the most appropriate biomarker, or combinations of biomarkers, that can predict important health outcomes in the ageing population of PLWHA.

Increasing evidence has shown that intestinal microbiome is altered in PLWHA, including changes in both composition and diversity, as well as short-chain fatty acid metabolism associated with the intestinal microbiome. In HIV-uninfected elderly populations, intestinal microbiome composition and diversity had been shown to correlate with frailty. In PLWHA, trimethylamine and carnitine produced by the intestinal microbiome were associated with age-related chronic diseases such as atherosclerosis.[2] Further studies should evaluate the role of the microbiome in the ageing process in PLWHA, which could potentially be targets of intervention for healthy ageing.

Although most PLWHA age after acquisition of HIV infection at a younger age, older adults are also at risk of HIV acquisition. Older adults who acquire HIV infection later in life are often diagnosed late, due to lack of awareness of both clinicians and patients, resulting in infrequent and low rates of HIV testing. Therefore, older adults more frequently present with AIDS-related complications at the time of diagnosis, with lower nadir CD4 count. Older adults also tend to experience lower magnitude of recovery of CD4 cell count and immunity than younger PLWHA who start HAART. As a result, PLWHA diagnosed at an older age are more prone to long-term complications.[1] Efforts should be paid to promote awareness of sexual health and HIV prevention in older adults, and reducing barriers and stigma in aiding early diagnosis in older PLWHA.

Conclusion

As we observe an ageing population of PLWHA, promotion of healthy ageing should be one of the targets in the HIV care continuum. Assessment of age-related comorbidities, physical function, psychosocial status and various geriatric syndromes should be considered as part of routine care of older PLWHA. Early identification of potential problems may help to prevent disability and care dependence in the future.

References

Further Reading