What is the measure of success in HIV? The fourth 90: quality of life or healthy aging?
Key summary points
The objective of this paper is to critically discuss potential new outcomes to be used as a measure of success for people living with HIV (PLWH) both in clinical and research settings.
This review critically discusses epidemiological, clinical, patient reported and public health outcomes in older adults living with HIV beyond the viro-immunological success. They include health adjusted life expectancy (HALE), frailty, health related quality of life (HRQoL), intrinsic capacity, all of which capture important aspects of the complexity of aging with HIV.
HIV outcomes should go beyond viral undetectability, and be patient-centred.
In the short time frame of 30 years, HIV research has been able to modify AIDS from a rapidly progressive disease leading inevitably to death to a chronic condition. Even more, the health status of people living with HIV (PLWH) has significantly improved reducing the burden of symptoms and improving quality of life (QoL). After introduction of the UNAIDS agenda on the “90–90–90 targets”, it remains unclear what should be the next target in HIV care and research. The objective of this paper is to critically discuss potential new outcomes to be used as a measure of success in PLWH both in clinical and research settings.
To better portray potential outcomes, we will critically discuss epidemiological and clinical outcomes, patient-reported outcomes (PRO), and public health outcomes reported in literature. These outcomes intersect with one another which may suggest contemporary use of different outcomes depending on goals we want to achieve. New outcomes should go beyond undetectability, be patient-centred, and similar to those in geriatric medicine and the general population.
HIV care can take advantage of experience from geriatric medicine and teach-back by describing aging trajectories in PLWH that may be accentuated in comparison to general population. However, we still need to improve tools to measure quality of life, PROs, and healthy aging. Healthy aging assessment will allow us to recognize unmet needs in PLWH and represents an integrated model between community, the person, and healthcare providers, wherein all stakeholders are linked, increasing possibilities for effective intervention.
KeywordsQuality of life Healthy aging Measure of success Patient related outcomes Intrinsic capacity Frailty
HIV research and care represent a uniquely successful example in medicine. In the short time frame of 30 years it has been able to modify AIDS from a rapidly progressive disease leading inevitably to death to a chronic condition. Even more, the health status of people living with HIV (PLWH) has significantly improved reducing the burden of symptoms and improving quality of life (QoL).
Dividing the past 30 years into 3 treatment eras, we can simplistically state that the measure of success has changed over time raising the bar of patients’ and physicians’ expectations.
In the pre-ART era, up to 1996 when protease inhibitors (PI) were first available, the objective was to reduce HIV-related mortality due to opportunistic infections and cancers, and improving the immunological status of PLWH.
In the early-ART era, up to mid 2000s when second generation of PIs and Integrase Strand Transfer Inhibitors (INSTI) were introduced, the objective was to reduce the burden of drug-related toxicities and of non-infectious chronic-diseases (NICD).
In the late-ART era, which describes the contemporary period, the objective is to make life expectancy of PLWH similar to the general population. Although this goal has already been reached in several high-quality care settings, the reduction of HIV-related mortality fails to capture the gap in health status of PLWH when compared to the general population.
The contemporary HIV care framework is based on the “90–90–90 targets”  launched by the Joint United Nations Program on HIV/AIDS (UNAIDS). This public health campaign, which promises the end of AIDS, aims to achieve three ambitious goals by 2020: HIV diagnosis in 90% of all people living with HIV (PLWH), provision of antiretroviral therapy (ART) for 90% of the diagnosed individuals, and viral suppression for 90% of the treated patients.
At the global level, the accomplishment of these goals still requires much work. However, the international community should be proud that among the world’s 36.7 million PLWH, 25.5 million are diagnosed, 19.5 million receive ART, and about 82% of these are virally suppressed. It is also encouraging that the 90–90–90 goal has already been achieved in an increasing number of high and low-income countries .
In this context, it has been suggested to widen our perspective on outcomes: we must be ambitious enough to go beyond viro-immunological success secondary to extrinsic factors like effective and less toxic ART, to consider successful patient-centered outcomes based on intrinsic characteristics of the individual and their relation to the environment in which they live .
The objective of this paper is to critically discuss potential new outcomes to be used as a measure of success for PLWH both in clinical and research settings.
Public health outcomes
The evolving demographic changes occurring in people living with HIV (PLWH) are parallel to the general population and represent a paradigm of the global-aging scenario.
By 2050, the number of people over 60 years old is expected to reach 2 billion worldwide representing 22% of the population .
The most commonly used epidemiological outcome measure is life expectancy defined as ‘the average number of years an individual of a given age is expected to live if current mortality rates continue to apply’ .
Life expectancy in PLWH has been estimated by May et al., using data from the UK Collaborative HIV Cohort study, which combines patient data from over 30 HIV clinics across the UK. Although life expectancy at age 20 increased from 30.0 years.
During 1996–1999 to 45.8 years during 2006–2008, the presence of HIV infection reduced average life expectancy by 13 years compared to someone without HIV. Men had lower life expectancy than women (39.5 years compared to 50.2 years) and people who started treatment later than recommended by guidelines also had a worse prognosis .
More recent data from the Bristol Antiretroviral Therapy Cohort Collaboration (ART-CC) included 88504 patients starting antiretroviral therapy between 1996 and 2013 from 18 European and North American HIV cohorts. ART-CC reported that life expectancy continues to increase with calendar period of initiation of ART, for both men and women. Expected average age at death for Europeans aged 20 years starting ART in 2008–10, on the basis of mortality during the first 3 years of ART, was 67.6 years (95% CI 66.7–68.5) for men and 67.9 years (67.2–68.7) for women. The expected age at death of a 20-year-old patient starting ART during 2008–10, who had a CD4 count of more than 350 cells per μL 1 year after starting ART, was 78.0 years (77.7–78.3) .
The positive shift in life expectancy emphasises the need for better investigative methods to measure longevity and morbidity and to better understand changes in health status over an individual’s life course . To this end, health adjusted life expectancy (HALE), developed by Sullivan, is a method to compartmentalise states of health by characterising the number of years a person can expect to live in good and ill health, while considering age-specific mortality, morbidity, and disability .
The Dutch national observational cohort (ATHENA) which collected data from all PLWH in clinical care in the Netherlands since 1996, generated an individual-based model of PLWH receiving ART which predicted that the median age of PLWH will increase from 43.9 years in 2010 to 56.6 in 2030, and the proportion of PLWH aged more than 50 years will increase from 28% in 2010 to 73% in 2030. The most important implication of this model was to forecast age-related chronic disease (NICD). It was predicted that in 2030 84% of PLWH will have at least one NICD (up from 29% in 2010), and 28% of PLWH will have three or more NICD .
In Europe, the estimated life expectancy for women born in 2014 is 1.6 years longer than for those born in 2006; for men, it is 2.3 years longer. But the women born in 2014 can expect only 0.7 fewer years of good health, and the men zero .
Using data from the Comparative Outcomes and Service Utilization Trends (COAST) study, Hoggs et al., estimated HALE, with adjustment for potential selected comorbidities (cardiovascular, respiratory, liver, and renal diseases, and non-AIDS defining cancers) among PLWH and HIV-negative individuals selected from the Canadian population in British Columbia. This large administrative dataset consisted of electronic health records from 9310 HIV-infected and 510 313 uninfected adults over the period April 1, 1996, to Dec 31, 2012. At age 20 years, HALE was about 31 years (SD 0.16) among men living with HIV and 27 years (0.16) among women living with HIV. In the HIV-negative population, HALE was around 58 years (SD 0.02) for men and 63 years (0.02) for women. Women living with HIV, in particular, had much shorter overall life expectancies than did their HIV-negative counterparts in the general population [29.1 years (SD 0.1) vs 65.4 years (0.1)], and thus spent less time in a healthy state .
Although reproducibility of these findings is not certain in EU cohorts, these findings underline that when describing the greying of the HIV epidemic, life expectancy assessment and models should be rather be replaced or augmented by measures like HALE. This tool, a measure of health utility, better captures the complexity of contemporary clinical presentation of PLWH and underlines the need to address management of HIV as a chronic disease.
Clinical HIV outcomes have been described in European cohorts mainly in terms of NICD accumulating with advancing age into diseases clusters and complex multi-morbidity (MM) patterns . Nevertheless, the assessment of NICDs and MM alone does not reflect the complexity of aging as a health condition. Two people with the exact same comorbid conditions can have very different functional aging trajectories. These differing clinical pictures led geriatricians to conceptualise frailty and other geriatric syndromes as multifactorial health conditions that occur when the accumulated effects of impairments in multiple systems render an older person vulnerable to situational challenges .
A hallmark of aging is the increasing clinical heterogeneity of the population that ages, enhancing the discrepancy between chronological and biological age. Frailty may replace the metric of chronological age by providing a more accurate measure of an individual’s overall biological and functional status .
Both chronic inflammation and immune dysregulation play a central role in frailty as they do in HIV infection. These inter-related biological conditions may represent key gero-inducer forces that explain the high burden of frailty in middle-aged PLWH . For example, the COBRA European consortium recently attributed the difference between biological age (using an algorithm based on 10 biomarkers) and chronological age to persistent CMV, chronic HBV co-infection, CD8 T cell activation, and prior immunodeficiency when compared to general population .
In the geriatric perspective, the health care of an older adult extends beyond the traditional medical management of illness. It requires evaluation of multiple issues, including physical, cognitive, affective, social, financial, environmental, and spiritual components that influence an older adult’s health.
Comprehensive geriatric assessment (CGA) is defined as a multidisciplinary diagnostic and treatment process that identifies medical, psychosocial, and functional limitations of a frail older person to develop a coordinated plan to maximize overall health with aging [17, 18]. CGA comprises evaluation of: medical comorbidities, psychosocial disorders, specific geriatric conditions, cognitive impairment, previous or predicted high health care utilization, and consideration of change in living situation e.g., from independent living to assisted living, nursing home, or in-home caregivers .
The CGA approach has rarely been used in a structured fashion in general patients with HIV, but issues regarding multimorbidity, cognitive impairment, frailty, and disability are increasingly incorporated into the clinical assessment of older patients with HIV .
Rockwood et al., have suggested using the variables routinely collected in CGA to calculate an index of health deficit to operationalize frailty a so-called frailty index (FI). Each variable included in the FI is coded with a value of 1 when a deficit is present and 0 when it is absent. Missing values are removed from both the numerator and the denominator of the FI . The Canadian Study of Health and Ageing (CSHA) Clinical Frailty Scale  developed a tool to be used in the standard set to assess frailty. It mirrors clinical judgement, is objective  and can be used in places that do not have electronic health records.
Although the individual’s health status tends to generally worsen as he/she ages, the relationship between aging and health is extremely dynamic and does not follow a fixed time-related and/or linear trend. Therefore, the frailty index has the potentiality to capture the aging trajectory and be used to evaluate clinical interventions .
Given global aging and the weaknesses of traditional clinical paradigms, it is perhaps time to add or substitute frailty for age as a relevant outcome for HIV medicine. Its adoption as an additional criterion in the evaluation of new ARVs and strategies could be critical. It is also important to agree on reliable metrics for capturing the geroprotective effects of interventions in both research and clinical practice. The European Medicines Agency evaluated instruments for baseline characterization of clinical trial in geriatric populations. The following aspects of frailty were specifically considered: physical frailty, cognitive dysfunction, malnutrition, and multi-morbidity. In particular, the Short Physical Performance Battery (SPPB) was identified as the scale providing the overall best predictive value for the baseline characterization of physical frailty in older people enrolled in clinical trials .
In a clinical world dominated by older individuals with multi-morbidity and geriatric syndromes, the time has come to abandon disease as the primary focus of medical care. We should broaden the outcome perspective to include the assessment of health, addressing physical health, functional ability, and cognitive functioning, as well as emotional well-being and social circumstances. These should be measured to capture the individual expectation of each older person [25, 26]. Well-being and life expectations are health domains belonging to patient-reported outcome (PROs) measures. A PRO can be measured in absolute terms, such as a patient’s rating of the severity of pain, being directly reported by the patient without interpretation of the patient’s response by a clinician. It can also be measured as the patient’s health, quality of life, or functional status associated with health care or treatment .
In many circumstances PROs are the very reasons that patients seek care, and often define precisely the gap in achieving a good outcome . In the HIV setting one validated PRO instrument, the HIV-Symptom Index (HIV-SI), assesses the burden of 20 common symptoms associated with HIV treatment or disease , such as fatigue, difficulty sleeping, anxiety, diarrhoea, changes in body composition, and feeling depressed. The HIV-SI has been used widely both in clinical and research settings to assesses ARV induced toxicities.
PROs can offer the insight into symptoms experienced by patients that may be underreported by standard screening methods for adverse drug events. Therefore, in the HIV setting, PROs can be a valuable tool to find the best ART strategies for individual patients. To our knowledge, there has been only one published study which compared PROs among PLWH who were either treatment naive or virologically suppressed and randomized to receive bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) versus abacavir/dolutegravir/lamivudine (ABC/DTG/3TC) . Despite the two-drug regimen are chemically very similar they differ substantially on PROs.
Findings showed that over approximately 1 year of follow-up after initiating or switching antiretroviral treatments, B/F/TAF was associated with fewer bothersome symptoms, especially nausea and vomiting, as well as sleep difficulties, than with ABC/DTG/3TC, as measured with HIV-SI and Pittsburgh Sleep Quality Index. These results demonstrate that PROs may contribute importantly to appropriate treatment choice and clinical decision making.
The most widely considered PRO in HIV is Health Related Quality of life (HRQoL). This is a multidimensional construct concerned with the impact of health on an individual’s perception of their wellbeing and level of functioning in important areas of their life . The constitution of the World Health Organisation, adopted in 1946, states that “Health is a state of complete physical, mental and social well-being” . Reflecting this, HRQoL is often conceptualised as having physical, mental and social domains .
A systematic review of reviews identified several validated generic and HIV specific pragmatic tools for assessing HRQoL in HIV interventions and clinical care. The selection of a HRQoL measure is likely to be influenced by the context in which it is to be used. Several studies recommended the use of a health-utility measure, the EQ-5D alongside an HIV-specific measure (the MOS-HIV, PROQOL HIV, or WHOQOL BREF-HIV) to obtain HIV-specific quality of life [34, 35, 36, 37].
In a highly cited paper by Lazarus et al., it was suggested to add HRQoL as ‘fourth 90’ to the testing and treatment target, i.e., to ensure that 90% of people with viral load suppression have good health-related quality of life . This measure of success is still far from being reached. In a UK cross-sectional study comparing more than 3000 PLWH with more than 7000 members of the general population, HRQoL scores were significantly lower among PLWH, 75% of whom were virally suppressed. Scores remained significantly lower even when the analysis was restricted to virally suppressed PLWH .
Public health outcomes
In 2015, WHO attempted to combine clinical and public health outcomes for aging by defining healthy aging as the process of developing and maintaining the functional ability that enables well-being in older age . This construct derives from the relationship of two entities: “intrinsic capacity”, that is the composite of all cognitive and physical functioning of the individual, and the environment.
Assessing intrinsic capacity is both a multidisciplinary and a multidimensional process, designed to evaluate the individual’s biology on the basis of five functional domains: locomotion, cognition, psychology, vitality, and sensory . Healthy aging starts at birth with the genetic inheritance (one component of intrinsic capacity).
Personal characteristics such as sex, ethnicity, education and occupation influence the individual’s opportunities. The functional ability construct reinforces the need for a reshaped healthcare model. On this basis, HIV management should employ a patient-centred approach, in which community and health systems interact mutually.
The provision of integrated care is key for older people. The WHO guidelines on integrated care for older people (ICOPE) propose evidence-based recommendations for health care professionals to prevent, slow or reverse declines in the physical and mental capacities of older people . These recommendations require countries to place the needs and preferences of older adults at the centre and to coordinate care. The ICOPE Guidelines will allow countries to improve the health and well-being of their older populations, and to move closer to the achievement of universal health coverage with high quality care for all at all ages.
The ICOPE guidelines aim to assist health care professionals in clinical settings to detect declines in physical and mental capacity and to deliver effective interventions to prevent and delay progression of disease and disability. National guidance will also benefit from drawing on these ICOPE guidelines. The ICOPE guidelines can inform the inclusion of Healthy Ageing interventions in the basic benefits package for pursuing universal health coverage at the community level.
Services need to be oriented around the needs of older people rather than the needs of the providers themselves. Services should respond to a diversity of older people that ranges from those with high and stable levels of intrinsic capacity through those with declining capacity, to people whose capacity has deteriorated to the point of needing the care and support of others. This is the doorway to a more comprehensive assessment of the health and social care needs of older people. This assessment leads to a comprehensive care plan that integrates strategies to reverse, slow or prevent further declines in capacities, treatment of diseases and social care needs.
This implies the shift from a model exclusively based on disease management to a new paradigm of care focused on the prevention and maintenance of functional abilities that enable people to be and to do what they value in life.
A Babel of outcomes
Many of the above-mentioned outcomes appear to belong to different world views and cultural backgrounds. Most of the time they are collected by stakeholders who speak different language. Nevertheless, HALE, frailty, HRQoL, intrinsic capacity, all capture important aspects of the complexity of aging with HIV. Which are the barriers to solving this Babel of languages? Is there a possible synthesis?
One barrier is technology. To rapidly administer surveys, calculate scores, and trend results, the data should ideally be electronic . Multimodal data collection is optimal. In these context wearable biometric sensors including smartwatches and pedometers can routinely collect physical function data from the current first generation of “digital geriatric patients”. An increasing number of medical practices routinely collect PRO measures (PROMs) through their Electronic Health Record (EHR) using patient portals or WI-FI connected tablet compters. A common example is represented by fitness tracking devices able to count steps and estimate calories, collecting personalized data to help guide health behaviours and wellness . Another interesting method is Ecological Momentary Assessment (EMA), that collects PROMs in real-time by brief repeated queries. They can describe patients’ behaviour and experiences in their lived environment. EMA permits more dynamic insight into patients’ daily lives, permitting improved evaluation of contextual factors and temporal processes . Wearable biometric sensors and EMA can be integrated in an Internet of Medical Things (IoMT) platform that works with the EHR system so that results flow into the point of care in real time to be actionable.
A second barrier is operational. Even if the technology works perfectly, patients, clinic staff, and clinicians must work together to integrate health outcomes rather than simply disease measurements into care. Health assessment implies participatory reflection, and action planning. This implies an education and active engagement of patients and health care workers, and a more community-based health care approach. For example, the simple step count assessment engages patients to overcome sedentary life style and the physician to include life style into a health measurement.
To overcome operational barriers, require a change in cultural prospective.
Conceptual model 2 (Fig. 1) describes positive health features conceptualised as functional ability. These are the results of the interaction between Intrinsic Capacity and Environment, assessed using Internet of Medical Things framework.
Our group is actively involved in an ongoing multi-center prospective study, called My Smart Age with HIV (MySAwH) study. This study is designed to empower older adult living with HIV (OALWH) to achieve healthy life styles. It is based on collection of data on physical functioning and PROs through a dedicated smart phone app (MySAwH Ap) .
The aim of MySAwH is to detect health changes assessed with healthy aging exploring 5 different health domains: Locomotion, Vitality, Sensory, Cognition, Psychosocial. These domains were chosen according to WHO definition of Intrinsic Capacity to define functional abilities in elderly individuals. Variables were collected through a fitness tracking wearable device (Garmin-Vivofit) or through questionnaires provided via EMA using MySAwH App.
Thus, the key result of this study is the possibility to operationalize healthy aging into a score to be used in clinical practice. In years to come studies like this will be able to provide nomograms of health changes in OALWH. These will allow the early identification of patients who could benefit from reinforced health interventions. The vision is that healthy aging tools will be used by the epidemiologists, clinicians involved in the study, and in the future, by policy makers. But most important, they will be used by people themselves to increase awareness of individual health and promote life style interventions.
After significant improvement of health status and life expectancy in PLWH due to effective ART and reduction of mortality, drug toxicities and NICD, there is still debate about the best measures of success. The outcomes discussed in this paper intersect with one another, but still belong to different world views and are used by different stakeholders: epidemiologists, clinicians, policy makers.
In the future, new outcomes should go beyond viral undetectability, and be patient-centred. There are many benefits to borrowing from models and tools used in geriatric medicine. HIV treatment can describe aging trajectories for PLWH to accentuate comparisons to general population, and help direct individual care. There is still a need to improve tools to measure healthy aging. An integrated model of community, the patient, and healthcare providers, with all stakeholders are linked to one another, will increase the identification of both medical and social needs, and increase the possibilities for effective intervention.
There was no dedicated funding for this study.
Compliance with ethical standards
Conflict of interest
All other authors report no conflicts of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
For this type of study formal consent is not required.
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