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HIV & Aging Clinical Recommendations
Among those with HIV infection receiving ART (Antiretroviral Therapy), the proportion achieving viral suppression is growing, aging, and experiencing a widening spectrum of “non-AIDS” diseases. Concurrently, AIDS-defining conditions are less common (d’Arminio Monforte 2005; Greene 2013; Deeks 2009; Zhang 2015; Pacheco 2015; Masia 2013; Neuhaus 2010a). While life expectancy among those on antiretroviral therapy (ART) is near identical to that seen in the community, it is not “normal” (Siddiqi 2016). Most life expectancies for older adults with HIV are predictions. There is increasing evidence that people living with HIV (PLWH) on ART experience an excess burden of non-AIDS conditions. These aging related comorbidities are not typically associated with HIV infection, HIV treatment, and/or behaviors, conditions, and demographics that characterize PLWH (Deeks 2009; Justice 2010b; Justice 2010a; Justice 2010c; Greene 2015).
The cumulative evidence describes an older adult population living with HIV, most of whom are between the ages of 50 and 65 years, who are experiencing high rates of comorbid illnesses or multimorbidity (Greene 2013; Pacheco 2015; Levy 2017a; Wang 2016; Collaborators 2016; Balderson 2013; Armah 2012). The interaction of aging and HIV is frequently manifested by elevated risk for comorbidities associated with aging, which include liver disease (possibly hepatitis-related), cardiovascular disease, kidney impairment, cancers, osteoporosis, neurocognitive decline, and frailty (Slomka 2017; Salter 2012; Kim 2012; Akgun 2014). This multimorbidity [two or more chronic diseases] is a manifestation of the intersection of multiple chronic diseases, including HIV, all of which contributes to overlapping injury to multiple organ systems (Deeks 2009; Justice 2010a; Justice 2010b). The result is the transformation of HIV infection into a complex chronic disease associated with multimorbidity. The management of the health of older adults with HIV requires the attention and expertise of providers from multiple health care domains and disciplines (Greene 2013; Greene 2015; Siegler 2017; Singh 2017; Taddei 2016; Justice 2014; Justice 2010; Youssef 2017; Yoshimura 2017; Wing 2017).
The comorbid conditions occurring in those with HIV and on ART are often defined as “non-AIDS” conditions (Shiels 2017; Lopez 2016), but they are associated with HIV infection (HIV-associated non-AIDS, or, HANA) (Lesko 2016). These HANA conditions are common in the general aging population without HIV disease. But when they occur in association with HIV, clinicians must be aware of the contribution that HIV makes to their health and understand that the care paradigm must be different for managing multimorbidity in older PLWH. The Consensus Project, detailed in the chapters that follow, is intended to provide clinicians with the needed guidance to make informed care management decisions.
Multiple mechanisms have been hypothesized to explain the increased rates of multimorbidity in the aging HIV population. These include microbial translocation, chronic inflammation, oxidative stress, and immune senescence (Bastard 2015; Borges 2013; Crothers 2016; Falasca 2017; Margolick 2017; Fitch 2017; Longenecker 2016; Mooney 2015; Leng 2015; Maes 2011). The underlying etiology most commonly invoked is chronic inflammation (Lagathu 2017; Erlandson 2017). An inflammatory cascade occurs at initial HIV infection. Even when a patient is on ART, biomarkers of inflammation remain elevated. Yet there are significant sources of inflammation in this population which contribute to the increased risk for multimorbidity. Among PLWH these include significantly higher levels of alcohol and tobacco use (Conigliaro 2004; Cook 2013; Fuster 2014; Petoumenos 2016; Hile 2016), past and current illicit substance use including injection drug use (IDU) which is associated with hepatitis C (HCV) coinfection (Lesko 2016; Piggott 2017; Salek 2017). Add to that risk list mental health issues, especially depression and anxiety which can be exacerbated by stigma (including HIV-related stigma) and social isolation (Greene 2017a; Shippy 2005a; Tatum 2017; Tao 2017). Life stressors cause an increase in inflammation. Poor nutrition and lack of exercise are known to also contribute to increased levels of inflammation (Wirth 2017; Tang 2015; Szarc vel Szic 2015; Kamitani 2017; Simpson 2015; Oursler 2013). HIV aside, these combined risks which characterize the older adult with HIV can account for the observed high rates of multimorbidity (Karpiak 2017a).
Globally, there is increasing recognition of the growing incidence of multimorbidity in the industrialized and developing world (St Sauver 2015; Trikalinos 2014; Poblador-Plou 2014). Multimorbidity is a syndrome familiar to geriatricians and increasingly observed among older PLWH (Greene 2013; Greene 2015; Singh 2017; Greene 2017). Patients with HIV are surviving long enough to experience HIV as a chronic disease, as well as a broad spectrum of age related comorbidities.
Multimorbidity is more than simple comorbidity. It is conceptualized as several serious health conditions that cannot be cured to any great extent, occurring in an older person and engendering functional and/or cognitive debility. When considering treatment options in persons with multimorbidity, the whole is greater than the sum of its parts (Justice 2010b; Justice 2012a). Aging plus debilitating conditions have the propensity to synergize, making morbidity and mortality worse than might otherwise seem apparent. In addition, those with HIV experiencing multimorbidity (Tinetti 2012; Tinetti 2004) can also be at elevated risk for polypharmacy (five or more medications) (Smith 2017; McNicholl 2017; Kim 2017a; Krentz 2016; Greene 2014).
The Consensus Project Expert Panel, when conceptualizing optimal treatment strategies, sought to incorporate geriatric principles into the formulation of the clinical guidance. These considerations pervade each recommendation found in the chapters that comprise this Consensus Report (www.HIV-AGE.org).
Recently two editorials in high impact journals (Mohammadi 2017; Guaraldi 2017a) observed that as the number of older adults with HIV increases, clinicians and people living with HIV, need to assess what it means to have a “healthy life expectancy.” The editorials conclude that older adults with HIV can benefit from models of integrated care developed by geriatricians. Rather than focusing on disease, tested clinical geriatric principles focus on function. Diagnosing and treating comorbidities occurring in this aging HIV population is not sufficient to address the complexities of aging. Severe functional limitations and wasting are increasingly rare after ART initiation. Providers must be aware of conditions like frailty, dementia, compromised mobility, risk for falls, and polypharmacy. PLWH are becoming aware of these changes in their health status as they age. They expect their providers to exhibit similar awareness.
Besides describing the diverse etiologies that drive frailty and disability among those aging with complex chronic disease (Tinetti 2004; Walston 2006), the geriatric literature offers lessons for the management of those aging with HIV (Sangarlangkarn 2017).
First, geriatricians warn against the blind application of screening and treatment guidelines developed for use in a primary care population free of major comorbidity to those with complex chronic disease and multimorbidity (Tinetti 2004). We must prioritize and tailor care for those aging with HIV based upon a careful assessment of their risk of morbidity and mortality, and identify risks that are modifiable and align with the achievable goals of the individual patient (Tinetti 2012; Tinetti 2004; Bradley 1999).
Second, geriatricians emphasize syndromes and severity of disease over particular diagnoses (Tinetti 2004; Walston 2006; Bradley 1999; Lachs 1990; Karlamangla 2007; Cesari 2017). Geriatric syndromes are multifactorial conditions that stem from deficits in multiple areas, including clinical (organ system) as well as environmental and social deficits (Greene 2015). It may be important to consider organ systems that are at risk of dysfunction rather than to search for individual diseases. Some important diagnoses may never become symptomatic, whereas organ system failure is always associated with substantial morbidity and mortality.
Adapting geriatric care principles to the aging PLWH is being embraced (Singh 2017). This includes having the provider consider and emphasize the mental health and social vulnerability of these patients who confront the toxic impact of both HIV and aging stigmas that contribute to the patients’ increased vulnerability to disability and loss of function. Care delivery structural barriers are likely to increase as these older adults seek treatment for comorbid conditions from providers not sensitized to their needs and stigma driven fears (Herek 2012). When and how best to embrace geriatric care principles needs to be answered by research into the still unknown interactions between HIV and other comorbid illnesses and social vulnerabilities (Greene 2015; Singh 2017; Tinetti 2012; Sangarlangkarn 2017; Sangarlangkarn 2016a; Engel 2016; Chan 2017).
Overlapping geriatric syndromes such as “frailty,” “disability,” “multimorbidity,” and “polypharmacy” in PLWH requires a comprehensive approach to account for the ongoing role of HIV infection and its treatment in the aging process. Several approaches to the measurement of frailty have evolved within the geriatric literature, and these have been variably applied among those aging with HIV. The approach most often employed in the HIV literature uses wasting, slowing, and weakness which characterizes the frailty phenotype and the frailty-related phenotype (Desquilbet 2007). Another approach focuses on cumulative deficits across multiple physiologic systems (Desquilbet 2007; Desquilbet 2009; Desquilbet 2011), but it requires 30 separate measures and has been deemed less feasible for routine care. Rockwood (Rockwood 2016; Rockwood 2012; Rockwood 2015) has proposed a reduction in the number of measures from 30 to 10. Some have suggested that a single measure of function, such as grip strength or the six-minute walk test, might serve.
Whether you prefer a phenotype, accumulated deficits, or a test of strength or speed, the clinical variables most likely to indicate increased vulnerability among those aging with HIV infection are likely different from those in the overall aging population (Greene 2015). Immunodeficiency and persistent viral burden are important. Similarly, anemia, hepatitis C co-infection, and renal and liver disease are also more common and their important considerations.
A viable option to assess frailty and function is the VACS Index, a validated predictor of mortality among those with HIV (Tate 2013; Justice 2013). It discriminates risk of mortality more effectively than an index restricted to CD4 count, HIV-1 RNA and age (Restricted Index) especially among those with undetectable HIV-1 RNA and people in their fifth decade or greater of life (Tate 2013; Justice 2013). Its prediction accuracy of mortality meets or exceeds others used in clinical practices (Yourman 2012; D’Agostino 2001; Vasan 2006). It is robust among the HIV subgroups of women, people of color, and those with HCV (Tate 2013; Fischer 2010; Cohen 2015a; Marquine 2016).
Because the list of possible interventions is long, prioritization will become increasingly necessary (Boyd 2007). The VACS Index offers a comprehensive approach to estimating the burden of disease experienced by a patient with HIV infection and identifies organ systems at risk. The VACS Index uses laboratory tests routinely obtained in the course of HIV care.
The use of a more comprehensive risk index like the VACS could encourage us to consider more broadly the mechanisms that may contribute to total burden of disease among those aging with HIV infection. These include inevitable tradeoffs in chronic disease management between screening and aggressively treating every comorbid condition and the risk of injury from polypharmacy, drug-drug interactions, and cumulative toxicity (Li 2015; Justice 2008; See 2011; Perovic 2013; Parsons 2012).
Strategies of care that are likely to prevent and reverse functional compromise and frailty whenever possible include early ART, but also behavioral interventions to improve adherence, motivate decreased alcohol consumption, encourage smoking cessation, avoid obesity, and support exercise. Careful consideration of potential treatment toxicity from HIV and non-HIV medications is needed. This is especially true for those medications that may have cumulative cognitive effects like opioids, benzodiazepines, and other sedative-hypnotics (Justice 2008).
Taken together, these developments underscore the need to go beyond CD4 count, viral load, and AIDS-defining conditions to develop a more comprehensive risk index of morbidity and mortality in the older PLWH to guide clinical (Akgun 2014) care and research. The VACS Index can predict acute myocardial infarction events (Salinas 2016) as well as outcomes after admission for bacterial pneumonia including 30-day mortality, hospitalization length and readmission (Barakat 2015). The index is correlated with chronic inflammation markers, microbial translocation, and hypercoagulability (cystatin C, TNF alpha, IL-6, soluble CD14, soluble CD163, and D-dimer) (Justice 2012). In addition, the Index is associated with an immune composite score (Justice 2012; Duffau 2015).
The VACS Index appears to be a reasonable measure of frailty that is clinically feasible (Akgun 2014; Thurn 2017). It is associated with increased risk for geriatric syndromes (falls, fragility fractures [Yin 2016; Yin 2016a]) and cognitive decline (Marquine 2014), measures of function (Erlandson 2012), sarcopenia (Oursler 2011), and autonomic neuropathy. When compared with an adapted version of the frailty related phenotype, the VACS Index more accurately predicted all-cause mortality and hospitalization. The VACS Index is more attuned to the Rockwood conceptualization (Rockwood 2012; Rockwood 2015; Rockwood 2016) of frailty rather than that of Fried. Using the VACS Index as a physiologic frailty indicator is advantageous since it does not rely on administrative codes or clinical diagnoses that can be impacted by biases (Justice 2016). VACS Index Scores are impacted by smoking levels, alcohol consumption and hypertension. It is associated with dependence in one or more of the ADLs (John 2016) making it sensitive to significant changes in health and health behaviors (Nakahashi 2016).
VACS Index scores rise during negative health behaviors (alcohol and substance use) and fall when these behaviors are diminished or eliminated. It is likely that successful interventions in any of these domains would alter the VACS Index Score.
Certain data suggest that low social support translates into increased hospitalizations and overall mortality in this population (Greysen 2013). Almost 70% of older PLWH live alone, estranged from their families and friends as a function of AIDS-associated stigma (Brennan 2011). As a result, they have fragile social networks that are typically a resource of vital caregiving support (Mignone 2015; Wacharasin 2008). Their social isolation and often associated loneliness are predictors of poor health outcomes (Greene 2017a; Shippy 2005a; Greysen 2013; Webel 2014).
In addition, the co-occurrence of mental health issues and substance use is common for many PLWH (Tao 2017; Ngum 2017; Millar 2017; Willie 2016). They have high rates of depression and suicidal ideation that contributes to reduced health outcomes (Tao 2017; Millar 2017; Zuniga 2016; Quiles 2017; Fialho 2017). As they age, many use alcohol, tobacco, and/or illicit drugs, further compromising their health (Ventura 2017; Rehm 2017; Nolan 2017; Gurung 2017). This is an older population whose median age in 2015 was 58 years (CDC). They have difficulties with day-to-day tasks including housekeeping, transportation, meal preparation, employment, finances, and entitlements (Brennan 2011). The mental and social health of PLWH has been poorly managed.
This report contains many specific recommended treatment strategies for pairs of conditions, e.g., HIV and kidney disease. Some of these focus on HIV and the prevention of another disease, and some focus on the management of a patient with HIV and another condition. Cumulatively, this could result in a litany of recommendations for treatment of HIV, for the treatment of other illnesses, and for preventive treatments. But it is known that when disease-specific guidelines are applied to a patient with multiple illnesses (e.g., hypertension, diabetes, osteoporosis, COPD, osteoarthritis, and HIV) the resultant treatment regimen is complex, involves a large number of disease-specific medications, and presents a demanding dosing pattern (Deeks 2009).
The presence of multiple diseases is not uncommon in an older PLWH. The challenge is daunting when adding the management issues of HIV to an even more complicated multimorbidity treatment regimen, with the added implications of adherence as well as drug-drug, drug-disease, and disease-disease interactions (Braithwaite 2005).
Most studies in HIV have focused on adherence to antiretroviral treatment but how treatment of other conditions affects adherence to ART, and adherence to the overall treatment regimen, is not known. Research suggests that variations in adherence patterns to ART and other treatments varies depending on symptom attribution, medication concerns, and coping strategies (Batchelder 2014; Wendorf 2013).
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