The OATH Syndemic: Opioids and other substances, Aging, Alcohol, Tobacco, and HIV

Abstract

Purpose of review.

Persons living with HIV (PLWH) are aging, continue to use alcohol and other substances, and experience age-associated adverse effects. We explore a new syndemic: OATH (Opioids and other substances, Aging, Alcohol, Tobacco, and HIV).

Recent findings.

Frailty and falls are important problems that affect the health status of PLWH who continue to use alcohol and other substances. HIV, alcohol and other substance use, and aging each contribute to inflammaging. Multimorbidity and polypharmacy are also important pathways as alcohol and other substances interact with prescribed medications resulting in adverse drug interactions leading to potentially serious consequences. Social conditions including racism, poverty, sex bias, stress and stigma contribute to the existence and persistence of this syndemic.

Summary.

Substance use, HIV, and aging are linked in a new syndemic (OATH) that drives age-related outcomes such as frailty and falls. We need to expand our understanding of the “healthcare team” so that we include social and political advocates who can support necessary structural change. Treatment of substance use should be better incorporated into the management of HIV, including a focus on potential medication/substance interactions. Finally, we need to explore treatment of frailty rather than of individual manifestations of frailty (e.g. atherosclerosis, neurodegeneration).

Introduction

Singer defined a syndemic as:

… a set of 1) closely intertwined and mutual enhancing health problems that significantly affect the overall 2)health status of a population within the 3)context of a perpetuating configuration of noxious social conditions (1)

Many previously described syndemics include HIV and substance use (1–5). Singer and colleagues (2) characterized the interactions among substance abuse (primarily intravenous drug use), violence, and AIDS (2, 3). Perelman described a relationship among opioids, overdose, HIV and hepatitis C virus infection (HCV) (4). McKee and colleagues described linkages among substance use -- particularly intravenous drug use – HIV, HCV, and hepatitis B virus infection (5). While alcohol has been less emphasized in this context, it is likely equally important (6).

Substance use, including alcohol use, plays many enabling roles in the natural history of HIV. Alcohol and other substances alter judgment leading to risky sexual practices (7). Injection drug use (including opioids and other substances) is a major route of HIV transmission. Upon receiving a diagnosis of HIV, some individuals – at least temporarily – increase alcohol and substance use (2). Alcohol and other substance use interfere with care engagement causing gaps at each stage of the care continuum and leading to delays in treatment, prolonged periods of detectable viral titers, and increased HIV transmission (8). Structural conditions that exacerbate these harms include poverty, un- or under-employment, homelessness, racism, and inequality.

However, PLWH are aging and, along with their uninfected contemporaries, continue to use alcohol and other substances and experience age associated adverse effects. In 2020, more than 70% of PLWH in the US will be 50+ years of age (9) and rates of alcohol, tobacco, non-medical use of controlled medications, and illicit drug use are higher among Baby Boomers (those born 1946–1964) than they have been in previous generations (10). Rates of alcohol and substance use are even higher among those aging with HIV (11). Importantly, alcohol is the most commonly used and abused substance in the U.S, particularly among older adults (12). In addition, accentuated aging has been observed among PLWH and among those who use alcohol and other substances (13, 14). In both groups, conditions associated with aging often occur in middle-age (45–65 years). Substance use and aging both increase the risk of conditions that drive functional impairment and decreased health-related quality of life, including frailty (15, 16) and falls (17).

While syndemics which include alcohol, substance use and HIV are well-established, aging substantially changes the character of these interactions and their health outcomes. Herein, we describe a new syndemic that includes Opioids and other substances, Aging, Alcohol, Tobacco, and HIV (OATH). In consideration of Singer’s definition, we describe the resulting: 1) intertwined and mutually enhancing health problems 2) health status, e.g. health outcomes, and 3) perpetuating noxious social conditions.

Text of review

Intertwined, mutually enhancing health problems

Inflamm-aging and Immune Senescence

HIV, alcohol and other substance use, and aging each contribute to “inflammaging” --immune dysfunction, inflammation, hypercoagulability and immune senescence. Alcohol and HIV cause microbial translocation and result in chronic inflammation (18). Treatment toxicities – both HIV-specific and non-HIV related – particularly in the context of substance use – also drive the decline and loss of redundancy in organ systems.

HIV-associated immune dysfunction has been described in detail elsewhere, as has the immunosenescence that occurs with aging and HIV (19–21). What has been less thoroughly addressed is the association between alcohol and substance use and accentuated aging (22). Bachi and colleagues suggest that this expedited aging process is related to multi-system toxicity driven by pathophysiological processes that include oxidative stress, and inflammation (14). Cocaine dependence is associated with increased inflammation both at baseline and in response to stressful triggers (23). This response includes higher levels of pro-inflammatory cytokines such as TNF-α and IL-6 as well as lower levels of anti-inflammatory cytokines. Cocaine use has also been associated with alterations in lymphocyte subsets (e.g. decreased percentages of naïve T cells) and oxidative damage (24). Amphetamine use has been linked to increased levels of oxidative stress and inflammation (25). It also negatively impacts T cell function including proliferation, cytokine production and T cell-mediated immune response (26). Opioids have been associated with immune system impairment and suppression, including altered function of macrophages, natural killer cells, and T-cells, and a weakening of the gut-associated immune barrier (27). Alcohol consumption also has profound effects on the immune system. The impact of alcohol on the immune system looks very much like the decline in immune function that occurs as a result of aging, suggesting potentially synergistic effects (28). Alcohol contributes to microbial translocation (18). Tobacco also negatively affects both the innate and adaptive immune systems. Cigarette smoke increases production of pro-inflammatory cytokines (TNF-α, IL-1, IL-6, IL-8) and decreases anti-inflammatory cytokines (IL-10) (29). It is also associated with increased oxidative stress, and immune-suppressive effects such as reduced T- and B-cell activity (29). The association between marijuana, inflammation and immune cell function seems less clear. Some suggest that marijuana has a negative impact on the immune system. It may suppress the functional activities of B lymphocytes, T lymphocytes, macrophages, and NK cells (30). It may also be associated with elevated serum levels of TNFα and IL-6 (31). However, others suggest that marijuana has, primarily, an anti-inflammatory impact (32).

Multi-morbidity and Polypharmacy

Alcohol and other substance use, HIV and aging are also associated with multimorbidity (33–35) and polypharmacy (36–39). Polypharmacy is of particular concern among PLWH as they develop it at least 10 years before uninfected comparators (39). Research suggests that even modest levels of alcohol use are more harmful among PLWH than among uninfected comparators (40).

Adverse drug interactions (41) are driven by pharmacokinetic interactions that occur during the absorption, distribution, metabolism and excretion of medications and drugs as both are metabolized through common enzyme system and transporter pathways (41). Coadministration changes the expression and/or activity of these pathways, leading to potentially serious interactions. For example, cocaine is metabolized by human carboxylesterase 1 (hCE1) in the liver, by hCE2 in the intestines, serum butyryl cholinesterase (BChE) and cytochrome (CYP) 3A4. Medications that share these metabolic pathways include SSRIs, antibiotics, and antihypertensives. Co-administration of cocaine and SSRIs has resulted in serotonin syndrome (42). Alcohol impacts the pharmacokinetics of clinical medications by altering gastric emptying and inducing CYP 2E1. Clinical medications enhance the effect of alcohol through altering the rate of gastric emptying and by inhibiting gastric alcohol dehydrogenase (43). These interactions can enhance the negative impact of alcohol or medications on the individual. Among PLWH, as shown by Justice and colleagues, this can be particularly harmful as lower levels of alcohol result in negative outcomes than in uninfected comparators (6). Co-administration of CNS active medications and drugs may also enhance sedation and impair cognitive function, increasing falls. The more medications that a patient takes, the greater the risk of adverse interactions.

Alcohol and other substances, HIV, and aging are associated with declines in liver (44–46) and renal function (47–49) which in turn impact drug metabolism and reduce the rate at which alcohol and others substances are cleared. Increased duration of action enhances the opportunity for adverse drug interactions (6).

Health problems that affect health status: Frailty and falls

Depletion of organ system reserve, when sufficiently advanced, becomes frailty. Frailty is the biological vulnerability to stressors and decreased physiological reserves that leaves the body with a limited capacity to maintain homeostasis, exposing individuals to a higher risk of negative outcomes (50). Frailty, in turn, drives falls (51). While the exact mechanisms linking HIV, alcohol and other substance use, and aging to frailty and falls have yet to be specified, they likely include burden of comorbid disease, polypharmacy, and chronic inflammation and hypercoagulability, and oxidative stress (Figure 1) (18, 19, 52).

Figure 1.

OATH, frailty and falls

Modified from Justice AC. HIV and aging: time for a new paradigm. Current HIV/AIDS reports. 2010;7(2):69–76.

PLWH have higher rates of frailty and falls than uninfected comparators (15, 53). Frailty in this population has been linked to substance use, particularly methamphetamines (54), and alcohol (55). In our preliminary work using data from the Veterans Aging Cohort Study (VACS), we found that the unadjusted incidence of serious falls (falls that occur in the community and are serious enough to merit evaluation by a healthcare provider) is higher among PLWH than among uninfected comparators in those 50+ years of age (Figure 2). Subsequent work demonstrated that HIV-specific variables did not drive this association, rather the count of non-ART medications (per 5 medications) (OR 1.20, 95% CI: 1.17 to 1.23), illicit substance use/abuse (OR 1.44; 95% CI: 1.34 to 1.55), hazardous alcohol use (OR 1.30; 95% CI: 1.23 to 1.37), and an opioid prescription (OR 1.35; 95% CI: 1.29 to 1.41) were key risk factors for both PLWH and uninfected comparators.(17) Frailty has also been identified as a driver of falls in this population (56).

Figure 2.

Unadjusted Incidence of Serious Falls by HIV status and age

Generally, antiretroviral therapy (ART) is protective,(57) but some regimens have been associated with frailty and falls. Erlandson and colleagues found a link between frailty and use of efavirenz (58). Use of an protease inhibitor- as compared with an integrase inhibitor (INSTI)- based regimen was associated with increased frailty.(15) The same is true for ART use and falls: some identified a link between specific ART use and falls (58, 59), others found that ART use decreased falls, and no specific medication nor class was associated with falls (17).

…[P]erpetuating noxious social conditions

The social context that drives HIV and substance use, particularly in the inner city, has been described (2, 60). Less well-described in the context of HIV are the associations between aging and these structural factors. In this discussion, wherever possible, we use HIV-specific literature.

Race

Black race has been associated with accelerated aging: Blacks experience death and disease at earlier ages than Whites.(61) The physiological deterioration that accompanies aging is likely related to environmental factors encountered by racial minorities throughout their lives (62) including lower socioeconomic status (SES) (61), poor neighborhoods(63) unavailability of quality healthcare (64), and psychological stress (65). Blacks have less economic security, live in worse neighborhoods, and experience more discrimination than Whites. For example, research suggests that Blacks drink less than Whites but are more likely to have a diagnosis of alcohol use/abuse (66). Poorer neighborhoods can mean limited access to healthy foods, poor air quality, and poor access to recreational activities (67). May of these experiences directly impact health and well-being, but they also lead to higher levels of physical and psychological stress (68). Stress can negatively impact individuals at the tissue and cellular levels (68), resulting in damage to DNA and proteins that may influence the wear and tear on the body over time, resulting in accelerated aging (69).

Poverty

Independent of race, poverty has a negative impact on aging. Health in older age is the result of a lifetime of poverty differentials (70). People who live within 125% of the federal poverty level appear to age and die sooner than those with higher incomes. Even when including age, female sex, race, smoking, heavy drinking, no exercise, and BMI in the model, poverty remained independently associated with death and earlier biological decline.

Frailty, an age-related condition, has been associated with poverty among PLWH. Non-AIDS chronic comorbidities increase with age but are more prevalent among women, non-Hispanic Blacks, and those who are publicly insured (71). Erlandson and colleagues also found that PLWH on Medicare or Medicaid were more likely to be pre-frail or frail than those with private insurance (15).

Outside of the context of HIV, lower income and life course violence are linked with frailty (72, 73). Social/economic factors associated with frailty include being female, living in rural areas, low education, insufficient current income, black race, and poor economic status in childhood (74–77). Szanton and colleagues (75) report a strong association between socioeconomic status and frailty among older women in the general population. This association persists regardless of how SES is measured and when controlling for potential confounders (age, race, chronic disease, insurance, and smoking status).

SES has been linked to inflammation, decreased physical activity, decreased serotonin, and altered biological risk profiles. SES may also be linked to frailty through poor nutrition as those of low SES do not have easy access to micronutrients associated with a lower risk of frailty that come from healthy foods (75). Stolz and colleagues found a consistent, negative association between poverty and physical health, function, and frailty in older adults driven by psychosocial factors such as high levels of social isolation, a lack of well-being, and low levels of perceived control (78). It is also likely linked to behavioral factors such as physical activity, smoking, and alcohol use, all of which are more common among those living in poverty (69, 70).

Gender

It is well-established in the general population that while cisgender women live longer than cisgender men, they experience more morbidity late in life (79). This does not seem to be the case among PLWH. Life expectancy among women living with HIV is shorter than that of men (80). Preliminary research from our group suggests that in the Veterans Aging Cohort Study (VACS), women living with HIV have a mean age at death of 54 (relative to 58 among uninfected women), while the mean age at death for men living with HIV is 60 (relative to 63 among uninfected men).

Gender has not been addressed in many studies on frailty among PLWH, however Piggott and colleagues in the ALIVE Cohort found that in fully adjusted models, women were more likely to be frail than men (81). This is consistent with much of the literature on frailty in older adults.(82) There is, however, research to suggest that women living with HIV are far more likely to experience falls than men (17, 59, 83). One of the reasons that women living with HIV may be more likely to experience frailty and falls than men may be related to alcohol and other substance use in the context of polypharmacy and the elevated rates of adverse drug reactions that are known to occur in women relative to men (84).

Stress

A growing literature suggests that inflammation is one mechanism by which stress can negatively affect aging and age-related conditions (85). There are biological pathways such as increased norepinephrine release as a result of stress which activate gene expression of multiple inflammatory mediators (86). This process involves induction of inflammatory responses and downregulation of ani-inflammatory responses (87). Some conditions such as depression – common among PLWH -- or early life adversity can enhance pro-inflammatory cytokine release in response to stressors or pathogens (88, 89).

Stigma

Aging is stigmatized in industrialized countries and likely enhances the negative impact of HIV-related stigma on the health and well-being of individuals aging with HIV. Our prior research suggests that PLWH are exposed to stigma from a number of different sources including HIV, substance use, and aging (90). This often results in social isolation which has been linked to morbidity and mortality (91). An increasing number of PLWH are living alone and are therefore more likely to experience social isolation and its negative health consequences (92).

Conclusion

Substance use and HIV have long been linked. As the HIV epidemic evolves, the associations between it and substance use evolved. Substance use, HIV, and aging are linked in a new syndemic (OATH) that drives age-related outcomes such as frailty and falls. These components interact biologically through common pathways that include inflammation and immune dysregulation. They also share associations with multimorbidity and polypharmacy. These lead to depletion in organ system reserve which, when advanced enough, lead to frailty and falls. In addition to biological factors, structural conditions such as poverty, racism, un- or under-employment, discrimination, and stigma support and enhance this syndemic.

The syndemic lens highlights the role that social conditions play in the associations among these factors, making that point that while healthcare-specific modifications can help address these negative interactions, we also need to consider and intervene on key structural variables. Our understanding of who constitutes the “healthcare team” needs to expand. In the current healthcare system, most clinicians cannot provide comprehensive care to their patients and actively spearhead social change outside of the clinic. Science is political,(93) and scientists need to collaborate with those whose job it is to move social change forward in the context of government and non-governmental organizations.

The treatment of substance use must become more integrated into the management of HIV. It is not enough to be concerned about prescription medications. Providers, pharmacists, and patients need to engage in conversations about substance use in the context of the medications that they are taking in order to prevent dangerous interactions.

Given the importance of polypharmacy and its interactions with alcohol and other substance use, we need to develop better tools for addressing it, particularly in middle-aged populations. Equally, research needs to explore the possibility of treating age-related conditions based on the underlying shared pathophysiology. Rather than treating atherosclerosis, neurodegeneration, cancer, and diabetes separately, we need to learn how to treat frailty. (Figure 3). This approach is not as remote as one might think. Drugs often affect more than one disease or condition. For example, metformin has been shown to be a safe and effective antihyperglycemic agent. In addition, it also improves cardiovascular health,(94) fatty liver disease,(95) reduces the prevalence of certain cancers,(96) and improves thyroid function.(97) Lifestyle choices such as reducing smoking and obesity reduce the risk of most age-related conditions, and a good cardiovascular risk profile reduces the overall mortality risk from any disease.(98) Furthermore, recent research suggests that the same signaling pathways (e.g. mitochondrial function, DNA damage response and telomeres, inflammation) are involved in conditions related to old age. Treating these underlying pathways will reduce the number of medications prescribed to patients, thus reducing polypharmacy.

Figure 3.

Treatment of individual conditions versus treatment of frailty

Modified from Current Biology 22, R741–52, September 11, 2012

The syndemic perspective suggests multiple interventions including broader healthcare teams, identification of common pathways for treating frailty-related conditions, and treatment, as well as better incorporating substance use assessment and treatment into routine clinical practice.

Key points:

• Substance use, HIV, and aging are linked in a new syndemic (OATH) that drives age-related outcomes such as frailty and falls.

• Inflammaging, multimorbidity, and polypharmacy are important drivers of this new syndemic.

• The syndemic perspective suggests multiple interventions including broader healthcare teams, identification of common pathways for treating frailty-related conditions, and treatment, as well as better incorporating substance use assessment and treatment into routine clinical practice.