Neurocognitive Impacts and Aging with HIV/AIDS: Global Trends in Management
Journal of Psychiatry Reform vol. 10 #7, July 2023
Cynthia H. Chan1, Yujin Suk2, Ana Hategan3
1 Resident Physician, Department of Family Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada. [email protected]. iD: https://orcid.org/0009-0006-6464-5598.
2 MD Candidate, PhD Candidate, Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada; Michael G DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
3 Geriatric Psychiatrist, Clinical Professor, Department of Psychiatry and Behavioural Neurosciences, Division of Geriatric Psychiatry, Michael G DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada. [email protected]. iD: https://orcid.org/0000-0003-0221-1154.
Since the beginning of the global epidemic of human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) in the 1980s, treatment options have evolved to include combined antiretroviral therapies (CART) which can suppress HIV replication to undetectable levels. These regimens have enabled people living with HIV/AIDS (PLWHA) with access to these treatments to experience longer and healthier lives, thus producing a growing aging population among PLWHA. As with all aging populations, PLWHA are at risk of various comorbidities as they age, including HIV-associated neurocognitive disorders (HAND) of varying severity including HIV-associated dementia. With the widespread use of CART as part of HIV management, there has been a reduction in the severity of HAND and the prevalence of HIV-associated dementia. Although there are benefits to CART, there are also barriers to treatment access and adherence. This narrative review discusses the current state of HAND and HIV management as it pertains to the aging population among PLWHA.
When the global epidemic of human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) began in the 1980s, it carried a devastating prognosis (1). Prior to the development of effective antiretroviral medications and regimens such as combined antiretroviral therapies (CART), HIV regularly progressed to AIDS and resulted in death through AIDS-related complications. During the pre-CART era, an estimated median time from seroconversion to AIDS and death was approximately 9 and 10 years, respectively, with median survival time following a diagnosis of AIDS of about 20 months (1). The use of CART has allowed the life expectancies of PLWHA to approach that of people without HIV/AIDS. With the increased life expectancy and decreased severity of morbidity following infection with HIV in the post-CART era, this allowed for the emergence of a growing population: the aging population of PLWHA (1).
In addition to increasing chronological age, it has been hypothesized that accelerated aging may contribute to PLWHA experiencing neurocognitive changes as compared to people without HIV/AIDS (2, 3). A recent systematic review suggests that PLWHA experience premature neurocognitive aging (defined as interaction effect of HIV status on cross-sectional neurocognitive testing) and accelerated neurocognitive aging (defined as interaction effect of HIV status on longitudinal neurocognitive test performance or incidence of neurocognitive impairment) (2). On a biochemical level, further studies have found that the brain tissue of PLWHA have an age acceleration of 7.4 years using telomere length as compared to uninfected controls, although the clinical significance of this finding remains unclear (3).
The aging population of PLWHA requires special considerations including diagnosis, prevention, and treatment of neurocognitive impairment, long-term cognitive implications of HIV treatments, and the ability to access and adhere to treatment. These topics are further explored in this article.
HIV-Associated Neurocognitive Disorders (HAND)
Updated classifications of HIV-associated neurocognitive disorders: Since 1991, the American Academy of Neurology (AAN) previously categorized patients with neurocognitive changes associated with HIV as having HIV-associated dementia (HAD) and minor cognitive motor disorder (MCMD) (4). In 2007, to better classify individuals with demonstrable but mild cognitive difficulties who were not captured by the AAN criteria and to address the changing prognosis of HIV in the CART era, the HIV Neurobehavioral Research Center at University of California San Diego developed criteria for HIV-associated neurocognitive disorders (HAND), which encompass HIV-associated asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and dementia (HAD) (5). Table 1 shows a summary of criteria for these diagnoses adapted from Antinori et al 2007 (5).
Table 1. Summary of the criteria for HIV-associated neurocognitive disorders (HAND) (adapted from Antinori et al 2007 (5)).
|HIV-associated asymptomatic neurocognitive impairment (ANI)*|
|HIV-associated mild neurocognitive disorder (MND)*|
|HIV-associated dementia (HAD)*|
± When major depressive episode and HAD co-occur, the cognitive deficits do not generally improve with treatment of depression.
*For a prior diagnosis of ANI, MND, or HAD no longer meeting criteria, the diagnosis of ANI, MND, or HAD in remission can be made, respectively.
†If there is a concurrent major depressive episode or substance use disorder, the diagnosis of ANI, MND, or HAD should be deferred until major depression has remitted or at least 1 month has elapsed following cessation of substance use.
HAND prevalence and the impact of CART: Prior to the introduction of the current mainstay HIV treatment of CART in 1996, HAD was considered a terminal illness with a median survival time of less than a year among individuals with AIDS (6). In a 2003 Australian study, the use of CART improved HAD survival time to a median of 48.2 months and decreased HAD incidence (6). These two factors caused Australia to paradoxically experience an increase in HAD prevalence between 1995 and 2000 following the introduction of CART (6). Since then, newer global studies have shown the prevalence of HAD has significantly declined (7).
In a study comparing the prevalence of HAND in the pre-CART and post-CART eras, the estimated prevalence was approximately 41% and 39%, respectively, which are both comparable to the 2020 estimate of 42.6% (95% confidence interval [95%CI] 39.7-45.5) (7, 8). While there have been no significant changes in the overall prevalence of HAND, the prevalence of HAD, the most severe HAND subtype, has decreased from 15% in the 1980s to the 2020 estimate of 5.0%. (7, 8, 9) The unchanged prevalence of HAND is maintained by an increased prevalence of ANI, the mildest subtype of HAND. The recent 2020 estimates of the prevalence of ANI, MND, and HAD are 23.5% (95%CI 20.3-26.8), 13.3% (95%CI 10.6-16.3), and 5.0% (95%CI 3.5-6.8), respectively (7).
While ANI is defined by impairment not interfering with daily functioning, ANI is a risk factor for symptomatic decline (10, 11). Studies have found that participants with ANI are at a two- to six-fold increased risk to progress to symptomatic HAND subtypes than participants found to be neuropsychologically normal at baseline, with studies demonstrating 24% of participants with ANI progressing to MND and HAD within 34 months. (10, 11, 12) Therefore, as the population of individuals with ANI grows, this creates a growing population at risk for the progression to symptomatic HAND.
Clinical presentation, screening, and diagnosis: During the early stages of HAND, patients may complain of difficulties concentrating, memory loss, and impaired executive functions (5). As HAND progresses, patients may experience psychomotor slowing, with depressive and other affective symptoms (e.g., irritability), and mild/subclinical motor signs. With HAD, patients experience dementia, which can progress to a bedridden state with mutism and incontinence. About 5-10% of patients with advanced HAND have focal and generalized seizures (13).
There is variation among guidelines to inform the best screening practices for HAND. No superior screening tool has been identified, with possible tools including the Mini Mental State Examination, HIV Dementia Scale, International HIV Dementia Scale, the cognitive functional status subscale of the Medical Outcomes Study HIV Health Survey, the grooved pegboard test, executive interview, and the total recall measure of the Hopkins Verbal Learning Test-Revised (13-22).
Different screening regimens have been proposed. The Mind Exchange Working Group published a consensus report in 2013 to suggest that PLWHA should be screened for HAND within six months of diagnosis or as soon as clinically appropriate given that the central nervous system (CNS) is an early target of HIV infection (23). They also suggested that screening be done prior to initiation of CART to establish a baseline to accurately assess future neurocognitive changes, then be repeated every 6 to 12 months in higher risk patients, and every 12 to 24 months in lower risk patients, with risk stratification made on the basis of disease factors, treatment factors, demographic factors, comorbidities including other neuropsychiatric conditions, CART regimen, and biomarkers (23). These recommendations differ from the ones set forth by the European AIDS Clinical Society (EACS), whose most recent guidelines from 2021 suggest using screening questions inquiring about cognitive functioning (e.g., “Do you experience frequent memory loss?”) only when PLWHA or individuals in their lives note cognitive problems, followed by further testing if cognitive impairment is suspected (24). While perhaps this strategy is more likely to identify patients with symptomatic HAND, it is likely less sensitive at diagnosing people with asymptomatic or mild HAND (24). However, data is limited to truly inform what the best practice is. Notably, minimum criteria for HAND are met on the basis of performance on cognitive tests alone, which may not be appropriate for populations with diverse educational and linguistic backgrounds.
To diagnose HAND, other possible etiologies for neurologic changes must be excluded (5). For example, patients should not be febrile, excessively fatigued, sedated by medications, or have an acute condition impacting physical and mental condition within four weeks of the neurocognitive changes since this may indicate an alternative diagnosis (5). There is also overlap between the symptoms of major depressive disorder (MDD) and HAND, with cognitive dysfunction secondary to MDD referred to as “pseudodementia” (13). Therefore, psychiatric examination is valuable for the diagnosis of HAND in PLWHA with concomitant depression (13).
A comprehensive neuropsychological (NP) evaluation is the standard for HAND diagnosis, but its availability may be limited by resources such as access to professionals capable of administering and interpreting validated diagnostic instruments. A presumptive diagnosis of HAND is often made based on symptom questionnaires, screening tools, functional assessments, and limited NP testing rather than comprehensive NP testing (23). Patients who may be selected for comprehensive NP testing include those who demonstrate new or worsening neurocognitive symptoms, or for whom the diagnosis of HAND is uncertain (5). Of note, in 2023, the International HIV-Cognition Working Group has suggested moving away from a quantitative neuropsychological approach towards an emphasis on clinical context (25). This group has emphasized that the assessment of people suspected of having cognitive deficits should, at a minimum, involve a clinical history (ideally with an observer account), supported by a cognitive testing (25). Where uncertainty arises, serial assessments accomplished over longer periods of time can be useful. Other studies (e.g., brain MRI), biochemical analysis (e.g., cerebrospinal fluid [CSF]), and electrophysiological studies (e.g., EEG) may aid in diagnosis when other etiologies are on the differential (13).
General principles of the treatment of HAND: Given that HAND is a consequence of HIV infection, the goal of treatment is viral suppression using CART (23). In patients with HAND with detectable levels of HIV RNA, CART should be initiated in individuals not yet on a CART regimen (23). A longitudinal study with patients initiating CART found that individual with the lowest baseline cognitive performance defined by the Global Deficit Score experienced the most significant improvements with CART (26).
In individuals already on CART, clinicians should inquire about medication adherence, as individuals may struggle with adherence for a multitude of reasons as discussed later in this article. Adherence is especially important to inquire about for those with cognitive impairment, who may struggle to remember to take their medications (23). If adherence is optimized and there are persistently detectable viral loads, CART regimens can be adapted to HIV drug resistance profiles (23). It is also possible to modify regimens to include antivirals with higher levels of CNS penetration effectiveness (CPE), which is hypothesized to improve the ability of the antiviral to target viral replication within the brain and CSF. Antivirals with higher CNS penetrations have been associated with improved cognitive functioning but a causative relationship has not been demonstrated in large scale randomized control trials. Therefore, it remains unclear the true benefit of choosing an antiviral regimen based on CPE (23, 26).
For patients already on CART with undetectable viral loads and persistent or worsening neurocognitive impairment, the Mind Exchange Working Group developed an algorithm for the treatment of HAND in patients already on CART, available in a consensus report published in 2013 (23). This algorithm suggests when to consider alternative possible diagnoses for neurocognitive changes, to adjust CART regimens (e.g., creating a less neurotoxic regimen), and to consider daily living interventions, such as cognitive stimulation (23).
Aging, Adverse Effects of Antiretroviral Therapies, and Medication Adherence
HIV-associated neurocognitive disorders and aging: A recent prevalence study suggests that there is no increased frequency of overall HAND with each advancing decade but did observe an increased frequency of HAD with each advancing decade (12). Among people diagnosed with AIDS in both the pre- and post-CART eras, individuals with HAD were significantly older than individuals without HAD (6). Taken together, though there is limited data regarding the relationship between aging and HAND, it appears that aging is associated with the development of dementia in PLWHA.
Adverse effects of antiretroviral therapies and aging: Potential harmful effects of long-term antiretroviral therapy exposure have yet to be fully elucidated as the distinction between side effects of the antiretroviral therapeutics and those stemming from low residual viremia in the aging PLWHA population remains unclear. While CART regimens have significantly improved over the last decade, leading to decreases in the most serious adverse events and increases in patient adherence, the increases in survival rates of PLWHA now highlight the comorbidities associated with HIV as a chronic disease and long-term CART exposure (27).
An estimated 45% of PLWHA are aged 50 years or older and this is expected to increase to 73% by 2030 in some projections (28). Almost half of PLWHA aged 50 years or older have at least one medical comorbidity and PLWHA have more age-associated non-communicable comorbidities than their age-matched non-infected counterparts (29, 30).
It is suspected that chronic immune system activation and inflammation may play a role in immunosenescence (e.g., changes in the immune system associated with age) and development of non-AIDS comorbidities, increasing the need for routine metabolic screenings as part of long-term HIV care (31). Studies have reported that PLWHA have an increased risk of developing CNS disorders, osteoporosis, fractures, renal and metabolic disorders, cardiovascular disease, and liver disease (27). The prevalence of certain comorbid conditions such as cardiovascular disease, diabetes mellitus, and osteoporosis increases significantly as PLWHA age (27, 32). With additional comorbid conditions, the aging PLWHA are faced with additional pill burden, increasingly complicated medication schedules, and polypharmacy that may lead to drug-drug interactions that can impact treatment efficacy and increase healthcare costs (33).
In addition to the effects of aging and increasing comorbidities complicating the utility of CART, the use of antiretroviral drugs is associated with multiple adverse effects (27). Table 2 summarizes reported adverse effects of long-term use of different HIV treatment classes in older populations (27). Long-term antiretroviral use has been correlated with CNS toxicity and may also be implicated in accelerated aging, factors which may increase the risk of developing HAND (34).
Table 2. Summary of findings for long-term toxicity of antiretroviral therapies in older PLWHA (27, 34)
|Central nervous system disorders||Long term use of efavirenz (non-nucleoside reverse transcriptase inhibitor [NNRTI]) associated with worse speed of information processing, verbal fluency, and working memory and increased risk of suicidality, vivid dreams, and hallucinations
Nevirapine (NNRTI) associated with hallucinations, vivid dreams, delusions, mood changes, and depression
HIV integrase strand transfer inhibitors (e.g., dolutegravir, raltegravir, and elvitegravir) were more often discontinued in older patients compared to younger patients for neuropsychiatric adverse effects; raltegravir associated with psychosis, nightmares, and insomnia
Zivovudine (nucleoside reverse transcriptase inhibitor [NRTI]) associated with serious psychiatric symptoms including mania, hallucinations, and psychosis
|Bone disease||Nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) are associated with declines in bone mineral density (BMD) and increased risk of fracture
Possible increased risk of osteoporotic fractures with use of tenofovir disoproxil fumarate (NRTI)
|Renal and metabolic disorders||Increased risk of diabetes mellitus (DM) with long-term CART use, with increased risk of DM with longer cumulative use of NRTIs
Increased risk of chronic kidney disease (CKD) associated with tenofovir disoproxil fumarate (NRTI), atazanavir (protease inhibitor [PI]), and lopinavir/ritonavir (fixed-dose combination of two PI)
|Cardiovascular disease||Approximately 4 times higher incidence of myocardial infarction (MI) in people with long-term PI use compared to those not treated with PI
Current abacavir (NRTI) use was associated with a 98% increase in rate of MI among PLWHA compared to those not currently on abacavir
|Liver disease||Variable evidence regarding association with antiretroviral use and liver disease
Possible increased liver-related mortality with continued use of NRTI-based CART
Didanosine (NRTI) not recommended because of known liver-related adverse effects such as liver fibrosis
Medication adherence and aging: Given the chronic nature of HIV, PLWHA requires lifelong medication adherence to ensure adequate viral suppression. With improvements to HIV treatment including more effective antiretroviral therapies, adherence levels as low as 54% have been found to be sufficient for achieving viral suppression (35, 36). However, some people still struggle with medication adherence for a variety of reasons (37).
Patient-related barriers to adherence specifically pertinent to older individuals include cognitive impairment, comorbidities including possible alcohol and other substance use disorders, treatment fatigue, limited understanding of their disease and health literacy, and financial barrier (33, 37). Other social and structural factors possibly impacting adherence in older patients include poor patient-prescriber relationship, social stigma against disclosing HIV diagnosis and/or engaging in treatment, difficulty accessing and retaining HIV/AIDS care (e.g., limited access to health professionals), limited access to the medication, and limited social support (37, 38). Drug-related barriers may also include adverse effects, the number of drugs being taken, and the complexity of administration regimens (33, 37).
Studies have found that older PLWHA are as likely or more likely to be adherent to CART despite possibly having greater barriers to adherence as compared to younger PLWHA (33). However, CART adherence has also been found to be inversely correlated with cognitive impairment which is more prevalent among older PLWHA (39). The published data is difficult to interpret given the limited number of available studies and the heterogeneity of the studies. It has been concluded that the current lack of understanding of what are true significant barriers to medication adherence makes it difficult to effectively implement interventions to address these barriers (37).
Special considerations for aging PLWHA in sub-Saharan Africa: By the early 1990s, the HIV epidemic had developed in sub-Saharan Africa (SSA), a region which currently has the highest prevalence of HIV/AIDS in the world (40). Following the development of antiretrovirals, international initiatives in SSA initially prioritized women of childbearing years and children through using a single dose of nevirapine to reduce vertical mother-to-child transmission in pregnant individuals (40, 41). A single dose of nevirapine reduced risk of vertical transmission by half, thus presenting a cost-effective and convenient method of reducing HIV prevalence in contrast to chronic CART regimens aimed at lifelong viral suppression (40, 41). While an effective strategy at reducing HIV prevalence, this unfortunately meant that older PLWHA were not prioritized in the initial HIV response in SSA (41).
As previously emphasized, the aging PLWHA population continues to grow. In SSA, an estimated 1 in 7 PLWHA was aged 50 or older in 2011 (approximately 3.1 million people), with this number expected to rise to 1 in 4 by 2040 (approximately 9.1 million people) (42). Over time, the accessibility of CART in SSA has also continued to grow through global health initiatives, with an estimated increase from 100,000 people in 2002 to 10.7 million people in 2014, making up 41% of all PLWHA in the sub-Saharan region (40).
It is expected that PLWHA in SSA may experience the same barriers to CART adherence as discussed earlier in this article. In addition, further studies in the SSA region have highlighted additional barriers interfering with adherence, including pharmacy stockouts, transportation difficulties, and patient or region-specific reasons (43). In a Uganda based study, patients cited reasons for discontinuing treatment which included development of tuberculosis, lack of belief in the treatment, development of debilitating peripheral neuropathy, and financial difficulty obtaining the medications (44).
The intersection of aging, HIV, and cultural and region-specific nuances of SSA has had limited research, specifically regarding HAND and CART availability and adherence, thus highlighting yet another aspect of HIV management which would benefit from further studies (38).
The care of PLWHA has progressed significantly since the emergence of HIV/AIDs in the 1980s. PLWHA are living longer, and the prevalence of HIV-associated dementia has significantly decreased with the introduction of CART. However, while CART has proven to be an effective treatment regimen, medication adherence can be difficult for a variety of reasons touched upon in this article.
This review identified that data is still limited regarding the care of the aging population among PLWHA. Specific areas which may benefit from further research include HAND screening practices, altering CART regimens based on CPE, long-term effects of CART, the significance of the barriers to CART adherence and how to address them as PLWHA age. Research is also limited in the context of aging PLWHA in SSA. Further research into evidence-based practices and a deeper understanding of the patients’ perspectives will allow clinicians to assist the aging population among PLWHA to have more meaningful outcomes.
Disclosure Statement: The authors declare no direct conflicts of interest concerning the subject matter of this article.
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