Introduction

Worldwide approximately 38 million people live with human immunodeficiency virus (HIV) with 1.7 million new cases seen each year [1]. While life expectancy has greatly increased due to effective combination antiretroviral therapy (cART), cognitive disorders remain a significant issue for people living with HIV (PLWH) and those who care for them. HIV-associated dementia, which was seen in up to 50% of PLWH in the pre-cART era, is now rare, however, a mild to moderate profile of cognitive impairment impacting quality of life (QoL), medication adherence, and employment is widely reported [2–5].

HIV-associated Neurocognitive Disorder (HAND) is the term coined to refer to clinically significant declines in multiple domains of neuropsychological functioning that are not exclusively attributable to factors other than HIV infection. For research purposes, the gold-standard Frascati Criteria [6] is commonly used to identify HAND across three thresholds of impairment (asymptomatic Neurocognitive Impairment (ANI); mild neurocognitive Disorder (MND); and HIV-associated Dementia (HAD)). Frascati Criteria–based HAND involves testing across broad cognitive domains, with HAND identified when two or more domains are one or more standard deviations below normative scores and for MND and HAD when daily functioning is impacted. Notably, for a clinical diagnosis of HAND (based on Diagnostic and Statistical Manual of Mental Disorders (5^th ed; DSM-5) [7], impairment must be reported both objectively (e.g., decline in standard neuropsychological testing) and subjectively (e.g., complaints), whereas evidence of subjective impairment is not required for Frascati Criteria-based HAND identification. Additionally, there must be no evidence of a pre-existing cause for impairment. Prevalence rates vary depending on definitions of cognitive impairment used, with studies reporting cognitive impairment in as many as 52% of PLWH [8], which may or may not be related to HIV. Those with more stringent definitions estimate that between 14–28% of PLWH experience these issues [9]. Prevalence of cognitive impairment, however, is expected to rise as the HIV-population continues to age, whereby the impacts of aging and associated morbidities compound the cognitive vulnerabilities already seen in PLWH.

With 73% of PLWH in Europe estimated to be over 50 years of age by 2030, an emerging consensus that we need to measure broad patient-rated outcomes such as quality of life (QoL) along with discrete areas of function like cognition and mental health, has emerged. Examination of QoL allows healthcare providers a more thorough understanding of the factors impacting PLWH and facilitates the provision of optimum person-centred care [10]. QoL is commonly conceived as dynamic, subjective and multidimensional, with dimensions often including physical, psychological, social, and spiritual factors [11] relating to ‘an individuals’ perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns’ [12]. Assessment of QoL has been widely embraced in generic HIV clinical care, with the World Health Organization (WHO) endorsing QoL as an important and prominent patient-reported outcome in clinical care and intervention efficacy, along with HIV advocacy groups calling for its inclusion as an additional 90 in the 90-90-90 testing and treatment target introduced by the World Health Organization in 2016 [13]. However, PLWH with HAND have been recognised as an underserved population in healthcare [14]. To date much of the research into HAND has focused on etiology, diagnosis and treatment (e.g. improved management of clinical variables contributing to impairments) with little consideration for the experiential consequences of having two chronic, stigmatizing, and potentially debilitating conditions.

There is value in examining the literature to identify what is currently known about the relation between QoL in PLWH with HAND to provide a better overall picture of the experiences of these individuals. Mapping what is known about the QoL of those living with HIV with HAND, this review will identify the gaps in knowledge allowing the formulation of new research requirements. To the best of our knowledge, a synthesis or summary of the evidence pertaining to QoL in PLWH with HAND has not been previously conducted. Therefore, a mapping or scoping (i.e. summarising the range of evidence to report breadth and depth) of the research conducted will contribute to a better understanding of the situation. Here we describe the extent, range, and nature of the body of knowledge on QoL in PLWH with HAND for the purpose of providing a systematic, synthesised summary of the evidence. Examining the research on QoL in those PLWH with HAND will help provide a basis for mitigating negative outcomes, such as health risk and burdens for both those with HAND and their families/carers, along with interventions to advance wellbeing and QoL. With this in mind the research questions are:

1. How has QoL been investigated and measured with regard to PLWH with HAND?,
2. How do PLWH with HAND report and describe their QoL?

Methods

A scoping review was selected based on preliminary searches showing that studies examining QoL in PLWH with HAND were lacking, with the majority of studies found either not examining QoL (or any dimension associated with QoL) or not look at those PLWH with HAND. Munn et al. [15] states the utility of scoping reviews, as opposed to systematic reviews, when examining limited, disparate, or emerging evidence, and when broad as opposed to specific questions are posed. These indications allow for questions regarding types of available evidence, how the research has been conducted, key factors or characteristics of a topic, and the identification of gaps in knowledge, and as such, was considered most appropriate for this research topic. A scoping review was conducted with the assistance of an experienced librarian (A.F) using systematic search methods. Our objectives were to document the available evidence describing the methods used to measure and capture QoL experiences, along with describing how PLWH with HAND report their QoL. Our choice of review method was further informed following initial searches in Google Scholar and the database Scopus. This preliminary search showed that studies examining QoL in PLWH with HAND were lacking, with the majority of studies found either did not examine QoL (or any dimension associated with QoL) or did not look at those PLWH with HAND. The framework employed to structure and inform this review was developed by Arksey and O’Malley [16], with further guidance from later publications, including the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) (S1 Table) [17, 18]. It consists of six stages: identifying the research question; searching for relevant studies; deciding on studies for inclusion; charting the data; collating, summarizing, and reporting study findings; and consulting stakeholders [16]. Study limitations resulted in no stakeholder consultation for this review, however, all other steps were followed. So as to allow a broad map of the literature there was an agreement to include articles which describe a multi-dimensional evaluation of QoL and to extract and report associations related to QoL that were statistically significant (i.e. 95% Confidence Level).

Identifying relevant studies

We conducted a broad search of peer-reviewed literature. Searches were conducted of four electronic databases: Scopus, Web of Science, Medline and PsychInfo, to identify peer-reviewed literature, with the last searches performed on 25^th September 2020. Date limit was set at studies published from 1^st January 2003 onwards, due to this being the time with which access to cART became more widely available. Searches involved analysis of text words contained in the title and abstract, and of the index terms used to describe the article. A second search using all identified keywords and index terms was then conducted across all databases. Our search strategy was designed to be broad and sensitive enough to ensure we capture all relevant studies (Table 1) and included specifications of the context (PLWH), participant (HAND) and concept (quality of life). The context terms consisted of HIV, AIDS, HIV/AIDS, Human immunodeficiency virus. The participants term included HAND, HIV-associated neurocognitive impairment, cognitive impairment, neurocognitive impairment. The term concept consisted of quality of life, health-related quality of life, well-being, life satisfaction and functioning. In addition, reference lists of relevant studies and reviews found were also hand-searched to ensure there was comprehensive coverage of the research topic.

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Table 1. Search strategy terms.

https://doi.org/10.1371/journal.pone.0251944.t001

Table 1 presents the search strategy that was used for Scopus, which was adapted in minor ways for other databases.

Study selection

Inclusion and exclusion criteria.

Quantitative and qualitative peer-reviewed, original research papers were included, reviews, commentaries and editorials were excluded. Interventional studies were excluded, as it is possible that the mechanism with which the intervention impact QoL complicates the interpretation of the outcome and will affect the clarity of inferences drawn. Given the aim included summarising knowledge status, grey literature was not included as the findings had not been published in peer-reviewed journals. Only articles presented in English were considered for inclusion.

Context.

Studies must state that participants either were on Highly active antiretroviral therapy (HAART) or cART or had access to HAART or cART, to this end only studies dated 1^st January 2003 onwards were considered for review, as this is when the availability of HAART/cART became widespread. Prior to the advent of effective ARVs, the impacts HIV/AIDS and antiretroviral therapies had on QoL was hugely significant [19], this review seeks to consolidate QoL for those with HAND in the era of effective treatment (i.e. HAART or cART).

Participants.

Studies had to include populations over 18 years. Studies considered for inclusion must have demonstrated that the cognitive impairment seen in the sample are primarily due to HIV-associated factors (i.e. HAND) e.g. the primary reason for impairments is not a mental illness, Alzheimer’s dementia, or cardiovascular disease. For this to be evident, studies needed to demonstrate that the population selected for study has a diagnosis of HAND, which is based on the current ‘gold standard’ Frascati criteria [6]. Therefore, studies must have detailed evidence that the population sampled had i) acquired impairment in cognitive functioning, involving at least two domains, documented by performance of at least 1 standard deviation below the mean for age-education-appropriate norms on standardized neuropsychological tests, and ii) impairment decidedly due to primarily HIV-related factors, with no evidence of another pre-existing cause likely to be primarily responsible for the cognitive impairments seen.

Concept.

The key concept is QoL, including its multidimensional components. With this in mind studies examining the components of QoL will be considered for review. For the purpose of this review components included are physical health, psychological state, functionality, level of independence, social relations, environment, and spirituality/religion/personal beliefs [12]. While, functionality is not considered to comprise the QoL concept by the WHO [12], other authors argue it be a relevant and informative proxy or dimension of QoL [20, 21] (19), which has been validated in HIV populations [22]. With this in mind, studies examining functionality (e.g. activities of daily living; ADL) will be considered for review.

Search results.

The search strategy in the four different databases resulted in a total of 1005 articles being identified. These records were exported into EndNoteX8. Two articles were identified through hand-searching relevant articles reference list. The removal of duplicate records resulted in 543 records left for title and abstracts screening. The screening was performed by one author (KA), under the close guidance of the second author (JV) who was consulted where inclusion was unclear. KA and JV finally agreed to 92 records as relevant studies for full-text screening. KA and JV then independently screened full-text studies to assess eligibility for inclusion in the review. KA screened the reference lists of the included studies. Of the 92 records considered for inclusion, there was disagreement on 2 (2.2%), in which cases discussion meetings were held until an agreement was reached. Of the 92 screened full-text articles, 78 were excluded. The majority of articles were not considered to be examining HAND i.e. cognitive impairment was not distinguished from other potential causes, or participants were not assessed using a neuropsychological test battery and impairments were subjective. A number of studies did not examine QoL in any depth (i.e. a single-item QoL question was employed and no other QoL domains were examined or had ineligible study populations) or it could not be confidently concluded participants had access to effective ARV therapy. A total of 15 articles were included in the review (Fig 1).

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Fig 1. PRISMA flowchart.

https://doi.org/10.1371/journal.pone.0251944.g001

Charting the data

Information relating to QoL in PLWH with HAND were examined by two authors (KA and JV) who utilized processes from qualitative content analysis [23]. This required three phases of analysis: preparation, organization, and reporting, which was conducted using a structured data tool. KA extracted the study characteristics, which was then reviewed by JV, and any conflicts were discussed until resolution was reached. Given this was a scoping review, study quality (e.g. possible bias, sample sizes) was not evaluated [16]. Tables 2 and 3 detail the systematization and categorization of study characteristics and results included in the review, based on the research questions.

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Table 2. Study characteristics and main findings.

https://doi.org/10.1371/journal.pone.0251944.t002

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Table 3. QoL measures and dimensions.

https://doi.org/10.1371/journal.pone.0251944.t003

Results

The results of this review are reported in line with the review questions. Of the 1005 peer-reviewed abstracts, 75 were advanced for full-text review which yielded 15 articles that met inclusion criteria (Fig 1). The results section first describes the study characteristics (Table 2) and details how QoL has been assessed in this population, we then describe how PLWH with HAND report their QoL.

Eight studies were conducted in the United States [24, 31, 32, 35, 38, 40, 42, 47], three studies were conducted in Canada [45, 49, 51], two were conducted in Italy [27, 30], one study conducted in Brazil [50], and one in the United Kingdom [43]. The primary aim of the majority of studies was to examine functional deficits associated with HAND, which was assessed via ‘real-world’ functional assessments [24, 31, 32, 47] or through patient-reported outcome measures (PROMs) of functioning [24, 31, 32, 35, 40, 47], with broad QoL assessment or the assessment of a second QoL component an additional secondary aim in some studies [24, 32, 38]. Four studies examined the impact of HAND on health-related QoL (HRQoL) [27, 30, 38, 45], two studies assessed psychological state in those with HAND [50, 51], one study examined the impact of positive health behaviours on HAND [42], one study examined associations between different PROMs and HAND [43], and one study explored how HAND impacted well-being broadly [49]. In six of the studies patients were recruited from HIV outpatient clinics [32, 35, 38, 45, 50, 51], five studies recruited patients from ongoing research cohorts [24, 31, 40, 43, 47], two studies recruited from community settings [42, 49], and two studies recruited from a neurology clinic [27, 30]. Fourteen studies employed quantitative methodologies: seven studies were case-control studies [35, 38, 40, 42, 43, 47, 51] and seven has a cross-sectional design [27, 30–32, 45, 50]. One qualitative study was included, which employed interpretative qualitative methods [49].

Discussion

In chronic conditions ‘adding life to years’ is as essential as ‘adding years to life’ [55]. QoL has increasingly been recognised as a valuable patient-reported outcome which is now more routinely measured in HIV clinical care and within memory services. QoL research in these populations dictates the importance of specificity when applying QoL measurement [56, 57]: evidence from PLWH and from those with cognitive impairment finds unique dimensions influence QoL in these populations [22, 58–60]. Failure to capture and assess the relevant domains of QoL results in interventions which may lack meaning to patients along with potentially helpful interventions being undervalued, or the potential deleterious impacts of interventions being missed. This review provides an important first step in understanding how QoL is impacted for those PLWH with HAND by synthesizing what is currently known and identifying what is currently missing.

It is striking that across the literature we found only two studies focused on QoL exclusively as their main research outcome [27, 30]. These two studies found that QoL, as evaluated by the MOS-HIV, was significant worse for PLWH with HAND than PLWH without HAND, both overall and across a variety of QoL domains (all p < 0.04). An important consideration with regard to these findings is that these studies were conducted during the very early stages of effective ARV availability, with both studies reporting average time on effective ART as below 30 months. Therefore, while it can confidently be asserted that HAND impacts QoL, this finding is possibly relatively time specific, and must be applied with caution to today’s patients–who, in the vast majority of cases have been on effective ARV therapy for decades, of which the cumulative impact of considerably better health and the downstream impact on QoL, must be considerable.

Another finding across the majority of studies, is the impact HAND appears to have on psychological QoL. The quantitative findings regarding psychological QoL appear to suggest there is a significant impact of HAND on psychological QoL: three studies [27, 30, 43] employing standardised QoL instruments found a significant negative impact of HAND in PLWH vs. PLWH without HAND [27, 30] and HIV- controls [43]. However, it must be noted that the only recent study [43] (conducted in 2017 vs. 2003/4 [27, 30]), which examined this using a standardised QoL instrument found a difference between groups when HAND was categorised using the Multivariate Normative Method [61], and not when using Frascati Criteria diagnostics. The authors note that this may be explained by the considerably mild and asymptomatic participant sample used in the study, and thus finding should be generalised carefully [43]. Mental health measures conducted by studies overall found higher instances of depressive and anxious symptoms in those with HAND compared to controls [35, 40, 43, 50]. Given the robust and well evidenced relationship between psychiatric symptoms and QoL [62] this provides more tentative evidence for an important effect of HAND on psychological QoL. This is an important area for future research: it is well documented that PLWH report significantly higher levels of depression than HIV-negative controls [63], any additive impact of HAND on psychological QoL is important to understand so that psychological interventions in those with HAND can address the psychological factors most relevant to improving psychological QoL in this group.

A further key finding was the overwhelming focus on functional assessment seen in the studies included. All but one study [43] (the authors note the nature of HAND in their study was very mild, which likely effected ability to detect group differences in outcomes) found significant differences in functional ability and its impact on independent living. Areas of functioning examined by studies included instrumental ADL (Lawson & Brody IADL Scale [31, 54] or Lawson & Brody IADL Scale-modified [31, 54]), broad physical functioning ability and level of independence (Karnofsky Performance Scale [29]) and self-reported functional abilities with regard to memory, language and communication, dexterity, sensory-perceptual, and higher-level cognitive abilities (POAFI [26]). Studies show functional disability has been demonstrated consistently both within and across measures reflecting a wide array of functional skills, strongly suggesting functional deficits impacting ability to live independently are seen commonly in PLWH with HAND. Importantly, however, the functional impairments seen in those with HAND appear to be relatively mild, with impacts primarily seen on complex ADLs. Indeed, most studies did not provide contextual information pertaining the functional meaning of scores, however relatively few participants were reported to have diagnosis of HAD which is diagnosed based on severe functional impairments. Future research is needed to understand the impact poor functioning and lessening independence has on QoL broadly. This is particularly important given the relatedly mild form of HAND now most commonly seen, and given the push to enhance person-centred HIV care, which demands a holistic understanding of difficulties so that overall health is assessed along with the social, psychological, and environmental aspects of HIV and poor cognition that can lead to negative outcomes [64].

Significantly, there is the considerable lack of research in this field. Other than the impact of HAND on psychological QoL, functional ability, and impact on level of independence no other domains of QoL have been investigated in any depth, if at all. Of note, is the lack of research into the social effects of living with HAND. Indeed, there is a the wealth of literature describing increased levels of loneliness in PLWH (particularly older PLWH) [65] and in those with cognitive difficulties [66], and the downstream impact this has broad domains of QoL. The importance of social connectedness for good QoL is evidenced to be pivotal in other clinical populations [67, 68] and interventions addressing social factors such as loneliness have shown good efficacy in PLWH. It would certainly be of value to better understand the mechanisms which may be driving the poorer reported social QoL reported in this group [27, 30], so that interventions which build this skill and provide social support can be developed. Similarly, very little information was found on how one’s environment impacts QoL and no studies reported on the spiritual, religious, or existential dimensions of QOL purported to be important to overall QoL by the WHO [69]. More research is needed to identify what may serve as protective or mitigating factors on QoL, as this will be important to understand if we are seeking to improve it. It is also of interest that no studies have examined the intersectional impact, of having both HIV and HAND, two potentially stigmatised and long-term health conditions, on QoL and their joint effects on health and wellbeing. Qualitative research is particularly valuable here, and while the qualitative study included in this review [49] has shone light on some of these issues (e.g. participants reported struggling to maintain and form new friendships, how instances of enacted stigma have impacted their confidence), more qualitative studies looking at QoL directly would certainly be a beneficial first step in explicating the meaningful constituents of QoL, the relationships between different variables, and the protective factors on QoL in this group of patients.

The studies reviewed in this scoping review were predominately conducted in the USA, however studies from a range of other countries were seen. Notably, no studies were conducted in Africa, where the burden of HIV is highest, and samples were heavily weighted toward male participants, despite no there being on gender disparity in PLWH with HAND. Ethnicity of participants with HAND was infrequently reported, particularly in studies where examination of HAND was not a primary aim. The impact of demographic variables on QoL in this population is an important area of research missing from this field: in HIV clinical care, demographic variables provide important clues to guide intervention development and implementation. Interestingly, a recent meta-analysis examined the sociodemographic impacts on QoL in PLWH: finding low socioeconomic status, stigma, less education, and younger age to negatively influence QoL, and increased social support to positively influence QoL [70]. This study emphasises the importance of understanding sociodemographic influences on QoL in PLWH with HAND particularly given the intersectional and compounding issues facing these individuals. Studies were relatively evenly distributed across the time period, suggesting there has not been increased interest in the area in recent times, this is in contrast to the increasing attention QoL has been receiving in other chronic conditions, including HIV broadly [71]. One qualitative study met our inclusion criteria, all other studies examined QoL and/or domains of QoL quantitatively. Most studies did not explore QoL in PLWH with HAND as a primary aim, with comparisons between groups on QoL measures often part of a broad battery of outcome variables assessed with relative brevity. The majority of studies used established and generic instruments when examining QoL and its associated dimensions. Studies which assessed QoL broadly, used either the MOS-HIV [52], the SF-36 [39] or the EEVGGP [46]. The MOS-HIV and SF-36 can be compared with relative consistency, as both measures are based on the same concept and theoretical perspective of QoL [72]. However, neither of the two studies [38, 43] which used the SF-36, report sub-domain scores and only one study [43] reports MHS and PHS scores, making detailed conclusions challenging. Furthermore, unlike the MOS-HIV, the SF-36 does not assess cognitive functioning, which is likely an important area to assess this group of patients. We included studies which measured dimensions of QoL–most examined were function and psychological state. The use of measures for both dimensions was fairly homogenous: with the majority of studies employing either Lawson & Brody IADL Scale [54] or Lawson & Brody IADL Scale -Modified [31], Karnofsky Performance Status and Patient’s Own Assessment of Function Inventory [29], as measures of function (albeit domains of functioning varied greatly across measures (see Table 3), and the Beck Depression Inventory-II [34] and the Patient’s Health Questionnaire-9 [44], as measures of psychological state. Given the homogeneity across studies with regard to comparison groups used (i.e. HIV- and/or PLWH with HAND) comparisons between studies can broadly be drawn.

The main strength of this research is that it is the first review exploring and synthesising what is known about the impact of HAND on QoL in PLWH: taken cumulatively the findings appear to indicate a significant impact on QoL–which needs to be considered both with regard to patient clinical care and increased research attention. A second strength of this scoping review is the systematic way in which it was performed. The search was conducted with comprehensive search terms, which identified a large number of studies across four leading databases. Although the search was not exhaustive, the selected databases and the searches performed were advised by experienced academic librarians in order to generate the widest possible search for texts related to the population, concept, and context. Furthermore, we applied stringent eligibility criteria to the assessment of cognitive impairment in studies included, ensuring that the research ‘gold-standard’ Frascati criteria [6] was used to assess HAND. Limitations of this review include the paucity of studies from sub-Saharan Africa, where the burden of HIV is highest, along with a lack of examination of the sociodemographic factors impacting QoL in this population. Furthermore, important consideration must be paid to the context in which this research appears, whereby screening and diagnosing HIV-associated neurocognitive impairments remains relatively limited in clinical settings [2, 73], with no consensus on screening tools and concerns regarding the importance of routine testing [74, 75], given the majority of instances are asymptomatic and services extremely limited [76].

Conclusions

QoL in PLWH with HAND is a significantly under reported field in HIV clinical care. Few studies have examined QoL in this group of patients and in those that have the impact on function and subsequent level of independence of PLWH with HAND on QoL have been reported most frequently. Studies appear to suggest PLWH with HAND do report lower QoL overall, however more research is needed to confidently assert this. PLWH with HAND appear to experience greater levels of functional impairments, albeit mildly, which likely impact their QoL to varying extents. Psychological QoL appears to be lower in those with HAND, however whether this manifests into clinical illness is undetermined. This may represent an important target for interventions as improvements to mental health is likely lead to improved cognition, and improved QoL. More research is needed to understand the degree to which QoL is impacted by HAND, the dimensions of QoL which may be effected, and whether standard conceptualisations (or, indeed, HIV or dementia specific models) of QoL capture QoL experiences for this group, so that variables of interest can be identified and meaningful interventions developed to improve QoL in this population. QoL outcomes have received increased focus over the last two decades, and recent calls to include QoL in The WHO’s HIV/AIDS 90-90-90 target is justified based on multiple sources of evidence finding significant impacts of living with HIV on QoL [77–79]. While there is more need for research exploring QoL in those living with HAND, the emerging evidence detailed in this review along with evidence from those studies reporting poorer QoL in PLWH broadly, shows that a paradigm shift is required when thinking about those living with HIV. Clinical care needs to reflect the realities of patients’ lives and multidimensional support is required to ensure treatment effects are maximized and reflective of factors most important to patients.

Supporting information

Acknowledgments

We thank the staff at Brighton and Sussex Medical School Library for assistance with the systematic search.