Syndemic conditions and quality of life in the PISCIS Cohort of people living with HIV in Catalonia and the Balearic Islands: a cross sectional study

Background People living with HIV (PLWH) face structural and psychosocial factors that affect health-related quality of life (HRQoL). We aimed to evaluate how syndemic conditions affected HRQoL in PLWH. Methods A cross-sectional survey was conducted among 861 PLWH, to determine whether syndemic conditions (monthly income; sexual satisfaction; depressive symptoms; social role satisfaction; social isolation; cognitive function; nicotine dependence; perception of stigma) have an effect on HRQoL. A linear regression model and measures of Additive Interaction (AI) were used to determine the effects of syndemic conditions on HRQoL, controlling for other risk factors. Results Overall, the most frequently observed were stigma perception (56.9%), poor cognitive function (50.6%) and the perception of social isolation (51.6%). The presence of depressive symptoms was the risk factor most associated with worse Physical Health (PH) (B 3.93, 2.71–5.15) and Mental Health (MH) (B 5.08, 3.81–6.34) in linear regression model. Specifically, an interaction was observed between poor cognitive function and poor satisfaction with social role on worse PH and MH (AI 2.08, 0.14–4.02; AI 2.69, 0.15–5.22, respectively); and low income and perception of stigma (AI 2.98, 0.26–5.71), low income and perception of social isolation (AI 2.79, 0.27–5.32), and low income and poor satisfaction with social role (AI 3.45, 0.99–5.91) on MH. Conclusion These findings provide evidence that syndemic factors impact HRQoL. HIV prevention programs should screen and address co-occurring health problems to improve patient-centered health care and outcomes.


Introduction
HIV continues to be a global public health problem with between 1.5 and 1.8 million new HIV infections occurring each year [1]. Recent data indicates that there are 37.7 million (30.2 million-45.1 million) PLWH worldwide [1], 151,387 in Spain [2] and 33,736 in Catalonia [3]. Combined antiretroviral therapy (cART) has changed HIV infection from a terminal illness to a chronic condition in countries where treatment is widely available [4,5]. With the increasing availability of cART, PLWH enjoy almost the same life expectancy as the general population if the infection is diagnosed in an early stage and cART is prescribed right after diagnosis [6]. However, HRQoL can be adversely affected by a range of determinants such as cART side effects, chronicity of therapy, the ageing process, chronic inflammation and disease progression [7,8], amongst others, these affect various life domains including the physical, mental, emotional, and social well-being domains. Consequently, improving and ensuring a good HRQoL among PLWH is increasingly important [9].
HRQoL is a multidisciplinary and multidimensional term that considers that an individual has their own perception of well-being, satisfaction and level of functioning [10,11]. According to Urzúa et al., HRQoL is defined as the "level of well-being derived from the perception that a person has of various domains of her/his life, considering the impact that her/his state of health has on them" [12]. HRQoL is highly subjective, dynamic and unique to each individual [10], so ensuring standardized measurement of it is especially important to align HRQoL research priorities with the needs and values of patients, especially those with chronic illnesses such as HIV [11,13].
Several previous studies have assessed the HRQoL of PLWH in different countries, which vary in terms of the associated factors and the dimensions of HRQoL evaluated [4,7,[14][15][16][17][18][19][20]. Having symptoms of HIV, poor mental health, stigma, isolation and low social role were consistently reported to have adverse effects on HRQoL [14,17]. For example, in a study conducted in Sweden, depression, self-stigma and social stigma were associated with lower HRQoL [18]. Moreover, it is known that the fear of discrimination, social stigma and low social support resulting in mental conflicts, isolation, depression and substance use [15,19]. Similarly, another study carried out on PLWH in Uganda, all respondents identified low income as the main cause of worry and anxiety [4]. It has also been described that having a low income, has been associated with a lower satisfaction with sexual life, isolation, experiencing a fear of HIV transmission and not reporting a good HRQoL [21]. However, reports about the association of age, gender and antiretroviral therapy (ART) with HRQoL are inconsistent [7,[15][16][17]20], probably, due to the discrepancies in the research methodologies used in those studies.
The syndemics theory posits that the co-occurrence and synergistic interaction of multiple adverse conditions or diseases within a population produce worse health outcomes than if each of the conditions was experienced separately [22,23]. These problems can be biological, psychological, cultural, and environmental within the biopsychosocial concept of health [23] and are most likely to emerge under conditions of health inequality caused by poverty, low income, stigmatization, stress, or structural violence [22]. Singer's first findings indicated a combination of health issues (substance abuse, violence, and HIV/AIDS) and suggested that specific social factors such as poverty, discrimination, and exclusion from society were responsible for creating the environment in which these interactions took place [24]. In the United States a study among black HIV-positive individuals, which examined syndemic factors such as substance abuse, binge drinking, intimate partner violence, poor mental health, and risky sexual behavior, found that grouped syndemic conditions produced an effect that proportionally increased the risk of having an unsuppressed viral load, whereas when they were analyzed separately the risk was lower [25]. In line with these results, a study conducted among PLWH in Hong Kong, showed that those people who experienced co-occurring syndemic factors (stigma, social isolation and poor mental health) were more likely to engage in sexual risky behaviors, such as inconsistent condom use, compared to those who did not report syndemic conditions [26]. These psychosocial problems frequently occur in vulnerable populations, interact with each other, and the disease burden attributable to joint psychosocial problems exceeds the sum of the disease burden of these problems in isolation increasing the risk of poor clinical and health outcomes [27].
Although the existing evidence shows that the syndemic concurrent factors have a negative impact on the health of PLWH, very few studies have directly analyzed syndemic models to assess HRQoL among PLWH and most have used the cumulative approach to explain worse outcomes. Therefore, we propose that a psychosocial syndemic is an underlying mediator mechanism that negatively affects HRQoL of PLWH and clarifying the type of interaction has significant implications for intervention design. Consequently, this study is aimed at estimating the prevalence of syndemic conditions among PLWH and to describe the interaction pathways of these syndemic conditions on HRQoL.

Design and study population
Vive + is a cross sectional study conducted from October 2019 to March 2020 and nested in the PISCIS cohort, which is explained elsewhere [28]. Briefly, the PISCIS Cohort is a population-based cohort of PLWH from Catalonia and the Balearic Island (Spain) created in 1998 as a longitudinal, systematic, prospective, and multicenter study that provides population-based clinical, demographic and epidemiological data on patients with HIV infection. The Vive + study included PLWH ≥ 18 years of age who signed the informed consent and who attended one of the units of the PISCIS cohort. Exclusion criteria were unable speak Spanish, unable to complete the questionnaire by themselves due to a mental disability or failure to agree to sign the consent form.
The sample size was calculated from the population under follow-up in PISCIS in 2017 (n = 14,190), for a maximum error of 5% and a significance level of 95% and taking into account an expected prevalence of depression and anxiety of 30% [29,30], the total sample calculated was of 1,150 PLWH, assigned proportionally, according to the population on follow-up in each hospital. Women and people over 60 years of age were oversampled.
The study was approved by the Ethics Committee of the Germans Trias i Pujol Hospital (Nº PI-19-172) and by the ethics committee in each hospital where the recruitment was performed.

Study procedures
Patients were invited to participate in the study at the PISCIS HIV units during a regular HIV visit by a trained peer. After signing the informed consent, those individuals who agreed to participate were provided with a piloted and adapted self-administered questionnaire in a portable electronic device (Tablet), which lasted approximately 40 min. The participants did not receive any financial incentives, as it was an opportunistic study, which did not receive external funding.
The data was stored in a central database located in the study coordinating center, following access management policies and the current data protection law [31], as well as the biomedical research law 14/2007 [32]. Patient information was anonymized and deidentified before the analysis.
Data from Vive + and from PISCIS were linked by a unique anonymized identifier assigned to each participant, which allowed researchers to extract HIV health related data (such as CD4 cell count and viral load).

Questionnaire
The Vive + questionnaire collected information related to i). Sociodemographic and economic characteristics: gender (man, woman and transgender [given the small sample trans women and trans men are combined in this category]), age (< 39 years old; between 40 and 59 years old; > 60 years old), country of birth (Spain; outside Spain, educational level (≤ primary, or > primary [secondary, vocational training and/or university studies]), employment status (unpaid job: unemployed, student, housework; paid job: part-time or full-time employee, self-employed, retired, sick leave), monthly income (< 1000€; ≥ 1001€); ii) Psychosocial-sexual health characteristics: steady partner (person with whom they feel committed to above anyone else, includes partner, boyfriend or girlfriend, wife or husband), caring for others (responsibility to care for minors, adults or dependent elderly), perception of stigma and sexual satisfaction; ii). Lifestyle-related: nicotine dependence (Fageström test); polydrug use (used two or more illegal drugs in the last 12 months) for recreational purposes (Poppers  [33]) and viral load (detectable ≧ 50 copies/mL; undetectable < 50 copies/mL [34]).
HRQoL was measured through the 12-Item Short Form Health Survey v1 (SF-12v1), a freely distributed questionnaire [35], which consists of 12 items in 8 domains, with Likert-type response options that allow the generation of PH and MH summary scores, which are the two dimensions measure by the (SF-12v1) [36]. Each item has three to five options and the global score range from 0 to 100 points. The calculation of the scores is based on the Bidimensional Response Process Model Algorithm (BRP-12) [37], based on Item Response Theory [38]. The principal outcomes correspond to the dimensions that the SF-12 health questionnaire measures (PH and MH) and in this case, higher scores are indicative of poor PH and MH.
To assess the Perception of Stigma, the Neuro-QOL Item Bank Scale v1.0-Stigma [39], was used, a shortened version consisting of 8 questions with 5 response options on the Likert Scale. The final score ranges from 8 to 40 points. A higher perception of stigma is related to higher scores. To dichotomize the variable, the median was used as the cut-off point.
To assess the degree of physical dependence on nicotine, the Fageström Test [40] was used, which includes 6 items, generating a score between 0 and 10. It considers a standard classification, where scores greater than 7 indicate a high degree of nicotine dependence, but for the purposes of this study participants were classified as smokers (≥ 1 point) and non-smokers (0 point).
The presence of depressive symptoms in the last two weeks was evaluated through the Patient Health Questionnaire (PHQ-9), which is based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [41]. This instrument is made up of 9 items, each of which scores from 0 to 3, with a final score between 0 and 27 points. Scores of 5, 10, 15 and 20 represent the cut-off points to determine mild, moderate, moderately severe, and severe depressive symptoms, respectively. A score equal or less than 9 points was considered as an absence of symptoms or the presence of mild symptoms (coded 0) and a score higher than 9 points as an indicator of depressive symptoms (coded 1).
To measure satisfaction with participation in social roles and activities, and cognitive function, the Neuro-QOL Item Bank v1.1 and Neuro-QOL Item Bank v2.0 instruments were used, respectively [39,42]. Both scales are self-reported measures that assess HRQoL and correspond to 8-item abbreviated measures, with 5 Likert-type response options ranging from never (1 point) to always (5 points). The final score ranges from 8 to 40 points, where higher scores indicate greater satisfaction with social roles and better cognitive function. The study uses the median as the cut-off point for both scales.
To assess social isolation the Patient-Reported Outcomes Measurement Information System (PROMIS ® ) Item Bank v2.0 (Social 8a) [43] instrument was used, which assesses the perceptions of being avoided or socially isolated, and consists of 8 questions, with 5 response options on a Likert-type scale. The results have been standardized with the population values, therefore 50 (standard deviation of 10) is the mean of the study population and in Vive + scores higher than the mean indicate a greater perception of social isolation.
The dependent variables correspond to the dimensions that the SF12v1 health questionnaire measures, which are PH and MH.

Statistical analysis
A general descriptive analysis was performed based on the calculation of PH and MH scores by sociodemographic and clinical characteristics, and syndemic factors. Frequencies (proportions) for qualitative variables and medians (interquartile range [IQR]) for quantitative variables were included.
For each outcome (domain), two linear regressions were performed. The first included each syndemic factor individually. The second contained those variables with a p-value < 0.2 in the bivariate analysis and considered as possible confounding factors. Before this, the presence of multicollinearity was tested by inspecting the correlation coefficients. For each model, the goodness of Fit was measured by the F test of global significance, the R2, the independence of the residuals (Durbin-Watson test), the graphical analysis of the residuals and the variance inflation factor [44].
Finally, to test the assertion that syndemic factors interact to affect HRQoL among PLWH, measures of additive interaction between the syndemic variables were computed. In linear regression, the regression coefficient of the product term reflects interaction as departure from additivity and it has been argued that this type of analysis better reflects biological interaction [45]. One of the main arguments for using the additive interaction approach instead of simple summation of syndemic factors is that the summation does not account for the complexity of interactions between different factors [46,47]. The syndemic is not simply the co-occurrence of factors but is characterized by interaction between distinct factors that can amplify or diminish the effects of other factors [27]. In our study, we selected the Amount of Additive Interaction model because it is a robust and widely used approach to evaluate the extent to which the interaction of two factors explains differences in the variable of interest. The advantages of the Amount of Additive Interaction model are that it is easy to interpret, does not depend on the measurement scale of the factors or the variable of interest, is flexible and can be applied to different types of data and can be tailored to address specific questions, and can help identify factors that have significant interaction [48]. We opted for this model primarily because our variables were linear, making it a better fit for our data. To perform the analysis, we ran independent linear regression models for each outcome and for each pair of syndemic variables, where we regressed their interactions adjusting by the potential confounder variables previously described. From these models, we obtain the Amount of Additive Interaction [48] with their corresponding 95% confidence intervals. We were unable to test for additive interaction beyond two exposures, as there is no consensus in the literature on a rigorous way to conduct this computation [47].
Therefore, in statistical terms, when entering two determinants, A and B, and a product term in a linear regression model, the regression formula of the outcome Y is [48]: From this equation, there are three possibilities for the regression coefficient of the product term: i. If β3 = 0, the combined effect of A and B = β1 + β2-> exactly additivity-> no interaction as departure from additivity. ii. If β3 < 0, the combined effect of A < B = β1 + β2-> less than additivity-> "negative" interaction as departure from additivity. iii. If β3 > 0, the combined effect of A > B = β1 + β2-> more than additivity-> "positive" interaction as departure from additivity.
For this study, statistically significant Amount of Additive Interaction and different from 0, indicated the presence of interaction on the additive scale.
In the descriptive dataset, missing values are recorded under the name "No answer". The variable "years living with HIV" presented the highest number of missing values, with 10% of incomplete observations. In the linear regression model and in the interaction model, only variables with complete observations were included. Both models were adjusted for gender, age, country of birth, education level, and mode of transmission. For all the analyses, an alfa error level of 5% was considered. Data were analyzed with the Stata 16.1 program and R version 4.1.2.
In respect of the clinical characteristics, 77% of the individuals had a CD4 count > 351 cells/ml, while 2.2% had < 200 cells/ml with a median of 14 (IQR: 6-24) years living with HIV and 77.2% (n = 665) had an undetectable viral load at the time of surveying (  Table 1).
The most prevalent syndemic factors were perception of stigma (56.9%), perception of social isolation (51.6%) and poor cognitive function (49.4%) ( Table 2). Table 3 presents the association between each syndemic condition with the two HRQoL domain outcomes. In the unadjusted model, all syndemic conditions, except nicotine dependence in PH, were associated individually with a higher impairment in both domains (PH and MH) ( Table 3).      There was evidence for additive interaction (i.e., synergism) between some of the syndemic factors (Table 5). In particular, a positive interaction was detected between satisfaction with social role and cognitive function (2.08, 0.14-4.02) for a worse PH; and between monthly income with satisfaction with social role, perception of social isolation, and perception of stigma, (3.45, 0.99-5.91; 2.79, 0.27-5.32; and 2.98, 0.26-5.71, respectively). For a worse MH, an interaction was found between satisfaction with social role and cognitive function (2.69, 0. 15-5.22). Drawing on the original conceptualization of syndemic theory, these results would indicate a positive interaction or also an excessive burden of adversity for PH or MH, given that the combinations of previously described syndemic factors are greater than their individual burden. The rest of the factors studied did not reveal statistically significant synergies.

Discussion
To our knowledge, this is the first study that analyzes HRQoL in PLWH using a syndemic approach and syndemic factors interaction in Spain. Our findings describe a synergic interaction between psychosocial and structural factors that negatively impact on HRQoL in PLWH. With the exception of sexual satisfaction and perceptions of social isolation in the PH domain, and low income and nicotine dependence in the MH domain, the results were associated with worse PH and MH. The prevalence of syndemic factors was high, being the most prevalent stigma, poor cognitive function, and perception of social isolation. The presence of depressive symptoms was identified as the highest risk factor for a worse outcome in both PH and MH domains. In addition, an interaction was found between poor cognitive function and poor satisfaction with social role for PH and MH, as well as an interaction between low income, perception of stigma, perception of social isolation, and poor satisfaction with social role in MH. These findings highlight the importance of considering syndemic conditions as determinants of HRQoL, which means it is of major importance to include them when designing patient-centered strategies to improve outcomes in health among PLWH.
In accordance with previous studies [49][50][51], we found a high prevalence of syndemic factors. The association between a high prevalence of syndemic factors and a worse HRQoL was previously described by Oliveira et al. [49], who observed that the presence of syndemic factors led to poorer HRQoL scores in the psychological, social, independence and environmental domains. Similarly, other studies [4,17,26,52] have found an association between HRQoL and perception of stigma, a psychological symptom that affects PLWH greatly [53]. In this regard, Chan et al. [26], concludes that HIV-related stigma and discrimination positively predicts the number of psychosocial syndemic problems, given that a cluster of syndemic conditions may develop as a result of negative life experiences.
We found few studies evaluating cognitive function in PLWH and they are mainly focused on older people [54] or people with auto degenerative diseases [55]. Similar to our study, the reported prevalence of cognitive impairment in PLWH varies between 30 and 60% [56,57] and cognitive dysfunction is more prevalent among older adults living with HIV [54,55], which would be expected,  21:42 given that cognitive impairment is known to increase with aging. Greater age has also been associated with fewer social interactions and a smaller social network [57], this data is in agreement with our study. PLWH are likely to disengage from social interaction and withdraw from their community, resulting in social isolation [58,59]. Furthermore, secrecy of HIV status disclosure often leads to loneliness and isolation [51]. These psychosocial problems frequently co-occur among PLWH, potentially compounding the risk of poor clinical outcomes, contributing to worse HRQoL and potentially promoting syndemic interactions.
Although depressive symptoms were the syndemic factor with a stronger association with a worse HRQoL, most syndemic conditions were associated with an impairment in HRQoL in both domains (PH and MH), even after adjustment for several confounding variables. A range of factors could be related to high prevalence of depressive symptoms among PLWH, including those related to living with a chronic disease [14,60], low income or living in poverty [4,22], stigma and discrimination [26], feelings of loneliness [30,61] or fear of disclosure [61,62]. Whatever the drivers of depression, early identification and treatment are of great importance, as depression has been associated with poor adherence to antiretroviral therapy (ART) [63][64][65]. Therefore, depression represents a great challenge for health care workers and public health specialists, as treating depression pharmacologically might not ensure swift recovery when symptoms stem from problems in the patient's social life and coexist in a syndemic context. Thus, training health care professionals in mental health is needed to assure a holistic approach to detect depressive symptom in early stages to minimize its impact in HRQoL.
The relationship established between dissatisfaction with social role and poor cognitive function in PLWH is a complex interaction that produces more serious effects than those resulting from each factor separately. In particular, dissatisfaction with social role and poor cognitive function combine to affect real-life activities in PLWH, including adherence to ART [66,67], performance of tasks important to social function [68,69], emotional and social well-being [69], to cause unhealthy behaviors and medical complications [67]. Furthermore, this interaction can create a vicious cycle, in which poor mental and physical health can contribute to further social isolation and discrimination, which in turn can worsen poor cognitive function and dissatisfaction with social role [70,71]. Tozzi et al. concluded, that HRQoL is influenced by cognitive impairment and by the ability to engage in activities of everyday living [72]. In turn, it has been described that stress resulting from stigma and dissatisfaction with social role can increase cortisol levels in the body, which at the same time can negatively affect the immune system and worsen physical health [73,74]. These findings highlight the importance of addressing psychosocial factors in the care and treatment of PLWH, not only to improve their psychological well-being, but also to improve their long-term physical health.
Although at the individual level, low income did not show a relationship with worse MH, when combined variables were evaluated, there was evidence of an interaction between this variable and stigma, isolation, and dissatisfaction with the social role. There is little evidence regarding the mechanisms that link these factors, however, it is known that HIV is a disease that is rooted in social and economic inequality [75]. In this context, Kang et al., describe that poverty is associated with worse MH functioning and stigma of PLWH, and suggest that interventions that are integrated with economic livelihood programs [76]. In addition, the stigma associated with HIV can affect self-esteem and consequently the ability to seek employment, increase income or maintain regular employment [77,78]. On the other hand, the lack of economic resources can limit access to adequate treatments, adherence to ART and healthy eating, which can increase the risk of MH problems [76] and contribute to problems such as anxiety and depression [79]. Also, stigma and discrimination can make it difficult to build healthy social and emotional relationships, which can increase isolation, dissatisfaction with social roles, and emotional stress [80]. Prior studies of livelihood interventions for PLWH have similarly found that improved economic standing was coupled with "social reintegration and reversal of status loss" [78,81]. According to the syndemic theory [27], addressing one of these factors reduces costs, complexity, and overall intervention times, positively affecting the HRQoL of PLWH.
This study has limitations that should be considered. Firstly, our data came from a convenience sample in two Spanish autonomous communities, therefore, they cannot be extrapolated to the rest of the PLWH in Spain. In addition, the recruitment of participants was done in outpatient clinics (HIV care units), excluding hospitalized patients and those who cannot or were not attending clinics, however, the representative sample of PLWH was sufficiently powered to identify the variables being studied and showed important results given the scarcity of quantitative research that assess HRQoL in PLWH with a syndemic approach. Secondly, the study was based on self-reported data which may lead to under-reporting of certain responses, or measurement or social desirability biases, and lead to underestimating some sensitive behaviors. However, the high response rate and the help of a peer who created a confidential environment, make us confident in the validity of the responses, which can reduce the above-described bias, as has been shown in other studies [82]. In addition, at the time of the study and data collection, the comorbidity variable was not collected. Therefore, future studies should include this variable, since it is a key factor influencing HRQoL. Third, given the cross-sectional design, the direction of the associations between syndemic factors and HRQoL cannot be established, and it is not possible to discard reverse causality, for example, that worse HRQoL in the mental domain could be the cause of depression and social isolation and not conversely [83]. It is for this reason that Vive + will be performed periodically, as longitudinal assessment will be better to describe the onset and trajectory of syndemic factors as well as their impact on HRQoL. Finally, it is important to acknowledge that we conducted a secondary analysis of data collected for a HRQoL in PLWH. Therefore, syndemic theory did not influence the research design, data collection instrument or identification of constructs. The literature demonstrates that most contemporary syndemic studies are based on secondary analyses [25,26,49]. Future studies are urgently needed to advance the methodological basis of syndemic analysis and further elucidate relationships between syndemic factors and HRQoL in PLWH.

Conclusion
In summary, this study highlights the impact of syndemic factors on HRQoL in PLWH. While the approach used in this study only examined the impact of two syndemic factors at a time on HRQoL, the results suggest that certain characteristics can overlap and pointed out a group of PLWH with higher vulnerability. Harmful interactions are often overlooked, particularly in adverse socioeconomic and behavioral circumstances, which likely enhances syndemic clustering. Therefore, addressing multiple syndemic factors simultaneously is necessary to improve HRQoL outcomes in PLWH. Further research could help better understand the interaction of these factors and their role in promoting disease clustering at the population level, enabling a more holistic approach on the clinical management of PLWH.
Moreover, integrating HRQoL assessment into clinical practice will significantly advance public health because, at the individual level, this can predict behaviors that negatively affect health and at population level, it will help identify the weaknesses in the health system. This change of strategy is imperative and highlights the urgent need to reshape the conventional understanding of diseases as separate and independent from other diseases and to take into account the social contexts in which diseases are found. A syndemic-based perspective offers a holistic approach to address diseases, taking into consideration psychosocial factors or other adverse health conditions, as a set of conditions that threaten HRQoL.