HIV-associated morbidity and mortality have dramatically declined since the introduction of combination antiretroviral therapy (cART) [1,2]. As a result, the number of HIV-1-infected adults living into old age is steadily increasing wherever access to cART is ensured. However, even among well treated HIV-infected individuals without comorbidity or AIDS-defining events, life expectancy remains lower than in the general population . Currently, approximately 50% of individuals in care with HIV in The Netherlands are 45 years or older . In view of a longer life expectancy, the care for people living with HIV should increasingly be aimed at not only improving the quantity but also the quality of life.
Several studies have shown that people diagnosed with HIV have impaired health-related quality of life (HRQL) compared with the general population [5,6]. However, HIV-infected individuals may differ from general population samples with respect to background and behavioural characteristics. Sexual and ethnic minorities are more prevalent in the HIV-infected population than in the general population. Differences in lifestyle factors, notably substance use, have also been demonstrated between HIV-infected and HIV-uninfected populations [7,8]. Both minority status and lifestyle factors have previously been associated with a lower level of HRQL . The contribution of HIV on HRQL is therefore preferably studied by comparing individuals with HIV with uninfected individuals with similar demographic and lifestyle characteristics.
HIV-infected persons are at increased risk of age-associated noncommunicable comorbidities compared with the general population . Such comorbidities were previously shown to have a negative impact on the physical dimension of HRQL among persons with HIV infection [11–13]. Previous research has demonstrated that HIV infection [5,6,14–16] and ageing [15,16] also negatively impact HRQL both in general terms and concerning the physical dimension of HRQL. Older HIV-infected individuals were previously shown to have a worse performance on physical function tests such as walking speed and grip strength than older HIV-uninfected individuals. Lower walking speed and grip strength were associated with lower levels of physical HRQL and an increased mortality rate [17–19]. Furthermore, depression is more prevalent among HIV-infected individuals than among HIV-uninfected individuals [20,21]. The inflammatory pathway is a possible contributor to the high incidence of depression in HIV-positive individuals . Chronic inflammation is inherent to HIV-infection, whereas elevated levels of inflammatory markers have been associated with depression in HIV-positive and HIV-negative individuals .
The objectives of the current study were to compare HRQL and depression between HIV-infected and HIV-uninfected controls while adjusting for a range of socio-demographic, clinical/biological and lifestyle characteristics. In addition, we aimed to investigate the independent contribution of comorbidity, age and HIV-infection to HRQL and depression.
The AGEhIV Cohort Study is an ongoing, prospective comparative cohort study. Between 2010 and 2012, a total of 598 HIV-1-infected individuals were recruited from the HIV outpatient clinic of the Academic Medical Center in Amsterdam, The Netherlands. As a control group, 550 HIV-uninfected individuals were recruited during the same period from the sexual health clinic and the Amsterdam Cohort Studies on HIV/AIDS at the Amsterdam Public Health Service, from the same geographical region and with similar socio-demographic and behavioural (risk) factors. The inclusion criteria were age at least 45 years and laboratory confirmed presence or absence of HIV infection. After obtaining informed consent, participants were screened for the presence of the following age-associated noncommunicable comorbidities: hypertension, angina pectoris, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, diabetes mellitus type 2, obstructive pulmonary disease, impaired renal function (i.e. estimated glomerular filtrate rate <60 ml/min), non-AIDS cancer and atraumatic fractures/osteoporosis .
At enrolment, participants were asked to complete a questionnaire to collect data on socio-demographics, lifestyle factors, HRQL and depressive symptoms.
Detailed information concerning HIV and cART history was obtained from the Dutch HIV Monitoring Foundation. The study protocol was approved by the local ethics review committee and registered at www.clinicaltrials.gov (identifier NCT01466582).
For the current study, we included 541 of 599 (90%) of the HIV-infected participants and 524 of 550 (95%) of the HIV-uninfected participants who completed questions on HRQL and depressive symptoms at enrolment, that is we excluded participants with missing data on HRQL and depressive symptoms (Fig. 1).
Dependent, independent variables and covariates
HRQL was measured using the Medical Outcomes Study Short Form 36-item health survey (SF-36) . The SF-36 contains eight subscales from which a physical health summary (PHS) and mental health summary (MHS) score can be calculated. The subscales physical functioning, role-physical, bodily pain and health perceptions contribute most to PHS and vitality, social functioning, role-emotional and mental health contribute most to MHS. All subscales and summary scores range from 0 to 100, with higher scores indicating better HRQL. The summary scores are transformed into a standardized scale with a mean of 50 and SD of 10. The SF-36 subscales and the PHS and MHS yield high levels of reliability and validity .
Depressive symptoms were assessed using the nine-item Patient Health Questionnaire (PHQ-9) [26,27]. Scores may range from 0 to 27 with higher scores indicating more depressive symptoms. Scores equal to or higher than 10 are indicative of clinically relevant levels of depression . Depressive symptoms were also assessed by the Centers for Epidemiologic Studies Depression scale (CES-D) consisting of 20 items [28,29]. Scores may range from 0 to 60 with higher scores indicating more depressive symptoms. Scores equal to or higher than 16 are indicative of clinically relevant levels of depression .
The independent variables and demographic, clinical/biological, lifestyle-related and HIV and antiretroviral therapy (ART)-related covariates considered in the analyses are shown in Table 1. We considered a range of covariates previously shown or suspected to be related with HRQL and/or depression as potential covariates. In the context of a frailty assessment , we performed two physical functioning tests: grip strength and walking speed. Maximum grip strength was assessed using Jamar handheld dynamometer (Jamar Plus + Digital Hand Dynamometer; Jamar, Hatfield, Pennsylvania, USA), and the mean value of three consecutive measurements of the dominant hand was used for analysis. Walking speed was determined by asking the participants to walk a distance of 4.57 m (15 ft) at their own usual pace. The average of two consecutive measurements was used. Grip strength and walking speed were categorized according to the strata described by Fried . Stratification of grip strength was based on sex and BMI. Stratification of walking speed was based on sex and body height. Persons in the per stratum lowest quintile were considered to have low grip strength (yes/no) or low walking speed (yes/no).
Because depression may be driven by inflammation and immune activation, we also considered measures of inflammation and immune activation that were assessed in the AGEhIV Cohort Study.
Differences in characteristics at enrolment between HIV-infected and HIV-uninfected participants were examined with chi-square tests for categorical data and Wilcoxon rank-sum tests or Student t tests for continuous data, where appropriate.
To examine the magnitude of potential differences (PDs) in HRQL between HIV-infected and HIV-uninfected individuals, we calculated effect sizes by dividing mean differences by the pooled SD. Usual cut-off values to define small, medium and large effects are 0.2, 0.5 and 0.8, respectively . The magnitude of the difference in depression (PHQ-9 score ≥10) between HIV-infected and HIV-uninfected individuals was expressed as odds ratio (OR). Usual cut-off values to define small, medium and large ORs are 1.44, 2.47 and 4.25, respectively . To examine if PDs between HIV-infected and HIV-uninfected individuals were attenuated after adjustment for the independent variables and covariates, we first calculated unadjusted effect sizes (model 1). Next, we calculated effect sizes that were adjusted for the number of comorbidities (model 2). Next, subsequent models were additionally adjusted for age (model 3), demographic factors (model 4), clinical/biological factors (model 5) and for lifestyle factors (model 6).
To investigate factors independently associated with HRQL, we conducted multiple linear regression analyses with the PHS and MHS as the dependent variables. To investigate factors independently associated with depression (PHQ-9 score ≥10), we conducted multiple logistic regression analysis. The independent variables were HIV infection, the number of comorbidities and age. The demographic, clinical/biological and lifestyle variables were treated as covariates. First, we conducted a series of bivariate analyses. Factors that yielded bivariate associations with HRQL or depression with P values less than 0.20 were subsequently entered in a multivariate model using a backward selection of variables for the final model. We checked for violations of necessary assumptions in multiple regression by examining normal plots of the residuals of the linear regression models and by examining the possible presence of collinearity (Tolerance/Variance Inflation Factor statistics). In a sensitivity analysis, we used the Center for Epidemiologic Studies Depression scale (CESD) score at least 16 instead of a PHQ9 score at least 10 to define depression.
We explored if age and the number of comorbidities had a different impact on HRQL and depression in HIV-infected versus HIV-uninfected individuals by including an interaction term in the models, that is age by HIV status and comorbidities by HIV status. Two-sided P values less than 0.05 were considered statistically significant. Data were analyzed using SPSS version 20 (SPSS Inc., Chicago, Illinois, USA).
Characteristics at enrolment
The characteristics at enrolment of the HIV-infected and HIV-uninfected participants are shown in Table 2. HIV-infected participants were less likely to be of Dutch origin and to have a high educational level and more likely to be married/cohabiting; to have chronic hepatitis B virus (HBV) infection; low grip strength and low walking speed; a higher number of age-associated noncommunicable comorbidities; a lower CD4+ cell count and higher concentrations of high-sensitive C-reactive protein (CRP), sCD163 and sCD14 than HIV-uninfected participants. HIV-infected individuals were more likely to be a current smoker and to have ever used intravenous drugs and less likely to use ecstasy (XTC) daily to monthly. Virtually, all HIV-infected participants were on cART and had undetectable HIV-1 plasma viral loads.
Differences in health-related quality of life and depression between HIV-infected and HIV-uninfected individuals
HIV-infected individuals reported significantly worse HRQL than HIV-uninfected individuals on eight out of the 10 SF-36 scales, and they reported significantly more depression on the PHQ-9 in the unadjusted analysis (Table 3, model 1). The difference in HRQL on subscales related to physical functioning and the PHS score between HIV-infected and HIV-uninfected individuals was slightly attenuated after adjustment for comorbidities (model 2) and was attenuated even more after adjustment for the biological/clinical covariates (model 5). The difference in HRQL on subscales related to mental health, the MHS score and depression between HIV-infected and HIV-uninfected individuals became more pronounced after adjustment for the biological/clinical covariates (model 5). This was mostly due to adjustment for sCD14 concentrations. The difference between HIV-infected and HIV-uninfected individuals in HRQL and depression remained significant on six of the SF-36 scales and on the PHQ-9 after adjustment for all independent variables and covariates (model 6). These differences were of a small-to-medium magnitude with effect sizes ranging from 0.17 for role-physical and the MHS score, to 0.32 for vitality and 0.40 for health perceptions and an OR indicative of a medium effect for depression.
Association between HIV-status, comorbidities and age with health-related quality of life and depression
Table 4 shows the factors that were independently associated with physical and mental HRQL and with depression in a multivariate model. HIV-positive status was independently associated with worse physical HRQL, worse mental HRQL and with a higher likelihood of depression. A higher number of comorbidities were significantly associated with worse physical HRQL but not with mental HRQL or depression. Younger age was significantly associated with worse mental HRQL and with an increased likelihood of depression but not with physical HRQL. There was no evidence, that is insignificant interaction effects, that the difference in HRQL between HIV-infected and HIV-uninfected individuals became more pronounced with a higher number of comorbidities or at an older age. In fact, the difference in physical HRQL between HIV-infected and HIV-uninfected individuals tended to become smaller with increasing age (interaction HIV status by age, P = 0.07).
Demographic, clinical/biological and lifestyle covariates associated with health-related quality of life and depression
Covariates independently associated with a worse physical HRQL were low grip strength, low walking speed, hepatitis C virus (HCV) infection, lower educational level and not being MSM. Covariates independently associated with a worse mental HRQL were female sex, not being married or cohabiting, lower sCD14 concentrations, heavy daily drinking, being a current smoker and not using XTC daily to monthly. Covariates independently associated with an increased likelihood of depression were being of non-Dutch origin, having a low educational level, not being married or cohabiting, low walking speed, lower sCD14 concentrations and being a current smoker (Table 4). A sensitivity analysis using a CESD score at least 16 to define depression yielded fairly similar results with two exceptions. Using the CESD, female sex was significantly associated with depression, whereas being a current smoker was not associated with depression according to the CES-D (data not shown).
Of the HIV/cART-specific covariates, not being exposed to nucleoside reverse transcriptase inhibitor mono/dual therapy prior to cART initiation was independently associated with a better physical HRQL (2.7 point higher HRQL, P = 0.005). None of the HIV/ART-specific covariates were associated with mental HRQL or depression.
In this cohort of HIV-positive individuals with largely suppressed viraemia on cART and HIV-negative controls, all aged at least 45 years, we found that HIV-positive status was significantly and independently associated with worse physical and mental HRQL, as well as with an increased likelihood of depression. Differences in HRQL between HIV-positive and HIV-negative individuals, however, were of a small-to-medium magnitude. The difference in HRQL between HIV-positive and HIV-negative individuals did not become more pronounced with a higher age or with a higher number of comorbidities. A higher number of comorbidities were independently associated with worse physical HRQL. Younger age was independently associated with worse mental HRQL and a higher likelihood of depression.
Our findings that a higher number of comorbidities [12,13], reduced walking speed  and grip strength  are associated with lower physical HRQL are in line with previous studies among HIV-infected and HIV-uninfected controls. It has previously been suggested that HIV-infected individuals may age more rapidly than their HIV-negative counterparts. We therefore investigated whether the difference in HRQL between HIV-infected and HIV-uninfected individuals became greater with a higher age. We did not find such an age effect. Conversely, we observed the opposite trend in that the difference in physical HRQL between HIV-positive and HIV-negative persons decreased somewhat with higher age, which is in line with findings from a previous study . However, we cannot rule out survival bias, that is persons with poorest HRQL may not have lived long enough to be part of the oldest age categories. We found that the difference in HRQL between HIV-positive and HIV-negative individuals was statistically independent and did not become more pronounced with a higher number of comorbidities. This suggests that the negative impact of HIV on HRQL is not only entirely mediated through the increased risk of developing comorbidities with HIV infection.
If one of the main aims of healthcare is to enhance patients’ HRQL, then it is important to understand which factors may be associated with impaired HRQL. HIV-positive status, a higher number of comorbidities, low walking speed, low grip strength and being HCV-infected were all significantly and independently associated with a reduced physical HRQL. To the extent that these factors are modifiable, our findings suggest that optimizing the prevention and management of comorbidities and treatment of HCV coinfection may contribute to enhancing patients’ HRQL. However, our findings also suggest that a negative impact of HIV infection on HRQL will remain even in the presence of optimized prevention and management of comorbidities and HCV coinfection, because the impact of HIV infection was statistically independent of all other variables.
Mental HRQL and depression were independently associated with HIV-positive status, lifestyle factors, that is substance use, and demographic characteristics. Substance use can be both a cause and a consequence of a low mental health or depression. Given the cross-sectional nature of our analysis, we cannot make inferences about the direction of this relationship. Female sex, non-Dutch origin, a low educational level and living alone were all associated with an increased risk of having a low mental HRQL and/or depression. HIV healthcare providers need to be alert to individuals with one or more of these characteristics as they may require more additional support or referral to mental health services.
The question arises how the HRQL of persons with HIV infection compares with that of people with other chronic conditions. We could identify only a single preliminary report comparing HRQL among HIV-infected patients in the era of modern cART with that of patients with other chronic conditions, that is diabetes type 1 and type 2 and rheumatoid arthritis (RA). This study found no significant differences in physical HRQL between HIV-infected patients and patients with diabetes type 1 or type 2, whereas RA patients had a worse physical HRQL . However, HIV-infected patients had a significantly higher risk of a poor mental HRQL than patients with the other three chronic medical conditions.
Our finding that HIV-positive status was significantly and independently associated with lower mental HRQL and more depression is in line with a large body of evidence showing a high prevalence of depression in HIV. Negative affect in HIV infection has previously been linked to stressors such as HIV stigma and discrimination and also to poverty, unemployment and social isolation, which are disproportionately prevalent in the HIV-infected population .
We used both the PHQ-9 and the CES-D for the analysis of depression. The PHQ-9 has previously been used in a variety of medical settings, whereas the CES-D was designed for general population settings. We anticipated that the CES-D might therefore be more appropriate to assess depressive symptoms in the HIV-uninfected group and the PHQ-9 in the HIV-infected group. However, both measures yielded quite similar results according to our sensitivity analysis.
There is nowadays an extensive body of data showing significant associations between depression and increased inflammation and immune activation in persons with and without somatic conditions [23,37], although some investigations have reported a lack of association or occasionally an inverse relationship [38,39]. A few studies in HIV infection have investigated the relationship between inflammation and immune activation and depression, with some studies finding support for this relationship [25,26,40], whereas others did not [6,41]. Contrary to our expectation, we found that higher sCD14 concentrations were independently associated with better mental HRQL and a decreased likelihood of depression. This finding remained when we used the CES-D instead of the PHQ-9 to assess depression. In a previous study also finding such inverse relationship among a general population sample of middle-aged adults, it was hypothesized that persons with better mental health might be more likely to take on physiologically demanding occupational or social roles or tasks. These demanding roles or tasks could, in turn, have resulted in increased systemic inflammation even in the absence of emotional distress . Another study among patients with established coronary heart disease found that depression was associated with lower levels of inflammation. In this study, it was hypothesized that elevated levels of cortisol associated with depression might explain this relationship because cortisol has anti-inflammatory properties . Another explanation for the inverse relationship is the cross-sectional nature of our analysis that may not allow for properly capturing longitudinal relationships between variables. Finally, our finding might simply be due to chance.
The current study has limitations. The cross-sectional nature of our analysis does not allow for making causal inferences. Also, the current study attempted to include HIV-negative controls with comparable demographic and lifestyle characteristics. Although the HIV-positive and HIV-negative study groups were largely comparable, differences in some demographic and lifestyle-related factors were present, which was addressed by adjusting all regression analyses for a broad range of demographic and lifestyle-related factors. Nevertheless, we cannot rule out the possibility of unmeasured confounders potentially influencing our results. The percentage of study participants who regularly smoke cannabis is higher than that in the Dutch general population, that is 4.5% . The percentage of HIV-infected study participants in whom the reported mode of HIV transmission is injection drug use is in line with that in the entire Dutch HIV-infected population, that is 3.0% .
Another limitation consists of the potential generalization, our findings are from a small country with good healthcare and coverage. The significant and independent negative impact of HIV-positive status on HRQL and depression among well suppressed individuals in a country with good healthcare and coverage might be even more pronounced in resource-limited settings. This would imply that also in resource-limited settings, HRQL and depression are relevant issues that deserve attention.
In conclusion, HIV-infected individuals have a worse physical and mental HRQL and more depression than HIV-uninfected individuals. Our findings suggest that optimizing the prevention and management of comorbidities and treatment of HCV coinfection may contribute to enhancing patients’ HRQL. Nevertheless, our findings also suggest that the negative impact of HIV infection on HRQL will remain even in the presence of optimized prevention and management of comorbidities and HCV coinfection, because the negative impact of HIV infection was statistically independent. Future studies should continue to search for modifiable factors associated with HRQL with the aim to develop strategies tailored to the needs of the growing population of HIV-infected persons of older age to enhance their HRQL.
Authors’ contributions: P.R. conceived the study and all authors contributed to the study design. K.W.K. contributed to study coordination and data collection. P.T.N. conducted the statistical analysis. All authors contributed to data interpretation. N.L. and P.T.N. drafted the article. All authors critically reviewed and revised the article, and approved the final version submitted for publication.
The work was supported by The Netherlands Organization for Health Research and Development (ZonMW) together with AIDS Fonds (grant numbers 300020007 and 2009063, respectively). Additional unrestricted scientific grants were received from Gilead Sciences; ViiV Healthcare; Janssen Pharmaceutica N.V.; Bristol-Myers Squibb and Merck&Co. None of these funding bodies had a role in the design or conduct of the study, the analysis and interpretation of the results, the writing of the report, or the decision to publish.
AGEhIV Cohort Study Group
Scientific oversight and coordination: Academic Medical Center (AMC), Department of Global Health and Amsterdam Institute for Global Health and Development (AIGHD): P. Reiss (principal investigator), F.W.N.M. Wit, M. van der Valk, J. Schouten, K.W. Kooij, R.A. van Zoest, E. Verheij, S.O. Verboeket, B.C. Elsenga.
Public Health Service of Amsterdam, Department of Infectious Diseases M. Prins (coprincipal investigator), M.F. Schim van der Loeff, J. Berkel, M. Totté, T. Kruijer, L. del Grande, C. Gambier, G.R. Visser, L. May, S. Kovalev, A. Newsum, M. Dijkstra.
Datamanagement: HIV Monitoring Foundation: S. Zaheri, M.M.J. Hillebregt, Y.M.C. Ruijs, D.P. Benschop, A. el Berkaoui.
Project management and administrative support: AIGHD: W. Zikkenheiner, F.R. Janssen.
Central laboratory support: AMC, Laboratory for Viral Immune Pathogenesis and Department of Experimental Immunology: N.A. Kootstra, A.M. Harskamp-Holwerda, I. Maurer, T. Booiman, M.M. Mangas Ruiz, A.F. Girigorie, B. Boeser-Nunnink.
Participating HIV physicians and nurses: AMC, Division of Infectious Diseases: S.E. Geerlings, M.H. Godfried, A. Goorhuis, J.W.R. Hovius, J.T.M. van der Meer, F.J.B. Nellen, T. van der Poll, J.M. Prins, P. Reiss, M. van der Valk, W.J. Wiersinga, M. van Vugt, G. de Bree, F.W.N.M. Wit; J. van Eden, A.M.H. van Hes, M. Mutschelknauss, H.E. Nobel, F.J.J. Pijnappel, M. Bijsterveld, A. Weijsenfeld, S. Smalhout.
Other collaborators: AMC, Department of Cardiology: J. de Jong, P.G. Postema. AMC, Division of Endocrinology and Metabolism: P.H.L.T. Bisschop, M.J.M. Serlie. Free University Medical Center Amsterdam, Division of Endocrinology and Metabolism: P. Lips. AMC, Department of Gastroenterology: E. Dekker. AMC, Division of Geriatric Medicine: N. van der Velde. AMC, Division of Nephrology: J.M.R. Willemsen, L. Vogt. AMC, Department of Neurology: J. Schouten, P. Portegies, B.A. Schmand, G.J. Geurtsen. AMC, Department of Nuclear Medicine: H.J. Verberne, M. de Jong. AMC, Department of Ophthalmology: F.D. Verbraak, N. Demirkaya. AMC, Department of Psychiatry: I. Visser, Free University Medical Center Amsterdam, Department of Psychiatry: A. Schadé. AMC, Department of Medical Psychology: P.T. Nieuwkerk. N. Langebeek. AMC, Department of Pulmonary medicine: R.P. van Steenwijk, E. Dijkers. AMC, Department of Radiology: C.B.L.M. Majoie, M.W.A. Caan, T. Su. AMC, Department of Gynaecology: H.W. van Lunsen, M.A.F. Nievaard. AMC, Division of Vascular Medicine: B.J.H. van den Born, E.S.G. Stroes. HIV Vereniging Nederland: W.M.C. Mulder.
Conflicts of interest
There are no conflicts of interest.
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