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Determinants of reduced cognitive performance in HIV-1-infected middle-aged men on combination antiretroviral therapy
 
 
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"....cross-sectional analyses on these 103 HIV-1-infected and 74 HIV-uninfected .....median age of 54.....time since diagnosed with HIV 13.5 years average (9.4 to 17.1)...... majority of whom were men who have sex with men (MSM)...... .......
[predictors] ....

- avg nadir CD4 170 [60-250]
- known duration of CD4 <350 15.4 years [4.2 to 45.2]
- cannabis use,
- history of prior cardiovascular disease (borderline),
- impaired renal function (borderline),
- diabetes mellitus type 2,
- having an above-normal waist-to-hip ratio (borderline),
- presence of depressive symptoms (borderline), and
- lower nadir CD4-count to be independently associated with poorer cognitive performance (Table 3, Model 1)...
- hsCRP and sCD14 were significantly higher among HIV-positives....
- Increased urinary albumin-to-creatinine ratio (≥3 mg/mmol) was significantly more prevalent among HIV-positives (19.2% vs. 5.8%.....
- ecstasy use was more prevalent among HIV-uninfected controls (13% vs.2%......
- Among HIV-positives, BMI was significantly lower p=0.003 and waist-to-hip ratio significantly higher, p=0.02)......
- Smoking was more prevalent among HIV-positives (30% vs. 19% "

 
"In conclusion, our results indicate that reduced cognitive performance in HIV-1-infected men with sustained suppressed viraemia on cART is likely the result of a multifactorial process, in which not only HIV-associated factors such as having experienced more severe immune deficiency, but also cardiovascular/metabolic factors, cannabis use, and depressive symptoms are key contributors. These are likely to gain increased importance as the population of people living with HIV continues to age.
 
Neuropsychological assessment was performed on 103 HIV-1-infected men with suppressed viraemia on cART for ≥12 months and 74 HIV-uninfected highly similar male controls, all aged ≥45 years. CI and cognitive performance were determined by multivariate normative comparison (MNC). Determinants of decreased cognitive performance and CI were investigated by linear and logistic regression analysis, respectively.
 
Results:
 
CI as diagnosed by MNC was found in 17% of HIV-1-infected men.
 
Determinants for decreased cognitive performance by MNC as a continuous variable included cannabis use, history of prior cardiovascular disease, impaired renal function, diabetes mellitus type 2, having an above normal waist-to-hip ratio, presence of depressive symptoms, and lower nadir CD4-count.
 
Determinants for CI, as dichotomized by MNC, included cannabis use, prior cardiovascular disease, impaired renal function, and diabetes mellitus type 2.
 
Conclusions:
 
Decreased cognitive performance probably results from a multifactorial process, including not only HIV-associated factors such as having experienced more severe immune deficiency, but also cardiovascular/metabolic factors, cannabis use, and depressive symptoms.
 
We also found multiple metabolic/cardiovascular factors to be associated with cognitive impairment as well as decreased cognitive performance.
 
Both in the general population and among HIV-positives, hypercholesterolemia, diabetes mellitus type 2, and central obesity have been associated with decreased cognitive function.[25-35] .....We also found (prior) cardiovascular disease (i.e. angina pectoris, myocardial infarction, or peripheral arterial disease), to be associated with cognitive impairment/performance. In both the general and HIV-infected population, prior cardiovascular disease and subclinical atherosclerotic disease have been associated with cognitive decline.[28,31,36-38] .....Additionally, we found albuminuria to be associated with cognitive dysfunction, which is in line with other studies, both in the general and the HIV-infected population.....Evidence of renal impairment and past cardiovascular disease (each of which are associated with cognitive dysfunction in our analyses) are likely manifestations of (micro)vascular organ damage in many cases, and may (partly) share pathophysiological mechanisms with cerebral damage. ....Presence of depressive symptoms was identified as an additional risk factor for decreased cognitive performance (but not for CI). In the general population, depression has been associated with cognitive deficits....We also found severity of prior immune deficiency, as reflected in a lower nadir CD4-count, to be associated with decreased cognitive performance, which is also consistent with earlier findings.....Although HIV-infection is known to cause immune deficiency by depleting CD4-cells, it is also associated with activation of the immune system and inflammation .....Atherosclerosis and cardiovascular disease are also closely related to immune activation and inflammation, and have been shown to be highly prevalent among HIV-infected individuals, as is the case for many cardiovascular/metabolic risk factors (such as dyslipidemia, smoking, and central obesity).[52] Immune activation and inflammation may therefore contribute to CI in a direct manner, but also indirectly, by the association with vascular damage and cerebral small vessel disease. .....Three factors were identified as risk factors for decreased cognitive performance, but not for CI as a dichotomous outcome: having an above-normal waist-to-hip ratio, presence of depressive symptoms, and a lower nadir CD4-count. This discrepancy might very well be explained by reduced statistical power when using CI as a dichotomous outcome measure instead of cognitive performance as a continuous outcome measure.
 
As reported previously, using MNC, CI [cognitive impairment] was detected in 17 (17%) HIV-1-infected men......Linear regression analysis showed cannabis use, history of prior cardiovascular disease (borderline), impaired renal function (borderline), diabetes mellitus type 2, having an above-normal waist-to-hip ratio (borderline), presence of depressive symptoms (borderline), and lower nadir CD4-count to be independently associated with poorer cognitive performance (Table 3, Model 1).....Logistic regression analysis showed cannabis use, history of prior cardiovascular disease, impaired renal function, and diabetes mellitus type 2 (borderline) to be independently associated with CI (Table 3, Model 2). ....Our results being those of cross-sectional analyses, we are merely able to demonstrate associations rather than causality.....differences in remaining unmeasured confounders potentially influencing our results cannot be excluded....In addition, some unique characteristics of this cohort (participants being mostly Caucasian middle-aged MSM with sustained viral suppression, with a low prevalence of chronic. hepatitis B and C), may limit generalization of the results to other populations. Additional studies are needed to determine whether our findings apply equally to other populations with different characteristics.
 
When analyzing determinants of cognitive impairment/performance by MNC, we found cannabis use to be strongly associated with cognitive dysfunction. Both in the general population and among HIV-positives, cannabis use has been associated with decreased cognitive function.[21,22] In the context of HIV-infection, cannabis use is common, not only for recreational but also for medicinal use (treating neuropathic pain, anorexia, nausea, or mood disturbances).[23,24] Besides direct effects of cannabis on cognition, the observed association could also be partly explained by some of the abovementioned conditions for which medicinal use of cannabis is indicated, which themselves may be associated with effects on cognition. The underlying reason for cannabis use (medicinal vs. recreational) unfortunately was not captured as part of data collection, and we were therefore unable to explore this hypothesis further.
 
We performed cross-sectional analyses on these 103 HIV-1-infected and 74 HIV-uninfected substudy participants, exploring a broad range of possible determinants for decreased cognitive performance including HIV/ART-related factors, inflammatory markers, use of illicit drugs and/or alcohol, psychiatric conditions, and metabolic and cardiovascular risk factors.....Both groups were highly comparable, with a median age of 54 in both groups, the majority of whom were men who have sex with men (MSM)......Smoking was more prevalent among HIV-positives (30% vs. 19% currently smoking, p=0.048) and ecstasy use was more prevalent among HIV-uninfected controls (13% vs.2%, p=0.008), whereas cannabis, cocaine, and alcohol use were comparable between the two groups......Among HIV-positives, BMI was significantly lower (24.1 (IQR 22.2-26.0) vs. 25.4 (IQR 23.7-27.5) kg/m2, p=0.003) and waist-to-hip ratio significantly higher (0.96 (IQR 0.92-1.01) vs. 0.93 (IQR 0.89-0.99), p=0.02). Total, HDL, and LDL cholesterol, lipoprotein(a) and triglyceride levels were comparable between the two groups, as was use of lipid-lowering medication, physical activity, family history for metabolic/cardiovascular disease, history of cardiovascular disease, diabetes mellitus type 2, hypertension, and estimated glomerular filtration rate. Increased urinary albumin-to-creatinine ratio (≥3 mg/mmol) was significantly more prevalent among HIV-positives (19.2% vs. 5.8%, p=0.01). Levels of hsCRP and sCD14 were significantly higher among HIV-positives (1.5 (IQR 0.7-3.3) vs. 1.1 (IQR 0.6-2.1) mg/L, p=0.02 and 1548 (IQR 1318-2025) vs. 1207 (IQR 995-1558) ng/mL, p<0.001, respectively). hsCRP levels >10 mg/L were also significantly more prevalent among HIV-positives (10% vs. 0%, p=0.005). D-dimer and sCD163 levels were comparable between the two study groups.....As reported previously, using MNC, CI was detected in 17 (17%) HIV-1-infected men.......Linear regression analysis showed cannabis use, history of prior cardiovascular disease (borderline), impaired renal function (borderline), diabetes mellitus type 2, having an above-normal waist-to-hip ratio (borderline), presence of depressive symptoms (borderline), and lower nadir CD4-count to be independently associated with poorer cognitive performance (Table 3, Model 1)."
 
-------------------
 
Determinants of reduced cognitive performance in HIV-1-infected middle-aged men on combination antiretroviral therapy.
 
AIDS Jan 2016
 
AGEhiV cohort has been prolific in reporting aging-related studies at conferences over the past several and publishing-:
Comorbidity and ageing with HIV A prospective comparative cohort study.....http://www.natap.org/2012/IAS/IAS_55.htm
 
Frailty Predicts All-cause Mortality, Hospital Admission and Falls in HIV-infected and -uninfected Middle-aged Individuals....http://www.natap.org/2015/EACS/EACS_10.htm
 
Hypertension Increased in HIV+ vs HIV-neg in Amsterdam AgehIV Cohort Study (45% vs 31%) & HIV is Independently Associated with Hypertension.....http://www.natap.org/2014/IWCADR/IWCADR_12.htm
 
HIV Independently Boosts Odds of Hypertension in Older HIV+/HIV- Cohort - Lipodystrophy/heart disease.....http://www.natap.org/2015/EACS/EACS_06.htm
 
"HIV infection remained independently associated with a higher number of AANCC (OR 1.58) [age-associated non-communicable comorbidity]" HIV+ had more comorbidities & more than 3, 2 & 1 comorbidities respectively vs HIV-neg....new study published confirming prior studies.....http://www.natap.org/2014/HIV/090314_03.htm
......"HIV-positives had a significantly higher mean number of AANCC than HIV-uninfected controls (1.3 (SD 1.14) vs. 1.0 (SD 0.95), p<0.001)......The proportion of participants with ≥1 AANCC was also significantly higher among those with HIV (69.4% vs. 61.8%, p=0.009)......The mean number of AANCC within the 50-55, 60-65, and 65+ age-categories was significantly higher among HIV-infected than HIV-uninfected participants (Figure 1). Furthermore, the distribution of the number of AANCC for HIV-positives in each 5-year age-stratum resembled the distribution for those without HIV who are 5 years older"
 
Schouten, Judith; Su, Tanja; Wit, Ferdinand W.; Kootstra, Neeltje A.; Caan, Matthan W.A.; Geurtsen, Gert J.; Schmand, Ben A.; Stolte, Ineke G.; Prins, Maria; Majoie, Charles B.; Portegies, Peter; Reiss, Peter; on behalf of the AGEhIV Study Group
 
Abstract
 
Objective:
The spectrum of risk factors for HIV-associated cognitive impairment (CI) is likely very broad and includes not only HIV/ART-specific factors, but also other comorbid conditions. The purpose of this current study was to explore possible determinants for decreased cognitive performance.
 
Design and methods: Neuropsychological assessment was performed on 103 HIV-1-infected men with suppressed viraemia on cART for >=12 months and 74 HIV-uninfected highly similar male controls, all aged >=45 years. CI and cognitive performance were determined by multivariate normative comparison (MNC). Determinants of decreased cognitive performance and CI were investigated by linear and logistic regression analysis, respectively.
 
Results: CI as diagnosed by MNC was found in 17% of HIV-1-infected men. Determinants for decreased cognitive performance by MNC as a continuous variable included cannabis use, history of prior cardiovascular disease, impaired renal function, diabetes mellitus type 2, having an above normal waist-to-hip ratio, presence of depressive symptoms, and lower nadir CD4-count.
 
Determinants for CI, as dichotomized by MNC, included cannabis use, prior cardiovascular disease, impaired renal function, and diabetes mellitus type 2. Conclusions: Decreased cognitive performance probably results from a multifactorial process, including not only HIV-associated factors such as having experienced more severe immune deficiency, but also cardiovascular/metabolic factors, cannabis use, and depressive symptoms.
 
Introduction
 
With the introduction of combination antiretroviral therapy (cART), AIDS-associated mortality and morbidity have markedly diminished and HIV encephalopathy, previously known as AIDS dementia complex, has largely disappeared.[1-3] In the past few years however, a high prevalence (15-69%) of milder forms of cognitive impairment (CI) has been reported among HIV-infected individuals, including those with systemically well-controlled HIV-infection.[4-9]
 
To classify this broad clinical spectrum of HIV-associated neurocognitive disorders (HAND), a set of diagnostic criteria, commonly referred to as Frascati criteria, was developed.[10] These criteria however appear oversensitive, not only resulting in high prevalence estimates, but also high false-positive rates. We recently reported multivariate normative comparison (MNC), a technique which controls the false-positive rate while retaining sensitivity, to be a more accurate method of detecting CI in the HIV-infected population.[11]
 
In this previous report we found CI by MNC to be present in 17% of 103 HIV-infected men and in 5% of 74 HIV-uninfected controls participating in the AGEhIV Cohort Study (p=0.02, one-tailed). Applying Frascati criteria to the same study population, CI was highly prevalent in HIV-infected participants (48%), but nearly equally so in HIV-uninfected controls (36%, p=0.09, one-tailed), indicating a high-false positive rate. [11]
 
In the pre-cART era HIV-specific factors such as HIV viral load and CD4-count were most strongly associated with CI.[12] In cART-treated (and aging) individuals however, the relative contribution of other risk factors towards CI including cardiovascular, metabolic, and other comorbid conditions, is likely to gain relative importance besides HIV/ART-specific factors such as persistent immune activation and inflammation.[13] The relative contribution of each of such factors to the pathogenesis of CI remains to be further elucidated.
 
The purpose of this current study was to explore possible determinants for decreased cognitive performance as determined by MNC in the same abovementioned AGEhIV Cohort Study population. Within this study, which investigates age-associated comorbidity among middle-aged individuals with and without HIV-1-infection, a nested substudy was established focussing on cognitive functioning. We performed cross-sectional analyses on these 103 HIV-1-infected and 74 HIV-uninfected substudy participants, exploring a broad range of possible determinants for decreased cognitive performance including HIV/ART-related factors, inflammatory markers, use of illicit drugs and/or alcohol, psychiatric conditions, and metabolic and cardiovascular risk factors.
 
Results
 
Participants' characteristics

 
103 HIV-1-infected and 74 HIV-uninfected men were consecutively enrolled into the substudy between December 2011 and August 2013. Demographic and HIV-related characteristics are shown in Table 1. Both groups were highly comparable, with a median age of 54 in both groups, the majority of whom were men who have sex with men (MSM).
 
HIV-1-infected men were known to be infected and treated with antiretroviral medication for a prolonged period of time, and 35% had previously been diagnosed with AIDS. The majority had experienced substantial immune recovery on cART, with a median nadir CD4-count of 170 cells/mm3, current median CD4-count of 625 cells/mm3, and undetectable plasma viral load for a median 8 years.
 
Factors related to cognition, behaviour, comorbidity, and inflammation are presented in Table 2. Both groups were comparable regarding native language, educational level, premorbid intelligence, depressive symptoms, and use of psychotropic medication. Smoking was more prevalent among HIV-positives (30% vs. 19% currently smoking, p=0.048) and ecstasy use was more prevalent among HIV-uninfected controls (13% vs.2%, p=0.008), whereas cannabis, cocaine, and alcohol use were comparable between the two groups. Among HIV-positives, BMI was significantly lower (24.1 (IQR 22.2-26.0) vs. 25.4 (IQR 23.7-27.5) kg/m2, p=0.003) and waist-to-hip ratio significantly higher (0.96 (IQR 0.92-1.01) vs. 0.93 (IQR 0.89-0.99), p=0.02). Total, HDL, and LDL cholesterol, lipoprotein(a) and triglyceride levels were comparable between the two groups, as was use of lipid-lowering medication, physical activity, family history for metabolic/cardiovascular disease, history of cardiovascular disease, diabetes mellitus type 2, hypertension, and estimated glomerular filtration rate. Increased urinary albumin-to-creatinine ratio (≥3 mg/mmol) was significantly more prevalent among HIV-positives (19.2% vs. 5.8%, p=0.01). Levels of hsCRP and sCD14 were significantly higher among HIV-positives (1.5 (IQR 0.7-3.3) vs. 1.1 (IQR 0.6-2.1) mg/L, p=0.02 and 1548 (IQR 1318-2025) vs. 1207 (IQR 995-1558) ng/mL, p<0.001, respectively). hsCRP levels >10 mg/L were also significantly more prevalent among HIV-positives (10% vs. 0%, p=0.005). D-dimer and sCD163 levels were comparable between the two study groups.
 
CI as diagnosed by MNC
 
As reported previously, using MNC, CI was detected in 17 (17%) HIV-1-infected men. Transformed Hotelling's T2 statistics of the HIV-1-infected men ranged between -2.39 and 1.90, with a median of -0.15 (IQR -0.87-+0.48).
 
Determinants of decreased cognitive performance by MNC in HIV-1-infected cohort participants
 
Linear regression analysis showed cannabis use, history of prior cardiovascular disease (borderline), impaired renal function (borderline), diabetes mellitus type 2, having an above-normal waist-to-hip ratio (borderline), presence of depressive symptoms (borderline), and lower nadir CD4-count to be independently associated with poorer cognitive performance (Table 3, Model 1).
 
Determinants of CI as dichotomized by MNC in HIV-1-infected cohort participants (sensitivity analysis)
 
Logistic regression analysis showed cannabis use, history of prior cardiovascular disease, impaired renal function, and diabetes mellitus type 2 (borderline) to be independently associated with CI (Table 3, Model 2).
 
Discussion
 
Key results

 
Determinants for decreased cognitive performance by MNC, when used as a continuous variable, included cannabis use, history of prior cardiovascular disease, impaired renal function, diabetes mellitus type 2, having an above-normal waist-to-hip ratio, presence of depressive symptoms, and lower nadir CD4-count.
 
The first four determinants were also observed in a sensitivity analysis for which CI was dichotomized as being present or absent by MNC. The latter three variables were not significant determinants in this analysis.
 
Interpretation, limitations, and conclusion
 
To appreciate these findings, some aspects of the current report need to be addressed further. Strong features of the AGEhIV Cohort Study and its nested substudy are the large similarity between the HIV-1-infected and the HIV-uninfected study group, as well as the high level of detail by which all participants have been characterized. In addition, extensive clinical and biochemical data were obtained allowing for detailed assessment of relationships and adjustment for confounding.
 
Our results being those of cross-sectional analyses, we are merely able to demonstrate associations rather than causality. Although the HIV-1-infected and HIV-uninfected study groups were largely comparable, differences in some demographic and lifestyle-related factors were present, which was addressed by exploring the effect of each factor towards cognitive (dys)function, and incorporating adjustment for those factors with a significant effect. Nonetheless, differences in remaining unmeasured confounders potentially influencing our results cannot be excluded.
 
In addition, some unique characteristics of this cohort (participants being mostly Caucasian hepatitis B and C), may limit generalization of the results to other populations. Additional studies are needed to determine whether our findings apply equally to other populations with different characteristics.
 
When analyzing determinants of cognitive impairment/performance by MNC, we found cannabis use to be strongly associated with cognitive dysfunction. Both in the general population and among HIV-positives, cannabis use has been associated with decreased cognitive function.[21,22] In the context of HIV-infection, cannabis use is common, not only for recreational but also for medicinal use (treating neuropathic pain, anorexia, nausea, or mood disturbances).[23,24] Besides direct effects of cannabis on cognition, the observed association could also be partly explained by some of the abovementioned conditions for which medicinal use of cannabis is indicated, which themselves may be associated with effects on cognition. The underlying reason for cannabis use (medicinal vs. recreational) unfortunately was not captured as part of data collection, and we were therefore unable to explore this hypothesis further.
 
We also found multiple metabolic/cardiovascular factors to be associated with cognitive impairment as well as decreased cognitive performance. Both in the general population and among HIV-positives, hypercholesterolemia, diabetes mellitus type 2, and central obesity have been associated with decreased cognitive function.[25-35]
 
We also found (prior) cardiovascular disease (i.e. angina pectoris, myocardial infarction, or peripheral arterial disease), to be associated with cognitive impairment/performance. In both the general and HIV-infected population, prior cardiovascular disease and subclinical atherosclerotic disease have been associated with cognitive decline.[28,31,36-38]
 
Additionally, we found albuminuria to be associated with cognitive dysfunction, which is in line with other studies, both in the general and the HIV-infected population.[38-40]
 
Interpreting these results, cardiovascular/metabolic factors may contribute substantially to poorer cognitive performance among HIV-infected individuals. Cerebral damage resulting from (micro)vascular disease may therefore importantly contribute towards HIV-associated CI. Several neuroimaging studies among HIV-infected individuals have also demonstrated cardiovascular/metabolic factors to be associated with cerebral damage, thereby supporting this hypothesis.[41-43]
 
Evidence of renal impairment and past cardiovascular disease (each of which are associated with cognitive dysfunction in our analyses) are likely manifestations of (micro)vascular organ damage in many cases, and may (partly) share pathophysiological mechanisms with cerebral damage.
 
Presence of depressive symptoms was identified as an additional risk factor for decreased cognitive performance (but not for CI). In the general population, depression has been associated with cognitive deficits.[44] Among HIV-infected individuals, depressive symptoms have also been associated with decreased cognitive function[45], although one study did not report an association between cognitive function and depressive symptoms.[46]
 
We also found severity of prior immune deficiency, as reflected in a lower nadir CD4-count, to be associated with decreased cognitive performance, which is also consistent with earlier findings.[12,47-49]
 
Although HIV-infection is known to cause immune deficiency by depleting CD4-cells, it is also associated with activation of the immune system and inflammation. This is partly driven by depletion of CD4-cells within the intestinal mucosa resulting in increased permeability and translocation of microbial products across the mucosa. This results in stimulation of both the innate and adaptive immune systems which persists , albeit at a reduced level, among cART-treated HIV-infected patients with suppressed viraemia.[50,51]
 
Atherosclerosis and cardiovascular disease are also closely related to immune activation and inflammation, and have been shown to be highly prevalent among HIV-infected individuals, as is the case for many cardiovascular/metabolic risk factors (such as dyslipidemia, smoking, and central obesity).[52] Immune activation and inflammation may therefore contribute to CI in a direct manner, but also indirectly, by the association with vascular damage and cerebral small vessel disease.
 
Three factors were identified as risk factors for decreased cognitive performance, but not for CI as a dichotomous outcome: having an above-normal waist-to-hip ratio, presence of depressive symptoms, and a lower nadir CD4-count. This discrepancy might very well be explained by reduced statistical power when using CI as a dichotomous outcome measure instead of cognitive performance as a continuous outcome measure.
 
In conclusion, our results indicate that reduced cognitive performance in HIV-1-infected men with sustained suppressed viraemia on cART is likely the result of a multifactorial process, in which not only HIV-associated factors such as having experienced more severe immune deficiency, but also cardiovascular/metabolic factors, cannabis use, and depressive symptoms are key contributors. These are likely to gain increased importance as the population of people living with HIV continues to age.

 
 
 
 
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