title

Results

In the AGEhIV Cohort Study we identify various associated medical conditions, also referred to as comorbidities. Comorbidities become more frequent in the advancing age. Furthermore, we study the prevalence of risk factors for comorbidities and impaired organ functioning. Several analyses have been completed so far. We have examined which comorbidities occur more frequently in our cohort, and what risk factors are related to this increased frequency. This has also been examined separately for the different types of comorbidities and organ dysfunctions, such as cardiovascular diseases, arterial stiffness, high blood pressure, and bone density. In addition, we have studied frailty and participation in the labour market.

103 participants from the AMC and 78 participants from the GGD have participated in the neurological AGEhIV sub study. With the data collected in this sub study, we were able to look at the prevalence of neurocognitive (memory) impairment, the value of screening tests in predicting memory impairments, as well as retinal abnormalities of the eyes. Several other analyses are still ongoing.

Prevalence of comorbidities

Several studies have shown that different types of comorbidities occur more frequently among people living with HIV. In the AGEhIV Cohort Study, we study this topic extensively. The aim of the current analysis was to assess the prevalence of these comorbidities, and whether there is a difference between HIV-positive and HIV-negative participants with similar lifestyles. In addition, we were interested in identifying which factors are related to the prevalence of comorbidities.

During the first study visit all participants were asked to indicate whether they have had certain comorbidities in the past (e.g. heart attack, cancer or stroke). We verified this information by consulting either their hospital medical records in the case of HIV-positive participants, or by contacting their family doctors (GPs) in the case of HIV-negative participants.  The presence of several other comorbidities was assessed by using blood pressure measurements (hypertension), lung function measurements, and blood tests (diabetes and hyperlipidemia) carried out during the first study visit.

Figure 1

Figure 1

The analysis shows that HIV-positive participants on average had more comorbidities than HIV-negative participants (see Figure 1). The comorbidities that occur more frequently among people living with HIV are hypertension, myocardial infarction, peripheral artery disease in legs or abdomen and impaired renal function (see Figure 2). Our results suggest that having an HIV infection is an independent predictor for having more comorbidities. Also, having had prolonged impaired immune function in the past (i.e. immunodeficiency defined as a CD4 count less than 200 cells per milliliter of blood), signs of a stronger inflammatory response measured in blood samples, and the use of high dose ritonavir (Norvir) were all separately associated with higher frequencies of comorbidities.

With the follow-up study visits, we aim to assess whether the differences in comorbidities between HIV-positive and HIV-negative participants persist or increase even more, and which risk factors are related this difference.

Figure 2

Learn more about this topic? Click here

Cardiovascular Disease

Various studies have shown that cardiovascular disease is common among people living with HIV. The AGEhIV Cohort Study has done extensive research regarding cardiovascular disease. All study participants have indicated in the questionnaire whether they have had a myocardial infaction, stroke, peripheral artery disease in legs or abdomen, or chest angina in the past. We verified the exact diagnosis in participants’ medical records (of the HIV-positive participants), or by contacting their GP (of the HIV-negative participants).

cvd_en

The results show that HIV-positive participants had a higher prevalence of cardiovascular disease compared to HIV-negative participants (see figure). There is strong evidence that being HIV-positive is an independent predictor for having had cardiovascular disease, even after taking into consideration known risk factors such as smoking. Prolonged duration of immunodeficiency (CD4 count less than 350 cells per milliliter of blood) was independently associated with the prevalence of cardiovascular disease. In addition, prolonged use of ritonavir (Norvir) in a (nowadays no longer prescribed) high dose (400 mg/day) was associated with the prevalence of cardiovascular disease.

In the analysis, the role of AGEs has been studied in relationship with the prevalence of cardiovascular disease. AGEs (advanced glycation end products) are glycosylated proteins, which can accumulate in tissues. Older age, smoking, and inflammatory diseases lead to increased levels of AGEs. HIV-positive participants on average had a higher AGE-value (2.4) than HIV-negative participants (2.1). The analysis also shows that the increased AGE-value might explain part of the increased prevalence of cardiovascular disease in the HIV-positive group. This could suggest that AGEs may play a vital role in the development of cardiovascular disease in people with HIV.

Arterial stiffness

During the AGEhIV study visits the stiffness of the aorta has been measured in all participants using the Arteriograph®. The Arteriograph procedure is similar to a blood pressure measurement, and is performed using a cuff around the upper arm. The difference is that the cuff is more strongly inflated than during a conventional blood pressure measurement, in order to estimate the blood flow in the aorta. The stiffer the aorta is, the faster the blood flow. Aortic stiffness may indicate damage to the vessel wall, such as atherosclerosis. Increased arterial stiffness is related to an increased risk of cardiovascular disease.

In this study, we investigated whether arterial stiffness differs between HIV-positive and HIV-negative participants, and aimed to identify factors related to an increased arterial stiffness.

Arterial stiffness measurements obtained in the first study visit showed that HIV-positive individuals had a slightly higher blood flow (and hence increased arterial stiffness) than HIV-negative individuals. However, the difference in arterial stiffness is very small: pulse wave velocity was 7.9 m/s in HIV-positive and 7.7 m/s in HIV-negative participants.

We hope to better understand the risk factors associated with increased arterial stiffness, and the relationship between arterial stiffness and the onset of cardiovascular disease through long-term follow-up of AGEhIV study participants.

The results also showed that cigarette smoking is a major risk factor for an increase in arterial stiffness. In addition, HIV-positive people who have had serious immune deficiencies in the past (i.e. CD4 counts below 100 cells per milliliter of blood) in particular had an increased aortic stiffness. This may indicate that these patients have an increased risk of cardiovascular disease.

Learn more about this topic? Click here

arteriograph_en

Hypertension

Hypertension (i.e. high blood pressure) is a major risk factor for the development of cardiovascular diseases. During each study visit blood pressure measurements were carried out in all participants, and use of antihypertensives was identified via a questionnaire. Based on this information, we have assessed the prevalence of hypertension in HIV-positive and HIV-negative participants, as well as factors that were associated with the prevalence of hypertension.

Data obtained during the first study visit show that hypertension was more prevalent among HIV-positive participants in the AGEhIV Cohort Study (see figure).

Several factors play a role in the development of high blood pressure, including smoking, alcohol abuse, familial predisposition, insufficient physical activity, and obesity. The higher prevalence of hypertension among HIV-positive participants seemed mostly due to a larger waist-to-hip ratio in this group. This could partially be the result of the use of specific toxic antiretroviral drugs (stavudine) in the past.

We are interested to see whether there is an increase of the frequency of hypertension in HIV-positive and HIV-negative participants in follow-up study visits.

Learn more about this topic? Click here


Bone Mineral Density

In all participants bone density was measured with the use of a DEXA scan. Bone density in the lumbar vertebrae (the lower spine), the upper part of the femur (upper leg bone) and the femoral neck were all measured. From the analysis of the measurements taken during the first study visit we found that osteoporosis (a greatly reduced bone density) and osteopenia (slightly reduced bone density) are both more common among HIV-positive participants in the AGEhIV Cohort Study (see figure). Osteoporosis can increase the chance of a fracture.

Two important risk factors for osteoporosis are a low body weight and cigarette smoking. It seems that the frequent occurrence of osteoporosis among the HIV-positive participants is mostly explained by the fact that a large part of the group smoked and had an – on average – lower body weight. The group that seems to face an additional risk is the group of HIV-positive participants who have previously gone through severe HIV diseases (such as AIDS) and currently have a lower body weight.

We are very interested to know the results of the following study visits, in which we hope to examine whether the change in bone density over time for HIV-positive and HIV-negative participants is different.

Learn more about this topic? Click here


Frailty

All study participants answer questions during the study visits on unintentional weight loss. Also the pinching force of the writing hand and the walking speed is measured. Together these measurements are combined to determine if someone is “frail”, “pre-frail” or “robust” (not frail at all). In older people (65 years and over) it has been found that frailty is strongly associated with a risk of falling, hospitalization and death.

From the results of the first study visit it appears that HIV-positive study participants are more often frail or pre-frail (see bar chart). The relationship between HIV and frailty was independent of other factors that are also related to frailty. Our study showed some of these other factors to be older age, female gender, a chronic hepatitis C virus infection and symptoms of depression. All these conditions are independently associated with frailty. The results indicate that having more abdominal fat and less fat on the hips has been strongly associated with frailty. In HIV-positive people this can be a manifestation of the lipodystrophy syndrome associated with use of certain antiretroviral medication.

The precise meaning behind frailty in HIV-positive people, who are often younger, is not yet entirely clear. Regarding this subject, we hope to gain more knowledge during the follow up in the AGEhIV Cohort Study.

Learn more about this topic? Click here

Participation in the labor market

Although people living with HIV are living longer, there is evidence that this group faces age-related comorbidities earlier than people of the same age without HIV. This may have negative consequences for social participation, such as having a job. Among 885 participants of the working age (45-65 years) of the AGEhIV Cohort Study we have looked at the extent to which they participate in paid work, and if working, how their working functionality is.

We found that participation in paid employment was lower among HIV-positive participants (63.3%) than among HIV-negative participants (79.0%) (see Figure 1). This difference was largely due to a high percentage (21.7%) of  HIV-positive participants that was completely unable to work. (see Figure 2).

Important factors contributing to being able to participate in paid work were older age, having multiple comorbidities (illnesses) and experiencing stigmas on the workflow.

Figure 1

Among the working participants, we also examined their working capacity; a measure of how well a person can perform in his job. HIV-positive and HIV-negative participants reported the same level of working capacity. This suggests that those living with HIV who did not already have to stop working due to illness, will perform similar to those without HIV.

A diminished working capacity is  often reported by those – for example –  who have little flexibility to deal with recovery from illness at their workplace, such as being able to plan working hours or holidays freely.  Additionally, I appears that having a lower working capacity is also related to having larger work related fatigue and more absence due to illness. People with symptoms of depression, having a part-time job and those born outside of the Netherlands also report lower working capacities.

Learn more about this topic? Click here

Figure 2

Prevalence of cognitive impairment

Before the introduction of antiretroviral therapy, AIDS dementia was one of the most feared complications that could occur as a result of advanced HIV infection. Despite the currently highly effective treatment for HIV, mild memory impairments (HAND) still seem to be associated with being HIV-positive. The exact extent of this association remains unclear, as memory disorders occur in both HIV-positive and HIV-negative people and could be related to multiple other risk factors as well.

All participants of the AGEhIV neurological sub study underwent a comprehensive neuropsychological assessment. During this assessment six different domains were examined: speech, attention and information processing speed, as well as executive, memory and motor functions.

Results of the HIV-positive participants were then compared with results from HIV-negative participants with similar age and educational backgrounds. Hereby we determined whether a person was performing below expected levels or not and if the participant could be classified as having HAND (HIV-associated neurocognitive disorders). This classification can be performed in different ways. In the current study, we classified participants using the Frascati criteria, Gisslen criteria and the MNC method.

The estimated occurrence of HAND varies greatly depending on the classification method used. However, whichever method used, results show that HAND is more prevalent among HIV-positive participants (see figure). After the second study visit, we also hope to make a more elaborate statement about the occurrence of HAND over time.

Learn more about this topic? Click here


Predictors of Cognitive Impairment

Since HIV-positive participants demonstrated cognitive impairment more frequently, we explored the different factors associated with having HIV-associated neurocognitive disorders (HAND) or having lower scores during the neuropsychological assessments.

Among HIV-positive participants we identified seven factors that were associated with a worse score on neuropsychological assessments:

•  daily to monthly use of cannabis

•  prior cardiovascular disease

•  prior decreased kidney function

•  diabetes mellitus

•  an increased waist-to-hip ratio

•  symptoms of depression

•  prior low CD4 cell count (severe immunodeficiency in the past)

Four of these factors positively predicted whether an HIV-positive participant was diagnosed with HAND:

•  daily to monthly use of cannabis

•  prior cardiovascular disease

•  prior decreased kidney function

•  diabetes mellitus

This study shows that multiple factors play a role in the development of cognitive impairment in HIV-positive participants. Part of these factors are related to their HIV-infection, but others are only indirectly or not at all related to their infection.

After completion of the second study visit, we hope to more accurately describe the prevalence of HAND over time and define factors related to its development.

Learn more about this topic? Click here for the published paper or click here for more information.


Quality of Simple Memory Tests for the Diagnosis of Cognitive Impairment

Een goede screeningstest zal in bovenstaande grafiek zo dicht mogelijk bij de dikgedrukte zwarte lijn liggen. Een slecht screeningsinstrument ligt rondom de gestippelde lijn.

A perfectly reliable (hypothetical) screening test is represented by the black line. A completely unreliable (hypothetical) screening test is represented by the dotted line. A real-world good screening test will therefore resemble the pattern of the black line more closely than that of the dotted line.

A screening test is a test that is used to trace down people with a particular disease or condition in a large group of people. In the case of cognitive impairment a screening test could be used to identify those at increased risk for developing cognitive impairment. People that screen positive could then be examined more extensively by means of a complete neuropsychological examination. A good screening test has to meet certain requirements. The central question in this analysis is to determine to what extent some of the commonly used screening tests for memory deficits meet the requirements for identifying those at risk for HIV-associated neurocognitive disorders (HAND).

In the AGEhIV Cohort Study four different screening tests were studied: HDS (specifically developed for HIV dementia), Simioni questions (consisting of three questions that have been used in trials in mild HIV-associated neurocognitive impairment) MoCA and MMSE (two tests commonly used to screen for other forms of dementia, for example in Alzheimer’s Disease). The results of these screening tests were compared to the results from the extensive neuropsychological assessments performed within participants of the neurological sub study. All screening tests performed moderately to poorly when comparing them with the extensive neuropsychological assesments (see figure). The four screening tests are therefore unreliable and not sufficient to identify HAND, thus not useful for screening in clinical practice.

Learn more about this topic? Click here

Eye examination

Foto van het netvlies

Photograph of the retina

Former studies have suggested HIV causes premature aging of the retina. Within an AGEhIV sub study we performed an ophthalmic examination consisting of a number of function tests (e.g. measurement of the contrast sensitivity) and a number of imaging studies of the retina.

All participants have completed their first eye examination and the results have been analyzed. In conclusion, we found no differences in the structure or function of the retina between those with and without HIV. This is good news for the participants with HIV, as a well-suppressed HIV infection seems to prevent changes to the retina.

Treatment of cardiovascular disease and its risk factors

At each study visit, we ask participants whether they have developed cardiovascular disease, for example whether they have had a stroke or a heart attack. We also evaluate whether the participants have risk factors for cardiovascular disease, such as high cholesterol levels, high blood pressure, or smoking. Using this information, we have been able to compare whether cardiovascular disease or its risk factors occur more often in people with HIV than in people without HIV. Moreover, we evaluated whether participants were appropriately treated for cardiovascular disease and the associated risk factors. Treatment of cardiovascular disease risk factors, such as the use of antihypertensive drugs to reduce blood pressure to normal levels, is important to reduce the risk of a new cardiovascular event.

At the first study visit, cardiovascular disease was more prevalent in HIV-positive participants than in HIV-negative participants (10% and 5%, respectively). Among the participants with no history of cardiovascular disease, we evaluated the risk of developing cardiovascular disease in the next 10 years. We calculated this risk based on the presence or absence of certain cardiovascular disease risk factors. We found that participants with HIV were more likely to have a high cardiovascular disease risk than people without HIV (figure 1). The most frequently-observed risk factors for cardiovascular disease were insufficient physical activity, smoking, high cholesterol levels, and high blood pressure. These risk factors were more common among participants with HIV.

Figure 1. Estimated 10-year cardiovascular disease risk among participants with and without HIV who had no history of cardiovascular disease.

When evaluating whether participants have been adequately treated for their cardiovascular disease risk factors, we focused on those participants at high risk of a cardiovascular event (i.e., those participants who had a history of cardiovascular disease or a high estimated cardiovascular disease risk due to a combination of several risk factors). We found that approximately half of these “high risk” participants had high blood pressure, which, in the majority of the cases, were not being treated with antihypertensive medication. Moreover, over 60% of  the “high risk” participants had elevated cholesterol levels, which, in the vast majority of cases, were not being treated with lipid-lowering medication. No significant differences were observed between people with and without HIV.

Next, we focused on participants who used medication to treat high blood pressure or high cholesterol. Approximately 50% of these individuals had optimal blood pressure and cholesterol levels (figure 2). Again, no significant differences were observed between people with and without HIV. However, we did observe that people with HIV who had a history of cardiovascular disease were more likely to use anticoagulant or antiplatelet drugs than people without HIV (85% versus 63%).

Figure 2: Percentage of participants who have optimal blood pressure/cholesterol levels while using medication for a high blood pressure/cholesterol.

This study shows that treatment of cardiovascular diseases and associated risk factors is suboptimal, both in people with and without HIV. To prevent cardiovascular disease, a healthy lifestyle and adequate treatment of risk factors for cardiovascular disease are important and therefore require the attention of both patients and their doctors.


Chronic Kidney Disease 

At each study visit, we take blood samples and ask study participants to provide a urine sample. We use this material to study kidney function and to look for indications of kidney damage in people living with HIV and those without HIV.

By looking at the levels of albumin in the urine and the levels of creatinine in the blood, we can detect the presence of a reduced kidney function. Our results showed a higher frequency of chronically reduced kidney function in people with HIV compared to people without HIV (figure 1).

In addition, we studied the course of kidney function over 4 years of follow-up. Kidney function declined in all participants, but we found a stronger decline in people living with HIV (figure 2).

There are several possible explanations for the poorer kidney function observed in people with HIV. First, there are several drugs against HIV (antiretroviral drugs) that are known to have a negative effect on kidney function. One of these is the frequently-used drug tenofovir. Tenofovir is used, or has been used, by a large proportion of the HIV-positive individuals in the AGEhIV Cohort (73% and 12%, respectively).

It remains unknown whether tenofovir use causes a more rapid decline in kidney function. Our study found no compelling evidence to support this theory. However, since such a large proportion of the HIV-positive study participants use tenofovir, we cannot rule out such an effect. To investigate it further, we would need a comparable group of people with HIV who have never used tenofovir. Unfortunately, we do not have such a group in our cohort.

The results of our study do, however, confirm that traditional risk factors, such as cigarette smoking and hypertension, contribute to a decreased kidney function in people with HIV. Moreover, poorer kidney function in people living with HIV may be due to higher levels of inflammation, which are known to persist in people with HIV despite adequate treatment of their HIV infection.

The older version of tenofovir (disoproxil fumarate tenofovir; TDF) is now frequently being replaced in many HIV treatment regimes by a newer version, namely tenofovir alafenamide (TAF). TAF has fewer negative effects than TDF, including less kidney damage.

Renal function is expressed in milliliter per minute (ml/min)

Cigarette smoking and inflammation 

Cigarette smoking increases the risk of cardiovascular disease and premature death. Some studies have suggested that the negative effects of smoking may be worse in people living with HIV than in people without HIV.

People living with HIV and people who smoke are more likely to have elevated levels of several markers of inflammation. It is thought that this type of chronic inflammation could lead to earlier onset of age-related illnesses, such as cardiovascular disease. In the AGEhIV study we therefore compared the levels of four of these inflammatory markers in the blood of smokers compared with those in non-smokers. In addition, we evaluated whether smoking has a stronger effect on the levels of these markers in people with HIV than in  people without HIV.

The markers we studied were C-reactive protein (CRP), D-dimer, sCD14, and sCD163. CRP is a general marker for inflammation in the blood and D-dimer is a marker for activation of the blood coagulation system. sCD14 and sCD163 are both markers for activation of monocytes, a specific type of white blood cell. Monocyte activation and coagulation may play a role in plaque formation, which may cause cardiovascular disease.

We found higher levels of CRP, D-dimer, and sCD14 in cigarette smokers, regardless of their HIV status. These elevated levels of inflammatory markers likely contribute to the negative health effects of cigarette smoking. We also found higher levels of CRP, sCD14, and sCD163 in people with HIV than in people without HIV, regardless of their smoking status. We found no evidence of smoking having a more marked negative effect on inflammatory markers in people with HIV.

At present, it seems that the reported additional negative effects of smoking on the health of people living with HIV cannot be explained by smoking having a stronger effect on either inflammation or blood coagulation. Further studies are therefore needed to explain this effect.

Proportion of people with a high level (i.e., a value in the upper quartile) of the following markers: C-reactive protein (A), soluble CD14 (B), soluble CD163 (C), D-dimer (D)

Pulmonary (lung) function  

Previous studies have shown that the pulmonary function of people living with HIV on average is worse than in people living without HIV. Often this can largely be explained by the on average more extensive smoking of tobacco by people living with HIV.

A very limited amount of studies have looked at the effects of a (well treated) HIV-infection on pulmonary function independent from risk behavior such as smoking. To understand this better the pulmonary function of all AGEhIV participants was measured using a spirometer. Participants were also questioned about their current and previous smoking behavior to be able to take this into account when analyzing the spirometry results. The results from the first spirometry measurements from the first study visits are described here.

Remarkable was that a spirometry-determined decreased pulmonary function was frequently present. An abnormal spirometry result means that too little air is exhaled in 1 second relative to the total lung volume. This was not only frequently observed in the HIV-positive, but also in the HIV-negative AGEhIV participants. In both groups almost 1 in 4 participants had a spirometry-result that could indicate (early) “obstructive lung disease”, such as asthma or COPD (chronic obstructive pulmonary disease). This was an unexpected finding, since HIV-positive AGEhIV participants were smoking more often. We therefore had expected to see a worse pulmonary function in people living with HIV, simply as a result of their smoking behavior.

We also found that non-smoking HIV-negative participants more frequently met the criteria for “obstructive lung disease” than non-smoking HIV-positive participants. We did not however find evidence for HIV potentially having (had) a protective effect on pulmonary function. In fact, our results suggested that HIV has had an effect on the lungs which has made them slightly more rigid, allowing the lungs to hold only a lower total amount of air.

When applying the spirometric criteria for “obstructive lung disease” this results in a seemingly favorable test result. As a result of this impact of HIV on the lungs, spirometry becomes unreliable to determine the presence of “obstructive lung disease” .

Only few conclusions can be drawn from these findings. First, the simple spirometry measurements appear to be insufficient in determining all aspects of pulmonary function in people living with HIV.

Second, the finding that HIV-negative AGEhIV participants also frequently showed a decreased pulmonary function is potentially due to the lifestyle these participants have had, resembling more the lifestyle of HIV-positive participants than that of the general population. The HIV-negative participants are largely STI-clinic attendants and men who have sex with men. It could well be that during their lifetime they on average have visited clubs and bars more often, where for a long time (passive) smoking was ubiquitous. This potentially has had an effect on the pulmonary function of these older HIV-negative men.

Continuing the spirometry measurements during the follow-up in the AGEhIV study nevertheless remains important, given that studying the changes in the spirometry results over time between HIV-positive and HIV-negative participants may provide further insight into the influences of treated HIV-infection on the lungs.

For more information, click here

Sexual function  

In this analysis we assessed whether people living with HIV experience more sexual problems than people who are HIV negative. The questionnaire which participants complete at each study visit includes questions about sexual functioning. We assessed what men who reported having sex with men had answered to these questions. The questions concerned three sexual domains: erectile function, sexual satisfaction and sexual desire. The responses to these questions revealed that men having sex with men living with HIV experienced decreased erectile function, decreased sexual satisfaction and decreased sexual desire more often than their HIV negative counterparts. This could partly be explained by the fact that the men living with HIV more often reported depressive symptoms, had more other diseases and more often used medication for high blood pressure – each of which are all also related to sexual functioning. The difference in erectile function (getting an erection) was most pronounced between the men with HIV and without HIV. Those who were treated for HIV with lopinavir/ritonavir (Kaletra) in the past or at the time of their first study visit more often experienced decreased erectile function. Based on these results, we have expanded the number of questions on sexual functioning in the study questionnaire, so that we can evaluate sexual functioning among study participants in more detail in the future.

For more information, click here

Up

 
AIGHD
AMC
HIV monitoring
GGD Amsterdam
 
Top