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Grey and white matter abnormalities in treated HIV-
disease and their relationship to cognitive function
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Key points
In successfully treated HIV-disease the prevalence of cognitive impairment is approximately 20%, which is lower than previous reports. Advanced neuroimaging suggests that white matter microstructural abnormalities rather than grey or white matter volume abnormalities are the likely underlying aetiology.
"To conclude, HIV-infection was associated with both lower grey matter volume and white matter microstructural injury. Cognitive impairment, present in approximately 20% of cases, was most clearly associated with white matter abnormalities. Grey and white matter abnormalities tended to occur together suggesting a common aetiology for HIV-associated brain injury, which may be related to prolonged untreated infection and immune activation, in common with other non-AIDS comorbidities.
.......In total, 134 HIV-positive participants were recruited to the COBRA study from London (n=59) and Amsterdam (n=75). For a graphical illustration of the methods see supplementary figure 1. A demographically comparable HIV-negative control population was recruited from sexual health clinics and specific community groups (London: n=29; Amsterdam: n=50)..Eligible participants were aged ≥45 with no significant neurological conditions, substance/alcohol abuse or moderate/severe depression (see supplementary data for specific exclusion criteria). All HIV-positive participants had to have plasma HIV RNA <50 copies/mL on antiretroviral therapy for >12 months prior to enrollment......the locations where we observed abnormalities are consistent with regions of greatest neuronal [34] and grey matter volume [11] loss observed in untreated HIV-infection. Together with the trend for those with prior AIDS to have the lowest grey matter volume, our findings suggest these regions are the earliest affected during the course of HIV-infection and that further atrophy may be prevented with successful treatment......Cognitive impairment was more prevalent in the HIV-positive group, regardless of the method used: GDS: 18.0% vs. 3.8% (odds ratio [95% confidence interval] 5.58 [1.86-24.1], p<0.01); Frascati: 18.0% vs. 3.8% (5.58 [1.86-24.1], p<0.01); MNC: 19.5% vs. 2.5% (9.36 [2.68-59.2], p<0.001). The HIV-positive group scored lower than the control group in the domains of attention, executive function, motor function and processing speed (Fig. 1, W210>6300 and p0.01 for all). Only 1.5% of the HIV-positive group and 1.2% of controls fulfilled the criteria for HIV-associated dementia......In the two-cluster model, cluster one (n=99) had higher grey matter volume and higher mean FA in all regions, whereas cluster two (n=109) had lower grey matter volume and lower mean FA in all regions. HIV-positive individuals were more likely to be members of cluster two, 61.2% vs. 36.4% (odds ratio 2.74 [1.53-4.98], p<0.001, Fig. 4). Furthermore, subjects in cluster two were older (median 59.3 vs 54.6 years, W206=3634, p<0.001) and had significantly poorer cognitive function in the domains of attention, executive function, motor function and processing speed......Our findings suggest that the pathophysiology of cognitive impairment in treated HIV-disease is predominantly due to white matter microstructural injury and support the use of FA as a biomarker to identify HIV-associated brain injury. Furthermore, we consistently showed a lack of interaction between HIV-status, age and neuroimaging biomarkers which suggests static rather than active brain injury in well-treated patients. However, longitudinal data are required to confirm this.....In our study, both study groups were high performing with nearly 40% having some form of tertiary education, which may explain the relatively low prevalence of cognitive impairment.Furthermore, the use of methods less likely to classify high numbers of individuals with cognitive impairment such as MNC [33], in comparisonwith a demographically-comparable control group and sustained suppression of viraemia in the patient group are likely to have contributed to the relatively low prevalence of HIV-associated cognitive impairment.....As we report cross-sectional data, we are unable to resolve the issue of whether these imaging changes reflect historical damage or an on-going pathological process.Using a multivariate approach to examine individual differences in volumetric and diffusion data simultaneously, we identified a brain phenotype that was associated with ageing, cognitive dysfunction, and HIV-status. Furthermore, this phenotype was associated with lower CD4+:CD8+ ratios. This biomarker of immune activation has previously been associated with other age-related comorbidities in well-treated cohorts [39]. Our findings suggest that persistent immune activation may also be associated with brain injury, which may reflect the legacy of prolonged untreated infection as normalisation of this ratio has been associated with earlier antiretroviral therapy initiation [40]."
Clinical Infectious Diseases April 5 2017 -Jonathan Underwood1, James H Cole2, Matthan Caan3, Davide De Francesco4, Robert Leech2, Rosan A. van Zoest5, Tanja Su3, Gert J Geurtsen6, Ben A Schmand6, Peter Portegies7, Maria Prins8, Ferdinand W.N.M. Wit5,9,10 Caroline A Sabin4, Charles Majoie3, Peter Reiss5,9,10 *Alan Winston1 and *David J Sharp2 for The Co-morBidity in Relation to Aids (COBRA) Collaboration
* Alan Winston and David Sharp contributed equally to this work.
1Division of Infectious Diseases, Imperial College London, UK
2Division of Brain Sciences, Imperial College London, UK
3Department of Radiology, Academic Medical Center, The Netherlands
4Department of Infection & Population Health, UCL, London
5Department of Global Health, Academic Medical Center, and Amsterdam Institute for Global
Health and Development (AIGHD), Amsterdam, The Netherlands
6Department of Medical Psychology, Academic Medical Center, The Netherlands
7Department of Neurology, Academic Medical Center, The Netherlands
8Public Health Service Amsterdam
9HIV Monitoring Foundation, Amsterdam, the Netherlands
10Department of Internal Medicine, Division of Infectious Diseases, Academic Medical Center, Amsterdam, The Netherlands
Some of this work has previously been presented orally at the Conference on Retroviruses and Opportunistic Infections 2016 (abstract 148) and at the British HIV Association Annual Conference (abstract O12).
Abstract
Background
Long-term comorbidities such as cognitive impairment remain prevalent in otherwise effectively treated people-living-with-HIV. We investigate the relationship between cognitive impairment and brain structure in successfully treated patients using multi-modal neuroimaging from the Co-morBidity in Relation to AIDS (COBRA) cohort.
Methods
Cognitive function, brain tissue volumes and white matter microstructure were assessed in 134 HIV-positive patients and 79 controls. All patients had suppressed plasma HIV RNA at cohort entry. In addition to comprehensive voxelwise analyses of volumetric and diffusion tensor imaging, we used an unsupervised machine learning approach to combine cognitive, diffusion and volumetric data, taking advantage of the complementary information they provide.
Results
Compared to the highly comparable control group, cognitive function was impaired in four out of the six cognitive domains tested (median global T-scores: 50.8 vs. 54.2, p<0.001). Patients had lower grey but not white matter volumes, observed principally in regions where structure generally did not correlate with cognitive function. Widespread abnormalities in white matter microstructure were also seen, including reduced fractional anisotropy with increased mean and radial diffusivity. In contrast to the grey matter, these diffusion abnormalities correlated with cognitive function. Multivariate neuroimaging analysis identified a neuroimaging phenotype associated with poorer cognitive function, HIV-infection and systemic immune activation.
Conclusions
Cognitive impairment, lower grey matter volume and white matter microstructural abnormalities were evident in HIV-positive individuals despite fully suppressive antiretroviral therapy. White matter abnormalities appear to be a particularly important determinant of cognitive dysfunction seen in well-treated HIV-positive individuals.
Introduction
As a result of modern combination antiretroviral therapy, HIV-infection is now a chronic disease with life expectancy approaching that of the general population [1]. Despite this, concerns remain regarding an increased prevalence of age-associated comorbidities and the possibility of an 'accelerated ageing' phenotype [2]. Cognitive impairment, which is associated with poorer clinical outcomes and higher mortality [3,4] reportedly affects up to 50% of HIV-positive individuals [5,6]. Yet, most data does not pertain to virologically suppressed cohorts, which are now the norm in Northern European settings [7] and hence there remains uncertainty about its etiology.
One possibility is that cognitive impairment results from structural damage to brain regions that support cognition. Earlier work has described lower grey and white matter volumes in numerous locations in HIV-positive individuals [8-13]. Diffusion-weighted imaging, an advanced MRI technique, is more sensitive at revealing white matter abnormalities than volumetric measures in HIV-positive individuals [14-19]. However, the relationships between imaging abnormalities and cognitive function remain uncertain, particularly in well-treated patients, with several studies failing to report any associations [13,17,19,20].
Given the advances in HIV-medicine and neuroimaging techniques we recruited virally suppressed HIV-positive individuals and a demographically comparable HIV-negative control group into the EU-funded Co-morBidity in Relation to AIDS (COBRA) study. We determined the prevalence of cognitive impairment and itsrelationships with grey and white matter abnormalities. Furthermore, we systematically investigated whether previously proposed sub-types of HIV-associated brain injury [21] were present using a multi-modal, 'machine-learning' approach. We tested the following hypotheses: i) despite successful antiretroviral therapy, HIV-positive individuals would exhibit cognitive impairment compared to an appropriate HIV-negative control population; ii) HIV-positive individuals would have lower grey and white matter volumes as well as multiple abnormalities on diffusion-weighted imaging; iii) cognitive impairment would be associated with abnormal brain structure; and iv) grey and white matter abnormalities would occur together and more commonly in HIV-positive individuals supporting the presence of a common pathogenic mechanism.
Methods
Participants
In total, 134 HIV-positive participants were recruited to the COBRA study from London (n=59) and Amsterdam (n=75). For a graphical illustration of the methods see supplementary figure 1. A demographically comparable HIV-negative control population was recruited from sexual health clinics and specific community groups (London: n=29; Amsterdam: n=50). Eligible participants were aged ≥45 with no significant neurological conditions, substance/alcohol abuse or moderate/severe depression (see supplementary data for specific exclusion criteria). All HIV-positive participants had to have plasma HIV RNA <50 copies/mL on antiretroviral therapy for >12 months prior to enrollment.
Neuropsychological tests
Participants completed a comprehensive neuropsychological test battery, assessing attention, executive function, language, memory, information processing speed and motor function (supplementary table 1). Raw scores were converted to standardised T-scores accounting for age and educational level with higher T-scores representing better cognitive function. Global T-score was the mean of the six domain T-scores. Three common classification methods, the HIV-associated neurocognitive disorder ('Frascati') criteria, the global deficit score (GDS) and multivariate normative comparison (MNC) were then applied according to published methods [22-24].
Neuroimaging acquisition
In London, images were acquired using a Siemens 3T Verio scanner with a 32-channel head coil (HIV-positive: n=59; HIV-negative: n=29) and in Amsterdam initially with a Philips 3T Intera with an 8-channel phased array head coil (HIV-positive: n=46; HIV-negative: n=20) and then using a Philips 3T Ingenia with a 16-channel head coil (HIV-positive: n=29; HIV-negative: n=30; both Philips Healthcare, Best, the Netherlands) due to a scanner upgrade (see supplementary data for scanning parameters).
Image processing
T1-weighted images were pre-processed using SPM12 (University College London, London, UK). Briefly, images were bias corrected, segmented into grey matter, white matter and cerebrospinal fluid (CSF) and volumes calculated. These were then registered to a custom template and normalised to Montreal Neurological Institute (MNI)-152 space using the Diffeomorphic Anatomical Registration using Exponentiated Lie algebra (DARTEL) algorithm [25].
Diffusion data were pre-processed using FMRIB Software Library v5.0.6 (FSL, FMRIB, University of Oxford). Briefly, images were corrected for eddy currents and head motion, non-brain tissue was deleted and the diffusion tensor model was fitted at every voxel. These were then registered to a custom template and standard space, using Diffusion Tensor Imaging ToolKit v2.3.1 [26]. Fractional anisotropy (FA), axial, mean and radial diffusivity maps for each participant were then 'skeletonised' using FSL and thresholded using FA 0.2 to exclude areas with considerable inter-individual variability prior to performing tract-based spatial statistics (TBSS) [27].
Statistical analyses
Group comparisons
Baseline group differences were assessed using chi-square, Fisher's exact, Wilcoxon rank sum and unpaired t-tests as appropriate. To account for variance associated with potential scanner and head coil differences, a three-level factor was entered into all models, an approach used previously in multisite studies of HIV-positive individuals[8,20]. These analyses were performed using R v3.1.3, with p-values <0.05 considered statistically significant.
Voxelwise inference testing
Voxelwise group differences in grey and white matter volume and diffusion measures were calculated using the general linear model, adjusting for age, intracranial volume and scanner. Correction for multiple comparisons used permutation testing [28] (n=10,000) and threshold-free cluster enhancement (TFCE) [29]. Permutation-corrected p-values <0.05 were considered significant.
Combining imaging and cognitive data
For each cognitive domain, a multiple linear regression model was fitted with age, intracranial volume, scanner, HIV-status and either total grey matter volume or mean skeleton FA as independent variables and the relevant cognitive domain T-score as the dependent variable. Separate models with an additional HIV-status and imaging measure interaction term were also tested. To investigate the relationship between localised brain structure and cognitive function, voxelwise regressions were calculated using similar methods.
Cluster analysis
T1-weighting provides good contrast between grey and white matter for volumetric assessment, whereas diffusion-weighting provides information about white matter microstructure. To take advantage of this complementary information we used multivariate k-means clustering to test whether distinct groups could be identifiedbased on neuroimaging measures. As a dimension reduction step, each participant's brain was summarised into 109 regions using the Harvard-Oxford and International Consortium of Brain Mapping (ICBM) DTI-81 atlases. To ensure comparable distributions, these were then scaled before entering into the clustering model. To assess the optimal number of clusters, separate models with 2-10 clusters were calculated. These were compared using the Calinski-Harabasz index and the average silhouette width. The Duda-Hart test was used to confirm cluster structure to the data (i.e., k>1). Cluster stability was assessed using the Jaccard coefficient, calculated using bootstrapping with 10,000 resamples [30]. Cluster analyses were performed with the R package 'fpc' v2.1.9.
Results
Participants
At entry, all HIV-positive participants (n=134) had an undetectable plasma HIV RNA with a median (interquartile range) CD4+ cell count of 618 (472-806) cells/μL and duration of antiretroviral therapy of 12.5 (7.4-16.9) years. The HIV-negative group (n=79) was comparable to the HIV-positive group in: age, gender, education level, cardiovascular risk factors, smoking and recreational drug use. The HIV-positive group included a greater proportion of Black-Africans (table 1). One participant did not complete the full cognitive battery, and neuroimaging data was missing for n=5 participants (T1 not useable n=1, incomplete diffusion-MRI n=1, excessive motion artefact on diffusion-MRI n=3).
Cognitive function
Cognitive impairment was more prevalent in the HIV-positive group, regardless of the method used: GDS: 18.0% vs. 3.8% (odds ratio [95% confidence interval] 5.58 [1.86-24.1], p<0.01); Frascati: 18.0% vs. 3.8% (5.58 [1.86-24.1], p<0.01); MNC: 19.5% vs. 2.5% (9.36 [2.68-59.2], p<0.001). The HIV-positive group scored lower than the control group in the domains of attention, executive function, motor function and processing speed (Fig. 1, W210>6300 and p0.01 for all). Only 1.5% of the HIV-positive group and 1.2% of controls fulfilled the criteria for HIV-associated dementia.
Brain tissue volumes and diffusion measures
HIV-positive individuals had lower total grey matter volume than controls (table 2). There was a significant negative correlation between age and grey matter volume (r=-0.31, p<0.0001) but no significant age and HIV-status interaction (t205=0.45, p=0.65). Voxelwise analysis demonstrated lower grey matter volume in the HIV-positive group, located principally in the intracalcarine and supracalcarine cortices (Fig. 2). In contrast, total white matter volume was not significantly different between the groups (p=0.59), nor were there any significant voxelwise differences.
Despite comparable white matter volumes, HIV-positive individuals had lower FA and higher mean and radial (but not axial) diffusivity than controls (table 2). There were age-associated changes to all diffusion metrics (r=-0.36, 0.45, 0.45 and 0.40 for FA, mean, radial and axial diffusivity respectively, p<0.0001 for all) but no significant interactions between age and HIV-status (p>0.5 for all). Voxelwise analyses revealed widespread abnormalities in FA, mean and radial diffusivity inHIV-positive individuals with a similar pattern of change to the whole brain diffusion metrics (Fig. 2).
In the HIV-positive group, grey and white matter volumes and mean FA were not associated with known duration of untreated HIV-infection, duration of antiretroviral therapy, current or nadir CD4+ cell counts or CD4+:CD8+ cell count ratio (p>0.15 for all). However, there were trends for patients with prior AIDS to have lower grey matter volume (difference 14.3 mL, t128=1.9, p=0.06) and lower mean FA (difference 0.0059, t128=1.7, p=0.08).
HIV-associated brain injury and cognitive function
Across patients and controls, larger grey matter volumes were associated with better cognitive performance. Total grey matter volume was positively correlated with executive function, motor function and global T-scores with no significant interactions between HIV-status and cognitive T-scores (table 3). Voxelwise analyses were then performed allowing regional differences in the relationship between brain structure and cognition to be explored. Spatial correspondence between the regions of grey matter correlated with cognitive function and the previously described HIV-associated grey matter volume reduction was generally modest, but greatest for executive function (Fig. 3, supplementary table 2).
Across both groups, higher FA was associated with greater cognitive performance. FA averaged across the main white matter tracts was positively correlated with attention, executive function, processing speed and global T-scores (table 3). Therewere no interactions between HIV-status, FA and cognitive T-scores. Across both groups, using a voxelwise approach, FA was positively correlated with attention, executive function, motor function and processing speed and global T-scores in many regions, primarily in the body and genu of the corpus callosum. In contrast to the grey matter volume results, these were similar to white matter tracts with reduced FA in the HIV-positive group (Fig. 3, supplementary table 2).
Cluster analysis
Using k-means clustering, two groups were identified that were stable with resampling (mean Jaccard coefficient 0.99). Other cluster models (i.e. k>2) were much less stable (mean Jaccard coefficient <0.7). In the two-cluster model, cluster one (n=99) had higher grey matter volume and higher mean FA in all regions, whereas cluster two (n=109) had lower grey matter volume and lower mean FA in all regions. HIV-positive individuals were more likely to be members of cluster two, 61.2% vs. 36.4% (odds ratio 2.74 [1.53-4.98], p<0.001, Fig. 4). Furthermore, subjects in cluster two were older (median 59.3 vs 54.6 years, W206=3634, p<0.001) and had significantly poorer cognitive function in the domains of attention, executive function, motor function and processing speed (Fig. 5, W205≥6307, p≤0.03 for all). Importantly, these cognitive differences between members of clusters one and two were not due to demographic differences, as the cognitive T-scores are adjusted for age and educational level. Although there were no significant differences in current and nadir CD4+ cell counts (p=0.10 and 0.17), HIV-positive individuals in cluster two had lower CD4+:CD8+ ratios (0.82 vs. 1.06, W132=2666, p=0.01) and were older (58.6 vs 53.2 years, W132=1380, p<0.001) than those in cluster one.
Discussion
We demonstrate that HIV-positive individuals have evidence of cognitive impairment, lower grey matter volume and widespread white matter microstructural abnormalities despite successful antiretroviral treatment. Generally, the grey matter volume reduction associated with HIV-infection was modest and did not occur in regions where brain structure correlated with cognitive function. In contrast, HIV-associated white matter abnormalities were widespread and found in many of the white matter tracts whose structure correlated with cognitive function. These findings extend previous work [13,17,19,20] by showing that white matter structure is correlated with cognitive impairment in chronic HIV-infection. Our findings suggest that the pathophysiology of cognitive impairment in treated HIV-disease is predominantly due to white matter microstructural injury and support the use of FA as a biomarker to identify HIV-associated brain injury. Furthermore, we consistently showed a lack of interaction between HIV-status, age and neuroimaging biomarkers which suggests static rather than active brain injury in well-treated patients. However, longitudinal data are required to confirm this.
The prevalence of cognitive impairment in well-treated HIV-positive patients has been uncertain. Although early studies reported high rates of cognitive impairment in chronically treated patients [5,6,31], some studies have failed to observe this [32]. In our study, both study groups were high performing with nearly 40% having some form of tertiary education, which may explain the relatively low prevalence of cognitive impairment. Furthermore, the use of methods less likely to classify high numbers of individuals with cognitive impairment such as MNC [33], in comparisonwith a demographically-comparable control group and sustained suppression of viraemia in the patient group are likely to have contributed to the relatively low prevalence of HIV-associated cognitive impairment.
Total grey matter volume was lower in the HIV-positive group with reductions occurring primarily in the intracalcarine and supracalcarine cortices. Previous studies in populations with variable suppression of HIV-replication have described more widespread grey matter volume reductions [8,10,12]. However, the locations where we observed abnormalities are consistent with regions of greatest neuronal [34] and grey matter volume [11] loss observed in untreated HIV-infection. Together with the trend for those with prior AIDS to have the lowest grey matter volume, our findings suggest these regions are the earliest affected during the course of HIV-infection and that further atrophy may be prevented with successful treatment.
Diffusion-weighted imaging showed widespread evidence of HIV-associated white matter microstructural injury, with the disparity in radial but not axial diffusivity suggestive of white matter demyelination [35]. The characteristics and location of this injury are consistent with histopathological reports from the pre-antiretroviral era, where myelin damage was found in the central white matter [36]. The decoupling of diffusion abnormalities and white matter atrophy is interesting and has been reported previously in HIV-positive individuals with relatively preserved immunity (mean CD4+ 613 cells/uL) [17]. Together with the trend for the most severe abnormalities to occur in patients with prior AIDS, our findings suggest that diffusion abnormalities may reflect historical damage prior to antiretroviral therapy initiation and that progression to white matter atrophy may be aborted with sustained suppression ofHIV-replication. Although cardiovascular disease may also be implicated in well-treated patients [37], this is unlikely to explain the observed group differences, given the similarity in measured cardiovascular risk factors between groups. As we report cross-sectional data, we are unable to resolve the issue of whether these imaging changes reflect historical damage or an on-going pathological process.
The HIV-associated microstructural injury occurred in white matter tracts correlated with cognitive function. In contrast, the HIV-associated grey matter volume reduction generally did not occur in brain regions correlated with cognitive function. Although this could reflect the cognitive battery we employed, these data suggest that white matter abnormalities may be a more important determinant of cognitive impairment in treated HIV-disease. White matter abnormalities of this type correlate with cognitive function in other disease states [38], and are thought to disrupt the synchronised functioning of large-scale, distributed brain networks that cognition depends on.
Using a multivariate approach to examine individual differences in volumetric and diffusion data simultaneously, we identified a brain phenotype that was associated with ageing, cognitive dysfunction, and HIV-status. Furthermore, this phenotype was associated with lower CD4+:CD8+ ratios. This biomarker of immune activation has previously been associated with other age-related comorbidities in well-treated cohorts [39]. Our findings suggest that persistent immune activation may also be associated with brain injury, which may reflect the legacy of prolonged untreated infection as normalisation of this ratio has been associated with earlier antiretroviral therapy initiation [40].
Our study benefits from comprehensive neuropsychological, volumetric and diffusion assessments in patients and demographically-appropriate controls. However, our study has a number of limitations. Whilst our cohort is not representative of the entire HIV-positive population, it is representative of older HIV-positive adults receiving care in a Northern European setting where over 90% are successfully treated [7]. Cohort studies are potentially limited by unmeasured differences confounding group comparisons. This is particularly an issue when studying HIV-positive populations and age-related comorbidities given high rates of smoking, alcohol and recreational drug use. We limited this by recruiting a comparable control population but unmeasured differences between the two groups may remain. One previous study of virally suppressed patients [41], which used different MRI modalities, may have had a less comparable control group (81% of the HIV-positive group vs 47% of the HIV-negative group were male), which may lead to an overstatement of the HIV association. Differences in scanner and head coil parameters between sites may potentially confound multi-site neuroimaging studies, however, bias was minimised by adjusting for these factors in our models. Furthermore, restricting the analyses to data acquired in London only resulted in HIV associations of a similar magnitude and direction as the entire study population (supplementary table 3), giving confidence that scanner differences did not bias our main findings. Cluster analysis may split the participants into potentially arbitrary groups and the 'good'/'bad' brain phenotype may, in reality, be more of a continuum. Although exploratory, we found excellent internal validity by demonstrating a high level of cluster stability with resampling and good external validity by the associations of cluster membership with age, HIV-status, cognitive function and markers of systemic immune activation.
To conclude, HIV-infection was associated with both lower grey matter volume and white matter microstructural injury. Cognitive impairment, present in approximately 20% of cases, was most clearly associated with white matter abnormalities. Grey and white matter abnormalities tended to occur together suggesting a common aetiology for HIV-associated brain injury, which may be related to prolonged untreated infection and immune activation, in common with other non-AIDS comorbidities.
Funding
This work was supported by a European Union Seventh Framework Programme grant to the Comorbidity in Relation to AIDS (COBRA) project (FP-7-HEALTH 305522, all authors), National Institute for Health Research (NIHR) Professorship (NIHR-RP-011-048; DJS), NIHR Imperial Biomedical Research Centre, the Netherlands Organisation for Health Research and Development (ZonMW) (grant number 300020007) & Stichting AIDS Fonds (grant number 2009063), Nuts-Ohra Foundation (grant number 1003-026) and unrestricted scientific grants from: ViiV Healthcare, Gilead Sciences, Janssen Pharmaceutica N.V. Bristol-Myers Squibb (BMS), and Merck & Co to the AGEhIV cohort study, as well as investigator initiated grants from BMS, Gilead Sciences, Janssen, Merck and ViiV Healthcare to the POPPY cohort study.
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