Imperial College London

Dr Jonathan Underwood

Faculty of MedicineDepartment of Infectious Disease

Honorary Clinical Research Fellow
 
 
 
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Contact

 

+44 (0)20 3312 1466jonathan.underwood Website CV

 
 
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Location

 

Winston Churchill WingSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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40 results found

Underwood J, de francesco D, Cole JH, Caan MWA, Van Zoest RA, Schmand BA, Sharp D, Sabin CA, Reiss P, Winston Aet al., 2019, Validation of a novel multivariate method of defining HIV-associated cognitive impairment, Open Forum Infectious Diseases, ISSN: 2328-8957

BackgroundThe optimum method of defining cognitive impairment in virally suppressed people-living-with-HIV is unknown. We evaluated the relationships between cognitive impairment, including using a novel multivariate method (NMM), patient reported outcome measures (PROMs) and neuroimaging markers of brain structure across three cohorts.MethodsDifferences in the prevalence of cognitive impairment, PROMs and neuroimaging data from the COBRA, CHARTER and POPPY cohorts (total n=908) were determined between HIV-positive participants with and without cognitive impairment defined using the HIV-associated neurocognitive disorders (HAND), global deficit score (GDS) and NMM criteria.ResultsThe prevalence of cognitive impairment varied by up to 27% between methods used to define impairment (e.g. 48% for HAND vs. 21% for NMM in the CHARTER study). Associations between objective cognitive impairment and subjective cognitive complaints were generally weak. Physical and mental health summary scores (SF-36) were lowest for NMM-defined impairment (p’s<0.05).There were no differences in brain volumes or cortical thickness between participants with and without cognitive impairment defined using the HAND and GDS measures. In contrast, those identified with cognitive impairment by the NMM had reduced mean cortical thickness in both hemispheres (p’s<0.05), as well as smaller brain volumes (p<0.01). The associations with measures of white matter microstructure and brain-predicted age were generally weaker.ConclusionDifferent methods of defining cognitive impairment identify different people with varying symptomatology and measures of brain injury. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer self-reported health status. This may be due to the statistical advantage of using a multivariate approach.

Journal article

Dhillon S, Sabin CA, Alagaratnam J, Bagkeris E, Post FA, Boffito M, Anderson J, Vera J, Williams I, Johnson M, Sachikonye M, Babalis D, Mallon PW, Winston A, Pharmacokinetic and Clinical Observations in People over Fifty POPPY studyet al., 2019, Level of agreement between frequently used cardiovascular risk calculators in people living with HIV, HIV Medicine, Vol: 20, Pages: 347-352, ISSN: 1464-2662

OBJECTIVES: The aim of the study was to describe agreement between the QRISK2, Framingham and Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cardiovascular disease (CVD) risk calculators in a large UK study of people living with HIV (PLWH). METHODS: PLWH enrolled in the Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) study without a prior CVD event were included in this study. QRISK2, Framingham CVD and the full and reduced D:A:D CVD scores were calculated; participants were stratified into 'low' (< 10%), 'intermediate' (10-20%) and 'high' (> 20%) categories for each. Agreement between scores was assessed using weighted kappas and Bland-Altman plots. RESULTS: The 730 included participants were predominantly male (636; 87.1%) and of white ethnicity (645; 88.5%), with a median age of 53 [interquartile range (IQR) 49-59] years. The median calculated 10-year CVD risk was 11.9% (IQR 6.8-18.4%), 8.9% (IQR 4.6-15.0%), 8.5% (IQR 4.8-14.6%) and 6.9% (IQR 4.1-11.1%) when using the Framingham, QRISK2, and full and reduced D:A:D scores, respectively. Agreement between the different scores was generally moderate, with the highest level of agreement being between the Framingham and QRISK2 scores (weighted kappa = 0.65) but with most other kappa coefficients in the 0.50-0.60 range. CONCLUSIONS: Estimates of predicted 10-year CVD risk obtained with commonly used CVD risk prediction tools demonstrate, in general, only moderate agreement among PLWH in the UK. While further validation with clinical endpoints is required, our findings suggest that care should be taken when interpreting any score alone.

Journal article

Underwood J, De Francesco D, Cole J, Wit F, Sharp D, Sabin C, Reiss P, Winston Aet al., 2019, Antiretroviral central nervous system toxicity, British HIV Association, Publisher: WILEY, Pages: 36-36, ISSN: 1464-2662

Conference paper

De Francesco D, Underwood J, Bagkeris E, Boffito M, Post FA, Mallon PWG, Vera JH, Williams I, Anderson J, Johnson M, Sabin CA, Winston A, Babalis D, Boffito M, Burgess L, Mallon P, Sabin C, Sachikonye M, Winston A, Asboe D, Garvey L, Pozniak A, Sabin C, Sachikonye M, Clarke A, Vera J, Bexley A, Richardson C, Kirk S, Gleig R, Asboe D, Pozniak A, Bracchi M, Pagani N, Cerrone M, Bradshaw D, Ferretti F, Higgs C, Seah E, Fletcher S, Anthonipillai M, Moyes A, Deats K, Syed I, Matthews C, Fernando P, Chiwome C, Hardwick S, Anderson J, Mguni S, Clark R, Nevin-Dolan R, Pelluri S, Post F, Campbell L, Yurdakul S, Okumu S, Pollard L, Santana-Suarez B, Macken A, Ghavani-Kia B, Maher J, Byrne M, Flaherty A, Babu S, Otiko D, Phillips L, Laverick R, Beynon M, Salz A-L, Severn A, Winston A, Garvey L, Tembo L, Stott M, McDonald L, Dransfield F, Whitehouse A, Burgess L, Babalis D, Ngwu N, Hemat N, Jones M, Carroll A, Kinloch S, Youle M, Madge S, Sabin Cet al., 2019, Depression, lifestyle factors and cognitive function in people living with HIV and comparable HIV-negative controls, HIV MEDICINE, Vol: 20, Pages: 274-285, ISSN: 1464-2662

Journal article

De Francesco D, Wit FW, Burkle A, Oehlke S, Kootstra NA, Winston A, Franceschi C, Garagnani P, Pirazzini C, Libert C, Grune T, Weber D, Jansen EHJM, Sabin CA, Reiss P, Reiss P, Winston A, Wit FW, Prins M, van der Loeff MFS, Schouten J, Schmand B, Geurtsen GJ, Sharp DJ, Caan MWA, Majoie C, Villaudy J, Berkhout B, Kootstra NA, Gisslen M, Pasternak A, Sabin CA, Guaraldi G, Burkle A, Libert C, Franceschi C, Kalsbeek A, Fliers E, Hoeijmakers J, Pothof J, van der Valk M, Bisschop PH, Portegies P, Zaheri S, Burger D, Cole JH, Biirkle A, Zikkenheiner W, Janssen FR, Underwood J, Kooij KW, van Zoest RA, Doyle N, van der Loeff MS, Schmand BA, Verheij E, Verboeket SO, Elsenga BC, Hillebregt MMJ, Ruijs YMC, Benschop DP, Tembo L, McDonald L, Stott M, Legg K, Lovell A, Erlwein O, Kingsley C, Norsworthy P, Mullaney S, Kruijer T, del Grande L, Olthof V, Visser GR, May L, Verbraak F, Demirkaya N, Visser I, Majoie CBLM, Su T, Leech R, Huguet J, Frankin E, van der Kuyl A, Weijer K, Siteur-Van Rijnstra E, Harskamp-Holwerda AM, Maurer I, Ruiz MMM, Girigorie AF, Boeser-Nunnink B, Kals-Beek A, Bisschop PHLT, de Graaff-Teulen M, Dewaele S, Garagnani P, Pirazzini C, Capri M, Dall'Olio F, Chiricolo M, Salvioli S, Fuchs D, Zetterberg H, Weber D, Grune T, Jansen EHJM, De Francesco D, Sindlinger T, Oehlke Set al., 2019, Do people living with HIV experience greater age advancement than their HIV-negative counterparts?, AIDS, Vol: 33, Pages: 259-268, ISSN: 0269-9370

Objectives: Despite successful antiretroviral therapy, people living with HIV (PLWH)may show signs of premature/accentuated aging. We compared established biomarkersof aging in PLWH, appropriately chosen HIV-negative individuals, and blood donors,and explored factors associated with biological age advancement.Design: Cross-sectional analysis of 134 PLWH on suppressive antiretroviral therapy, 79lifestyle-comparable HIV-negative controls aged 45 years or older from the Co-morBidity in Relation to AIDS (COBRA) cohort, and 35 age-matched blood donors.Methods: Biological age was estimated using a validated algorithm based on 10biomarkers. Associations between ‘age advancement’ (biological minus chronological age) and HIV status/parameters, lifestyle, cytomegalovirus (CMV), hepatitisB (HBV) and hepatitis C virus (HCV) infections were investigated using linear regression.Results: The average (95% CI) age advancement was greater in both HIV-positive [13.2(11.6–14.9) years] and HIV-negative [5.5 (3.8–7.2) years] COBRA participants comparedwith blood donors [7.0 (4.1 to 9.9) years, both P’s< 0.001)], but also in HIV-positivecompared with HIV-negative participants (P < 0.001). Chronic HBV, higher anti-CMVIgG titer and CD8þ T-cell count were each associated with increased age advancement, independently of HIV-status/group. Among HIV-positive participants, ageadvancement was increased by 3.5 (0.1–6.8) years among those with nadir CD4þT-cell count less than 200 cells/ml and by 0.1 (0.06–0.2) years for each additionalmonth of exposure to saquinavir.

Journal article

Pool ERM, Winston A, Bagkeris E, Vera JH, Mallon PWG, Sachikonye M, Post FA, Pozniak A, Boffito M, Anderson J, Williams I, Johnson M, Burgess L, Sabin CAet al., 2019, High-risk behaviours, and their associations with mental health, adherence to antiretroviral therapy and HIV parameters, in HIV-positive men who have sex with men, HIV MEDICINE, Vol: 20, Pages: 131-136, ISSN: 1464-2662

Journal article

De Francesco D, Winston A, Underwood J, Cresswell FV, Anderson J, Post FA, Williams I, Mallon PWG, Sachikonye M, Babalis D, Vera JH, Bagkeris E, Milinkovic A, Sabin CAet al., 2019, Cognitive function, depressive symptoms and syphilis in HIV-positive and HIV-negative individuals, International Journal of STD and AIDS, ISSN: 0956-4624

© The Author(s) 2019. We evaluated associations between history of syphilis infection and both cognitive function and depressive symptoms in people living with HIV (PLHIV) and comparable HIV-negative controls. Syphilis serological tests, cognitive function and depression were assessed in PLHIV and controls participating in the Pharmacokinetic and Clinical Observations in People Over Fifty study. Cognitive test scores were converted to demographically adjusted T-scores (mean = 50, SD = 10) and then averaged to obtain a global T-score. Severity of depressive symptoms was assessed via the Patient Health Questionnaire-9. Associations of syphilis with global T-scores and depression were assessed using median regression. The 623 PLHIV and 246 HIV-negative controls were predominantly male (89.3% and 66.5%) with median age (interquartile range [IQR]) of 57 (53–63) and 58 (53–63) years, respectively. PLHIV had lower global cognitive T-scores (median [IQR] 48.7 [45.1, 52.1] versus 50.5 [47.0, 53.9], p < 0.001), more severe depressive symptoms (median [IQR] 4 [1, 10] versus 1 [0, 3], p < 0.001) and were more likely to report history of syphilis infection (22.0% versus 8.1%) than controls. There was no significant association between history of syphilis and global cognitive function in either PLHIV (p = 0.69) or controls (p = 0.10). Participants with a history of syphilis had more severe depressive symptoms (median [IQR] 4 [1, 9] versus 2 [0, 8], p = 0.03); however, the association became non-significant (p = 0.62) after adjusting for HIV status and potential confounders. Despite the higher prevalence of syphilis infection in PLHIV, there was no evidence of an association between history of syphilis infection and impaired cognitive function nor depressive symptoms after accounting for potential confounders.

Journal article

Francesco DD, Verboeket SO, Underwood J, Bagkeris E, Wit FW, Mallon PWG, Winston A, Reiss P, Sabin CA, Pharmacokinetic and Clinical Observations in PeoPle Over fiftY POPPY study and the AGEhIV Cohort Studyet al., 2018, Patterns of co-occurring comorbidities in people living with HIV, Open Forum Infectious Diseases, Vol: 5, ISSN: 2328-8957

Background: The aims of this study were to identify common patterns of comorbidities observed in people living with HIV (PLWH), using a data-driven approach, and evaluate associations between patterns identified. Methods: A wide range of comorbidities were assessed in PLWH participating in 2 independent cohorts (POPPY: UK/Ireland; AGEhIV: Netherlands). The presence/absence of each comorbidity was determined using a mix of self-reported medical history, concomitant medications, health care resource use, and laboratory parameters. Principal component analysis (PCA) based on Somers' D statistic was applied to identify patterns of comorbidities. Results: PCA identified 6 patterns among the 1073 POPPY PLWH (85.2% male; median age [interquartile range {IQR}], 52 [47-59] years): cardiovascular diseases (CVDs), sexually transmitted diseases (STDs), mental health problems, cancers, metabolic disorders, chest/other infections. The CVDs pattern was positively associated with cancer (r = .32), metabolic disorder (r = .38), mental health (r = .16), and chest/other infection (r = .17) patterns (all P < .001). The mental health pattern was correlated with all the other patterns (in particular cancers: r = .20; chest/other infections: r = .27; both P < .001). In the 598 AGEhIV PLWH (87.6% male; median age [IQR], 53 [48-59] years), 6 patterns were identified: CVDs, chest/liver, HIV/AIDS events, mental health/neurological problems, STDs, and general health. The general health pattern was correlated with all the other patterns (in particular CVDs: r = .14; chest/liver: r = .15; HIV/AIDS events: r = .31; all P < .001), except STDs (r = -.02; P = .64). Conclusions: Comorbidities in PLWH tend to occur in nonrandom patterns, reflecting known pathological mechanisms and shared risk factors, but also suggesting potential previously unknown mechanisms. Their identification may assist in adequately addressing the pathophysiology of increasingly prevalent multimorbidity in PLWH.

Journal article

Underwood J, Cole JH, Leech R, Sharp DJ, Winston Aet al., 2018, Multivariate pattern analysis of volumetric neuroimaging data and its relationship with cognitive function in treated HIV-disease, Journal of Acquired Immune Deficiency Syndromes, Vol: 78, Pages: 429-436, ISSN: 1525-4135

BACKGROUND: Accurate prediction of longitudinal changes in cognitive function would potentially allow targeted intervention in those at greatest risk of cognitive decline. We sought to build a multivariate model using volumetric neuroimaging data alone to accurately predict cognitive function. METHODS: Volumetric T1-weighted neuroimaging data from virally suppressed HIV-positive individuals from the CHARTER cohort (n=139) were segmented into grey and white matter and spatially normalised before were entering into machine learning models. Prediction of cognitive function at baseline and longitudinally was determined using leave-one-out cross validation. Additionally, a multivariate model of brain ageing was used to measure the deviation of apparent brain age from chronological age and assess its relationship with cognitive function. RESULTS: Cognitive impairment, defined using the global deficit score, was present in 37.4%. However, it was generally mild and occurred more commonly in those with confounding comorbidities (p<0.001). Although multivariate prediction of cognitive impairment as a dichotomous variable at baseline was poor (AUC 0.59), prediction of the global T-score was better than a comparable linear model (adjusted R=0.08, p<0.01 vs. adjusted R=0.01, p=0.14). Accurate prediction of longitudinal changes in cognitive function was not possible (p=0.82).Brain-predicted age exceeded chronological age by mean (95% confidence interval) 1.17 (-0.14-2.53) years, but was greatest in those with confounding comorbidities (5.87 [1.74-9.99] years) and prior AIDS (3.03 [0.00-6.06] years). CONCLUSION: Accurate prediction of cognitive impairment using multivariate models using only T1-weighted data was not achievable, which may reflect the small sample size, heterogeneity of the data or that impairment was usually mild.

Journal article

Cole JH, caan M, Underwood J, de Francesco D, van Zoest R, Wit F, Mutsaerts H, Leech R, Geurtsen G, Portigies P, Majoie C, Schim van der Loeff M, Sabin C, Reiss P, Winston A, Sharp Det al., 2018, No evidence for accelerated ageing-related brain pathology in treated HIV: longitudinal neuroimaging results from the Comorbidity in Relation to AIDS (COBRA) project, Clinical Infectious Diseases, Vol: 66, Pages: 1899-1909, ISSN: 1058-4838

BackgroundDespite successful antiretroviral therapy people living with HIV (PLWH) experience higher rates of age-related morbidity, including abnormal brain structure, brain function and cognitive impairment. This has raised concerns that PLWH may experience accelerated ageing-related brain pathology.MethodsWe performed a multi-centre longitudinal study of 134 virologically-suppressed PLWH (median age = 56.0 years) and 79 demographically-similar HIV-negative controls (median age = 57.2 years). To measure cognitive performance and brain pathology, we conducted detailed neuropsychological assessments and multi-modality neuroimaging (T1-weighted, T2-weighted, diffusion-MRI, resting-state functional-MRI, spectroscopy, arterial spin labelling) at baseline and after two-year follow-up. Group differences in rates of change were assessed using linear mixed effects models.Results123 PLWH and 78 HIV-negative controls completed longitudinal assessments (median interval = 1.97 years). There were no differences between PLWH and HIV-negative controls in age, sex, years of education, smoking, alcohol use, recreational drug use, blood pressure, body-mass index or cholesterol levels.At baseline, PLWH had poorer global cognitive performance (P<0.01), lower grey matter volume (P=0.04), higher white matter hyperintensity load (P=0.02), abnormal white-matter microstructure (P<0.005) and greater ‘brain-predicted age difference’ (P=0.01). Longitudinally, there were no significant differences in rates of change in any neuroimaging measure between PLWH and HIV-negative controls (P>0.1). Cognitive performance was stable across the study period in both groups.ConclusionsOur finding indicate that when receiving successful treatment, middle-aged PLWH are not at increased risk of accelerated ageing-related brain changes or cognitive decline over two years, when compared to closely-matched HIV-negative controls.

Journal article

Underwood J, De Francesco D, Leech R, Sabin CA, Winston Aet al., 2018, Medicalising normality? Using a simulated dataset to assess the performance of different diagnostic criteria of HIV-associated cognitive impairment, PLoS ONE, Vol: 13, ISSN: 1932-6203

ObjectiveThe reported prevalence of cognitive impairment remains similar to that reported in the pre-antiretroviral therapy era. This may be partially artefactual due to the methods used to diagnose impairment. In this study, we evaluated the diagnostic performance of the HIV-associated neurocognitive disorder (Frascati criteria) and global deficit score (GDS) methods in comparison to a new, multivariate method of diagnosis.MethodsUsing a simulated ‘normative’ dataset informed by real-world cognitive data from the observational Pharmacokinetic and Clinical Observations in PeoPle Over fiftY (POPPY) cohort study, we evaluated the apparent prevalence of cognitive impairment using the Frascati and GDS definitions, as well as a novel multivariate method based on the Mahalanobis distance. We then quantified the diagnostic properties (including positive and negative predictive values and accuracy) of each method, using bootstrapping with 10,000 replicates, with a separate ‘test’ dataset to which a pre-defined proportion of ‘impaired’ individuals had been added.ResultsThe simulated normative dataset demonstrated that up to ~26% of a normative control population would be diagnosed with cognitive impairment with the Frascati criteria and ~20% with the GDS. In contrast, the multivariate Mahalanobis distance method identified impairment in ~5%. Using the test dataset, diagnostic accuracy [95% confidence intervals] and positive predictive value (PPV) was best for the multivariate method vs. Frascati and GDS (accuracy: 92.8% [90.3–95.2%] vs. 76.1% [72.1–80.0%] and 80.6% [76.6–84.5%] respectively; PPV: 61.2% [48.3–72.2%] vs. 29.4% [22.2–36.8%] and 33.9% [25.6–42.3%] respectively). Increasing the a priori false positive rate for the multivariate Mahalanobis distance method from 5% to 15% resulted in an increase in sensitivity from 77.4% (64.5–89.4%) to 92.2% (83.3–100%) at a cost of specificity from

Journal article

Francesco DD, Underwood J, Vera JH, Bagkeris E, Asboe D, Mallon PWG, Post FA, Johnson M, Williams I, Boffito M, Greliak P, Anderson J, Sabin CA, Winston Aet al., 2018, Associations between cognitive function and cardiovascular risk factors: differences between people with HIV and HIV-negative controls, Publisher: WILEY, Pages: S10-S11, ISSN: 1464-2662

Conference paper

De Francesco D, Winston A, Choi JY, van Zoest RA, Underwood J, Schouten J, Ku NS, Kim WJ, Reiss P, Sabin CAet al., 2018, Determinants of cognitive function differ in a European and a Korean cohort, Publisher: WILEY, Pages: S75-S75, ISSN: 1464-2662

Conference paper

De Francesco D, Wit FW, Cole JH, Kootstra NA, Winston A, Sabin CA, Underwood J, van Zoest RA, Schouten J, Kooij KW, Prins M, Guaraldi G, Caan MWA, Burger D, Franceschi C, Libert C, Bürkle A, Reiss P, COmorBidity in Relation to AIDS COBRA collaborationet al., 2018, The 'COmorBidity in Relation to AIDS' (COBRA) cohort: Design, methods and participant characteristics, PLoS ONE, Vol: 13, ISSN: 1932-6203

BACKGROUND: Persons living with HIV on combination antiretroviral therapy (cART) may be at increased risk of the development of age-associated non-communicable comorbidities (AANCC) at relatively young age. It has therefore been hypothesised that such individuals, despite effective cART, may be prone to accelerated aging. OBJECTIVE: The COmorBidity in Relation to AIDS (COBRA) cohort study was designed to investigate the potential causal link between HIV and AANCC, amongst others, in a cohort of middle-aged individuals with HIV with sustained viral suppression on cART and otherwise comparable HIV-negative controls. METHODS: Longitudinal cohort study of HIV-positive subjects ≥45 years of age, with sustained HIV suppression on cART recruited from two large European HIV treatment centres and similarly-aged HIV-negative controls recruited from sexual health centres and targeted community groups. Both HIV-positive and HIV-negative subjects were assessed at study entry and again at follow-up after 2 years. RESULTS: Of the 134 HIV-positive individuals with a median (IQR) age of 56 (51, 62) years recruited, 93% were male, 88% of white ethnicity and 86% were men who have sex with men (MSM). Similarly, the 79 HIV-negative subjects had a median (IQR) age of 57 (52, 64) and 92% were male, 97% of white ethnicity and 80% were MSM. CONCLUSIONS: The results from the COBRA study will be a significant resource to understand the link between HIV and AANCC and the pathogenic mechanisms underlying this link. COBRA will inform future development of novel prognostic tools for earlier diagnosis of AANCC and of novel interventions which, as an adjunct to cART, may prevent AANCC.

Journal article

Ferretti F, Mora-Peris B, Underwood J, Waldman A, Everitt A, Winston Aet al., 2018, Cognitive Impairment in a Clinical Setting, Journal of Acquired Immune Deficiency Syndromes, Vol: 77, Pages: e10-e13, ISSN: 1525-4135

Journal article

Ferretti F, Mora-Peris B, Underwood J, Waldman A, Everitt A, Winston Aet al., 2018, Cognitive Impairment in a Clinical Setting, JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES, Vol: 77, Pages: E10-E13, ISSN: 1525-4135

Journal article

Van Zoest RA, Underwood J, De Francesco D, Sabin CA, Cole JH, Wit FW, Caan MWA, Kootstra NA, Fuchs D, Zetterberg H, Majoie CBLM, Portegies P, Winston A, Sharp DJ, Gisslén M, Reiss P, Co-morBidity in Relation to AIDS COBRA Collaborationet al., 2017, Structural brain abnormalities in successfully treated HIV infection: associations with disease and cerebrospinal fluid biomarkers., Journal of Infectious Diseases, Vol: 217, Pages: 69-81, ISSN: 0022-1899

Background: Brain structural abnormalities have been reported in persons with HIV (PWH) on suppressive combination antiretroviral therapy (cART), but their pathophysiology remains unclear. Methods: We investigated factors associated with brain tissue volumes and white matter microstructure (fractional anisotropy) in 134 PWH on suppressive cART and 79 comparable HIV-negative controls, aged ≥45 years from the Co-morBidity in Relation to AIDS (COBRA) cohort, using multimodal neuroimaging and cerebrospinal fluid (CSF) biomarkers. Results: Compared to controls, PWH had lower grey matter volumes (-13.7 mL [95%-confidence interval -25.1, -2.2 mL]) and fractional anisotropy (-0.0073 [-0.012, -0.0024]), with the largest differences observed in those with prior clinical AIDS. Hypertension and CSF soluble CD14 concentration were associated with lower fractional anisotropy. These associations were independent of HIV serostatus (Pinteraction=0.32 and Pinteraction=0.59, respectively) and did not explain the greater abnormalities in brain structure in relation to HIV. Conclusions: The presence of lower grey matter volumes and more white matter microstructural abnormalities in well-treated PWH partly reflect a combination of historical effects of AIDS, as well as the more general influence of systemic factors such as hypertension and ongoing neuroinflammation. Additional mechanisms explaining the accentuation of brain structure abnormalities in treated HIV infection remain to be identified.

Journal article

Booiman T, Wit FW, Maurer I, De Francesco D, Sabin CA, Harskamp AM, Prins M, Garagnani P, Pirazzini C, Franceschi C, Fuchs D, Gisslén M, Winston A, Reiss P, Kootstra NA, Comorbidity in Relation to AIDS COBRA Collaborationet al., 2017, High Cellular Monocyte Activation in People Living With Human Immunodeficiency Virus on Combination Antiretroviral Therapy and Lifestyle-Matched Controls Is Associated With Greater Inflammation in Cerebrospinal Fluid., Open Forum Infectious Diseases, Vol: 4, ISSN: 2328-8957

BACKGROUND: Increased monocyte activation and intestinal damage have been shown to be predictive for the increased morbidity and mortality observed in treated people living with human immunodeficiency virus (PLHIV). METHODS: A cross-sectional analysis of cellular and soluble markers of monocyte activation, coagulation, intestinal damage, and inflammation in plasma and cerebrospinal fluid (CSF) of PLHIV with suppressed plasma viremia on combination antiretroviral therapy and age and demographically comparable HIV-negative individuals participating in the Comorbidity in Relation to AIDS (COBRA) cohort and, where appropriate, age-matched blood bank donors (BBD). RESULTS: People living with HIV, HIV-negative individuals, and BBD had comparable percentages of classical, intermediate, and nonclassical monocytes. Expression of CD163, CD32, CD64, HLA-DR, CD38, CD40, CD86, CD91, CD11c, and CX3CR1 on monocytes did not differ between PLHIV and HIV-negative individuals, but it differed significantly from BBD. Principal component analysis revealed that 57.5% of PLHIV and 62.5% of HIV-negative individuals had a high monocyte activation profile compared with 2.9% of BBD. Cellular monocyte activation in the COBRA cohort was strongly associated with soluble markers of monocyte activation and inflammation in the CSF. CONCLUSIONS: People living with HIV and HIV-negative COBRA participants had high levels of cellular monocyte activation compared with age-matched BBD. High monocyte activation was predictive for inflammation in the CSF.

Journal article

Underwood J, Creswell F, Salam AP, Cleland C, John L, Davidson Ret al., 2017, Complications of miliary tuberculosis: low mortality and predictive biomarkers from a UK cohort, BMC Infectious Diseases, Vol: 17, ISSN: 1471-2334

BackgroundUntreated, miliary tuberculosis (TB) has a mortality approaching 100%. As it is uncommon there is little specific data to guide its management. We report detailed data from a UK cohort of patients with miliary tuberculosis and the associations and predictive ability of admission blood tests with clinical outcomes.MethodsRoutinely collected demographic, clinical, blood, imaging, histopathological and microbiological data were assessed for all patients with miliary TB identified from the London TB register from 2008 to 2012 from Northwest London Hospitals NHS Trust. Multivariable logistic regression was used to assess factors independently associated with the need for critical care intervention. Receiver operator characteristics (ROC) were calculated to assess the discriminatory ability of admission blood tests to predict clinical outcomes.ResultsFifty-two patients were identified with miliary tuberculosis, of whom 29% had confirmed central nervous system (CNS) involvement. Magnetic resonance imaging (MRI) was more sensitive than computed tomography (CT) or lumbar puncture for detecting CNS disease. Severe complications were frequent, with 15% requiring critical care intervention with mechanical ventilation. This was independently associated with admission hyponatraemia and elevated alanine aminotransferase (ALT). Having an admission sodium ≥125 mmol/L and an ALT <180 IU/L had 82% sensitivity and 100% specificity for predicting a favourable outcome with an area under the ROC curve (AUC) of 0.91. Despite the frequency of severe complications, one-year mortality was low at 2%.ConclusionsAlthough severe complications of miliary tuberculosis were frequent, mortality was low with timely access to critical care intervention, anti-tuberculous therapy and possibly corticosteroid use. Clinical outcomes could accurately be predicted using routinely collected biochemistry data.

Journal article

Underwood J, Cole JH, Caan M, De Francesco D, Leech R, van Zoest RA, Su T, Geurtsen GJ, Schmand BA, Portegies P, Prins M, Wit FW, Sabin CA, Majoie C, Reiss P, Winston A, Sharp DJ, Co-morBidity in Relation to Aids COBRA Collaborationet al., 2017, Grey and white matter abnormalities in treated HIV-disease and their relationship to cognitive function., Clinical Infectious Diseases, Vol: 65, Pages: 422-432, ISSN: 1537-6591

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.

Journal article

Underwood J, Leech R, Winston A, Sabin C, De Francesco Det al., 2017, Medicalising normality? Using a simulated dataset to assess the performance of different diagnostic criteria of cognitive impairment, 23rd Annual Conference of the British HIV Association (BHIVA, Publisher: Wiley, Pages: 40-41, ISSN: 1464-2662

Conference paper

Chhabra S, Underwood J, Cole JH, Waldman A, Sharp DJ, Winston A, Sabin Cet al., 2017, Clinical research cerebral MRI findings in HIV positive subjects and appropriate controls, BHIVA annual conference, Publisher: WILEY, Pages: 10-10, ISSN: 1464-2662

Conference paper

Cole JH, underwood J, Caan MWA, De Francesco D, van Zoest RA, Leech R, Wit FWNM, Portegies P, Geurtsen GJ, Schmand BA, Schim van der Loeff MF, Franceschi C, Sabin CA, Majoie CBLM, Winston A, Reiss P, Sharp DJet al., 2017, Increased brain-predicted ageing in treated HIV disease, Neurology, Vol: 88, Pages: 1349-1357, ISSN: 0028-3878

Objective: To establish whether HIV disease is associated with abnormal levels of age-related brain atrophy, by estimating apparent “brain age” using neuroimaging and exploring whether these estimates related to HIV-status, age, cognitive performance and HIV-related clinical parameters.Methods: A large sample of virologically-suppressed HIV-positive adults (N = 162, aged 45-82 years) and highly-comparable HIV-negative controls (N = 105) were recruited as part of the COBRA collaboration. Using T1-MRI scans, a machine-learning model of healthy brain ageing was defined in an independent cohort (N = 2001, aged 18-90 years). Neuroimaging data from HIV-positive and HIV-negative individuals were then used to estimate brain-predicted age; then brain-predicted age difference (brain-PAD = brain-predicted brain age - chronological age) scores were calculated. Neuropsychological and clinical assessments were also carried out.Results: HIV-positive individuals had greater brain-PAD score (mean ± SD = 2.15 ± 7.79 years) compared to HIV-negative individuals (-0.87 ± 8.40 years; b = 3.48, p < 0.01). Increased brain-PAD score was associated with decreased performance in multiple cognitive domains (information processing speed, executive function, memory) and general cognitive performance across all participants. Brain-PAD score was not associated with age, duration of HIV-infection or other HIV-related measures.Conclusions: Increased apparent brain ageing, predicted using neuroimaging, was observed in HIV-positive adults, despite effective viral suppression. Furthermore, the magnitude of increased apparent brain ageing related to cognitive deficits. However, predicted brain age difference did not correlate with chronological age or duration of HIV-infection, suggesting that HIV disease may accentuate, rather than accelerate brain ageing.

Journal article

Yilmaz A, Blennow K, Hagberg L, Nilsson S, Price RW, Schouten J, Spudich S, Underwood J, Zetterberg H, Gisslen Met al., 2017, Neurofilament light chain protein as a marker of neuronal injury: review of its use in HIV-1 infection and reference values for HIV-negative controls, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 17, Pages: 761-770, ISSN: 1473-7159

Journal article

De Francesco D, Underwood J, Post FA, Vera JH, Williams I, Boffito M, Sachikonye M, Anderson J, Mallon PWG, Winston A, Sabin CAet al., 2016, Defining cognitive impairment in people-living-with-HIV: the POPPY study, BMC Infectious Diseases, Vol: 16, ISSN: 1471-2334

BackgroundThe reported prevalence of cognitive impairment (CI) varies widely in cohorts of people living with HIV (PLWH); this may partly be due to the use of different diagnostic criteria. Agreement between diagnostic criteria of CI, the optimal definition to use, and associations with patient-reported cognitive symptoms have not been fully investigated.MethodsTwo hundred ninety PLWH aged >50 years and 97 matched negative controls completed a detailed assessment of cognitive function and three questions regarding cognitive symptoms. Age- and education-adjusted test scores (T-scores) determined if subjects met the following definitions of CI: Frascati, global deficit score (GDS) and the multivariate normative comparison (MNC) method.ResultsPLWH were more likely than controls to meet each definition of CI (ORs were 2.17, 3.12 and 3.64 for Frascati, GDS and MNC, respectively). Agreement of MNC with Frascati and GDS was moderate (Cohen’s k = 0.42 and 0.48, respectively), whereas that between Frascati and GDS was good (k = 0.74). A significant association was found between all the three criteria and reporting of memory loss but not with attention and reasoning problems. The 41 (14 %) PLWH meeting all the three criteria had the lowest median global T-score (36.9) and highest rate of symptom reporting (42 %).ConclusionsDifferent CI criteria show fair diagnostic agreement, likely reflecting their ability to exclude CI in the same group of individuals. Given the lower overall cognitive performance and higher rates of symptom reporting in those meeting all three criteria of CI, further work assessing this as a definition of CI in PLWH is justified.

Journal article

Underwood J, De Francesco D, Post FA, Vera JH, Williams I, Boffito M, Mallon PW, Anderson J, Sachikonye M, Sabin C, Winston A, Pharmacokinetic and Clinical Observations in People Over Fifty POPPY study groupet al., 2016, Associations between cognitive impairment and patient-reported measures of physical/mental functioning in older people living with HIV, HIV Medicine, Vol: 18, Pages: 363-369, ISSN: 1464-2662

OBJECTIVES: While cognitive impairment is frequently reported in HIV-positive individuals and has historically been associated with poorer functional outcomes, the associations between cognitive impairment and patient-reported outcome measures (PROMs) in contemporary cohorts are unclear. METHODS: We tested cognitive function using a computerized battery (CogState(™) ) in 290 HIV-positive and 97 HIV-negative individuals aged ≥ 50 years participating in the Pharmacokinetic and Clinical Observations in People Over Fifty (POPPY) study. Participants completed questionnaires detailing physical and mental health [Short Form Health Survey (SF-36)], cognitive function [European AIDS Clinical Society (EACS) questions], activities of daily living [Lawton Instrumental Activities of Daily Living (IADL)], depression [Patient Depression Questionnaire (PHQ-9) and Centres for Epidemiologic Studies Depression scale (CES-D)], falls and sexual desire. Cognitive impairment was defined using the Frascati criteria, global deficit score (GDS) and multivariate normative comparison (MNC). In the HIV-positive group, the classification performances of the different definitions of cognitive impairment and dichotomized questionnaire results were calculated. RESULTS: The prevalence of cognitive impairment in the HIV-positive group was 34.5% (GDS), 30.0% (Frascati) and 22.1% (MNC), with only 2% diagnosed with HIV-associated dementia. In general, the associations between cognitive impairment and PROMs were weak regardless of the definition used: mean c-statistics were 0.543 (GDS), 0.530 (MNC) and 0.519 (Frascati). Associations were similar using the global T-score to define cognitive impairment. Summary health scores (SF-36) were lower, but only significantly so for those with cognitive impairment identified using MNC, for both mental health (61.4 vs. 75.8; P = 0.03) and physical health (60.9 vs. 75.0; P = 0.03). CONCLUSIONS: The associations between cognitive impairment and PROMs were wea

Journal article

De Francesco D, Underwood J, Boffito M, Post F, Mallon P, Vera J, Williams I, Anderson J, Johnson M, Sabin C, Winston Aet al., 2016, Cognitive function and depression in HIV-positive individuals and matched controls, JOURNAL OF THE INTERNATIONAL AIDS SOCIETY, Vol: 19

Journal article

Underwood J, Winston A, 2016, Guidelines for Evaluation and Management of Cognitive Disorders in HIV-Positive Individuals, Current HIV/AIDS Reports, Vol: 13, Pages: 235-240, ISSN: 1548-3576

Antiretroviral therapy has revolutionised the treatment for people living with HIV (PLWH). Where antiretroviral coverage is high, the treatment paradigm for HIV-disease is now one of managing the long-term consequences of the virus and its treatment rather than the consequences of untreated HIV-disease such as immunosuppression and opportunistic infections. One such long-term consequence is HIV-associated cognitive impairment which is reported to occur in up to 50 % of treated PLWH and has been associated with poorer outcomes. Given the ageing cohort and increased frequency of comorbidities, the prevalence of symptomatic cognitive impairment may increase with time. High quality evidence for management strategies including screening, diagnosis and treatment of HIV-associated cognitive impairment are lacking and in general guidelines are based on best clinical practice. In this article, we assessed recent guidelines concerning the management of HIV-associated cognitive impairment by performing a systematic review of the MEDLINE database using PubMed. We report that, in general, guidelines from around the world regarding the management of HIV-associated cognitive impairment are converging. Screening is generally not recommended in asymptomatic PLWH. Diagnosis of HIV-associated cognitive impairment should be made only after a comprehensive assessment and exclusion of other potential causes. Antiretroviral therapy forms the cornerstone of management of HIV-associated cognitive impairment and should be guided by plasma and cerebrospinal fluid (CSF) genotype(s).

Journal article

Mora-Peris B, Stevens E, Ferretti F, Underwood J, Taylor S, Winston Aet al., 2016, Evolution of changes in cognitive function after the initiation of antiretroviral therapy., AIDS Research and Therapy, Vol: 13, ISSN: 1742-6405

BACKGROUND: Cognitive function is reported to improve after the initiation of combination antiretroviral therapy (cART). Data on the evolution of such changes are limited. We assessed the dynamics of changes in cognitive parameters, in HIV-positive subjects initiating cART. METHODS: Cognitive function in seven domains was evaluated for HIV-infected patients without clinically significant cognitive impairment prior to the initiation of cART, and 24 and 48 weeks after. Cognitive scores were transformed using standardised z-scores according to the pooled baseline standard deviation. Global, speed, and accuracy composite z-scores were calculated with changes calculated using a paired t test. RESULTS: In 14 subjects, change in global cognitive z-scores from baseline was by 0.08 at week 24 (p = 0.59) and 0.15 at week 48 (p = 0.43). Change in composite speed and accuracy z-scores from baseline at weeks 24/48 were 0.07/0.05 (p = 0.45/0.82) and 0.13/0.23 (p = 0.47/0.45), respectively. In two of the cognitive domains assessing speed (learning and monitoring time), a continued improvement from baseline to weeks 24 and 48 was observed (changes of 0.06-0.08 and 0.10-0.19, respectively), whereas in two domains (detection and identification) an initial improvement at week 24 (changes of -0.10 and 0.04 from baseline, respectively) was followed by a deterioration in score at week 48 (changes of -0.12 and -0.08 from baseline, respectively). None of these changes were statistically significant. CONCLUSIONS: A trend for improvement in cognitive function was observed in naïve HIV-positive patients starting cART. The dynamics of this improvement differed both between cognitive domains and the time-points assessed.

Journal article

Thornhill J, Underwood J, Kuldanek K, Mahay K, Fidler S, Frater J, Hopkins E, Meyerowitz J, Fox J, Nwokolo N, Whitlock G, Mackie N, Porter Ket al., 2016, Impact of timing of ART on HIV DNA; findings from HEATHER, an observational cohort study, 22nd Annual Conference of the British HIV Association (BHIVA), Publisher: Wiley, Pages: 11-11, ISSN: 1464-2662

Conference paper

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