Positive predictive value of each diagnostic method by prevalence of impairment in the simulated study population.

<p>Positive predictive value of each diagnostic method by prevalence of impairment in the simulated study population.</p

Convergence of the critical value to determine cognitive impairment as the sample size increases.

<p>This model assumes a six test/domain model. The critical value from simulated data was the mean of 100 replicates.</p

Comparison of the cognitive domain correlation matrices for the HIV-positive and HIV-negative control groups from the POPPY study.

<p>Visualisation of the inter-domain correlation matrices for the HIV-negative (panel a) and HIV-positive (panel b) participants of the POPPY study. Colour scale determined by Pearson’s r (scale to the right of the figure).</p

Performance of five definitions of cognitive impairment in a simulated population with a 10% prevalence of cognitive impairment.

<p>Performance of five definitions of cognitive impairment in a simulated population with a 10% prevalence of cognitive impairment.</p

Histograms of a simulated study population with a 10% prevalence of cognitive impairment.

<p>Panel a) 90% of the population are ‘normal’ and have a mean (standard deviation) T-score of 50 (10)–red. 10% of the population are impaired and have a mean T-score of 30 (10). Panels b-d: how the population is labelled by method used to define impairment.</p

Medicalising normality? Using a simulated dataset to assess the performance of different diagnostic criteria of HIV-associated cognitive impairment

<div><p>Objective</p><p>The 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.</p><p>Methods</p><p>Using 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.</p><p>Results</p><p>The 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 <i>a priori</i> 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 94.5% (92.8–95.2%) to 85.0% (81.2–88.5%).</p><p>Conclusion</p><p>Our simulations suggest that the commonly used diagnostic criteria of HIV-associated cognitive impairment label a significant proportion of a normative reference population as cognitively impaired, which will likely lead to a substantial over-estimate of the true proportion in a study population, due to their lower than expected specificity. These findings have important implications for clinical research regarding cognitive health in people living with HIV. More accurate methods of diagnosis should be implemented, with multivariate techniques offering a promising solution.</p></div

Cognitive performance by domain and HIV/CDC status.

Data points are means with 95% confidence intervals. P-values compare the three groups (HIV, PHIV/no C, PHIV/C) using analysis of variance. Abbreviations: CDC, Centers for Disease Control and Prevention, HIV-, HIV negative; PHIV, perinatal HIV; PHIV/C, PHIV with a CDC C diagnosis; PHIV/no C, PHIV without a CDC C diagnosis.</p

Differences in neuroinflammation in people who started antiretroviral treatment during primary versus chronic HIV infection: an 18kDa Translocator protein (TSPO) positron emission tomography (PET) study

Persistent inflammation is described in people with HIV (PWH) on antiretroviral treatment (ART). Early ART initiation is associated with reduced inflammation. We aimed to evaluate neuroinflammation, using translocator protein (TSPO) [11C]PBR28 PET neuroimaging in PWH who initiated ART during acute HIV (aPWH) versus chronic HIV infection (cPWH) versus a control population. This was a cross-sectional, observational study. All participants underwent [11C]PBR28 PET-CT neuroimaging. Using a two-tissue compartment model, total volume of distribution (VT) and distribution volume ratios (DVR) using cortical grey matter as a pseudo-reference region at 20 regions of interest (ROIs) were calculated. Differences in VT and DVR were compared between groups using the Kruskall-Wallis test. Seventeen neuro-asymptomatic male PWH on ART (9 aPWH, 8 cPWH) and 8 male control participants (CPs) were included. Median (interquartile range, IQR) age was 40 (30, 46), 44 (41, 47) and 21 (20, 25) years in aPWH, cPWH and CPs, respectively. Median (IQR) CD4 (cells/µL) and CD4:CD8 were 687 (652, 1014) and 1.37 (1.24, 1.42), and 700 (500, 720) and 0.67 (0.64, 0.82) in aPWH and cPWH, respectively. Overall, no significant difference in VT and DVR were observed between the three groups at any ROIs. cPWH demonstrated a trend towards higher mean VT compared with aPWH and CPs at most ROIs. No significant differences in neuroinflammation, using [11C]PBR28 binding as a proxy, were identified between cPWH, aPWH and CPs. A trend towards lower absolute [11C]PBR28 binding was seen amongst aPWH and CPs, suggesting early ART may mitigate neuroinflammation.</p

The Relationship between Ct Pgp3 antibody positivity and self-reported Ct, number of sexual partners, number of sexual partners of those who had not reported Ct infection and age of first coitus by age 26, 32 and 38 years. Women.

<p>The Relationship between Ct Pgp3 antibody positivity and self-reported Ct, number of sexual partners, number of sexual partners of those who had not reported Ct infection and age of first coitus by age 26, 32 and 38 years. Women.</p

Flowchart showing the history of detectable Pgp3 antibody in women and men at age 26, 32 and 38 years.

<p>The number of women and men testing Pgp3 antibody positive at age 26 is given. Shown at age 32 and 38 are the numbers of these positive individuals who: i) maintained Pgp3 seropositivity with no self-report of re-exposure to Ct, ii) remained Pgp3 positive, but also reported a re-infection with Ct, iii) had become seronegative, and iv) were missing at that time point. Finally, the numbers of women and men who became Pgp3 seropositive between age 26 and 32 together with their subsequent antibody status and infection history by age 38 are shown.</p