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People living with HIV are at increased risk for depression, though the underlying mechanisms for this are unclear. In the general population, depression is associated with peripheral and central inflammation. Given this, and since HIV infection elicits inflammation, we hypothesised that peripheral and central inflammatory biomarkers would at least partly mediate the association between HIV and depressive symptoms. People living with HIV (n = 125) and without HIV (n = 79) from the COmorBidity in Relation to AIDS (COBRA) cohort were included in this study. Participants living with and without HIV had similar baseline characteristics. All participants living with HIV were on antiretroviral therapy and were virally suppressed. Plasma, CSF, and brain MR spectroscopy (MRS) biomarkers were measured. Using logistic regression models adjusted for sociodemographic factors, we found that participants with HIV were more likely to have Any Depressive Symptoms (Patient Health Questionnaire [PHQ-9] score >4) (odds ratio [95% confidence interval] 3.27 [1.46, 8.09]). We then sequentially adjusted the models for each biomarker separately to determine the mediating role of each biomarker, with a >10% reduction in OR considered as evidence of potential mediation. Of the biomarkers analysed, MIG (−15.0%) and TNF-α (−11.4%) in plasma and MIP1-α (−21.0%) and IL-6 (−18.0%) in CSF mediated the association between HIV and depressive symptoms in this sample. None of the other soluble or neuroimaging biomarkers substantially mediated this association. Our findings suggest that certain biomarkers of central and peripheral inflammation may at least partly mediate the relationship between HIV and depressive symptoms.

Increased prevalence of low bone mineral density (BMD) and increased fracture incidence are observed in persons living with HIV (PLWH). The trabecular bone score (TBS) is a novel index of bone microarchitecture which improves fracture prediction independent of BMD. The HIV UPBEAT study is a single centre, prospective cohort study that enrolled subjects with and without HIV from similar sociodemographic backgrounds for annual assessments of bone health. TBS was derived from lumbar spine (LS) dual-energy X-ray absorptiometry images. Univariate and multivariable linear regression was used to assess relationships between baseline TBS, BMD, sociodemographic and clinical factors. 463 subjects (201 HIV positive) were included; PLWH were younger and more likely male, of non-African ethnicity and current smokers. HIV was associated with a mean reduction of 0.037 [-0.060, -0.013] (p = 0.002) in TBS. Lower TBS was also associated with male gender, non-African ethnicity, current smoking status and lower LS BMD. HIV remained associated with lower TBS after adjustment for LS BMD, age, gender and ethnicity. However, adjustment for current smoking significantly attenuated the association between HIV and TBS, with further adjustment for higher bone turnover markers largely explaining any residual association. Among the sub-group of PLWH, exposure to protease inhibitors and lower nadir CD4+ T-cell counts were both predictors of lower TBS. PLWH have lower TBS independent of LS BMD. However, this is largely explained by higher current smoking rates and higher bone turnover in those with HIV. Exposure to PI, but not tenofovir disproxil fumarate, also contributed to lower TBS in those with HIV.

With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. 3909 of the 49 731 D:A:D study participants died during the 308 719 person-years of follow-up (crude incidence mortality rate, 12·7 per 1000 person-years [95% CI 12·3–13·1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17·5 in 1999–2000 to 9·1 in 2009–11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5·9 to 2·0), deaths from liver disease (2·7 to 0·9), and cardiovascular disease deaths (1·8 to 0·9). However, non-AIDS cancers increased slightly from 1·6 per 1000 person-years in 1999–2000 to 2·1 in 2009–11 (p=0·58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009–11 vs 1999–2000: 0·92 [0·70–1·22]). However, all-cause (0·72 [0·61–0·83]), liver disease (0·48 [0·32–0·74]), and cardiovascular disease (0·33 [0·20–0·53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999–2000 and 141/627 [22%] in 2009–11) and liver-related (40/256 [16%] in 1999–2000 and 64/627 [10%] in 2009–11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999–2000 to 142/627 [23%] in 2009–11). Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.

Background With the advent of direct acting antivirals, the World Health Organisation proposed eliminating Hepatitis C as a public health threat by 2030. To achieve this, countries need to diagnose, engage in care and treat their undiagnosed populations. This will require sensitisation campaigns. However previous media campaigns have had mixed impact. We conducted a scoping review to identify and understand the impact of previous Hepatitis C media campaigns. These findings could inform the delivery of future campaigns. Methods We searched five electronic databases for published literature on media campaigns conducted for Hepatitis C awareness, testing, and treatment in Organisation for Economic Co-operation and Development (OECD) countries since 2010. Two independent reviewers screened citations for inclusion. Additionally, we spoke to stakeholders in the Hepatitis C field in the UK and conducted a Google search to identify any unpublished literature. A quantitative synthesis was conducted to identify targeted populations, strategies and media used, aims and impact of the campaigns. Results A title and year of publication screening of 3815 citations resulted in 113 papers that had a full abstract screen. This left 50 full-text papers, 18 were included of which 9 (50%) were from Europe. 5 (27.8%) of campaigns targeted minority ethnicities, and 9 (50%) aimed to increase testing. A Google search identified 6 grey literature sources. Most campaigns were not evaluated for impact. Discussions with stakeholders identified several barriers to successful campaigns including lack of targeted messaging, stigmatising or accusatory messaging, and short-lived or intermittent campaign strategies. Conclusion Future campaigns will likely need to be multifaceted and have multiple tailored interventions. Campaigns will need to be sizeable and robust, integrated into health systems and viewed as an ongoing service rather than one-offs.

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. 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. 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 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 94.5% (92.8-95.2%) to 85.0% (81.2-88.5%). 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.

This study evaluated clinical features, organ function, and survival in a group of 374 patients with amyloid A amyloidosis. Median survival after diagnosis was 133 months; renal dysfunction was the predominant disease manifestation. Mortality, amyloid burden, and renal prognosis all significantly correlated with the serum amyloid A concentration during follow-up. This study evaluated clinical features, organ function, and survival in a group of 374 patients with amyloid A amyloidosis. Median survival after diagnosis was 133 months; renal dysfunction was the predominant disease manifestation. Reactive systemic AA amyloidosis can complicate chronic inflammatory disorders that are associated with a sustained acute-phase response. AA amyloid fibrils are derived from the acute-phase reactant serum amyloid A protein (SAA) protein through a process of cleavage, misfolding, and aggregation into a highly ordered abnormal β-sheet conformation. 1 Amyloid fibrils associate with other moieties, including glycosaminoglycans and serum amyloid P component (SAP), forming deposits that disrupt the structure and function of tissues and organs. 2 SAA is an apolipoprotein constituent of high-density lipoprotein 3 that is synthesized by hepatocytes under the transcriptional regulation of proinflammatory cytokines. 4 The median plasma concentration of SAA in . . .

There is evidence that the life expectancy (LE) of individuals infected with the human immunodeficiency virus (HIV) has increased since the introduction of combination antiretroviral therapy (cART). However, mortality rates in recent years in HIV-positive individuals appear to have remained higher than would be expected based on rates seen in the general population. A low CD4 count, whether due to late HIV diagnosis, late initiation of cART, or incomplete adherence to cART, remains the dominant predictor of LE, and thus the individual’s disease stage at initiation of cART (or thereafter) certainly contributes to these higher mortality rates. However, individuals with HIV also tend to exhibit lifestyles and behaviors that place them at increased risk of mortality, particularly from non-AIDS causes. Thus, although mortality rates among the HIV population may indeed remain slightly higher than those seen in the general population, they may be no higher than those seen in a more appropriately matched control group. Thus, further improvements in LE may now only be possible if some of the other underlying issues (for example, modification of lifestyle or behavioral factors) are tackled.

HIV-1-positive individuals on successful antiretroviral therapy (ART) are reported to have higher rates of age-associated non-communicable comorbidities (AANCCs). HIV-associated immune dysfunction has been suggested to contribute to increased AANCC risk. Here we performed a cross-sectional immune phenotype analysis of T cells in ART-treated HIV-1-positive individuals with undetectable vireamia (HIV-positives) and HIV-1-negative individuals (HIV-negatives) over 45 years of age. In addition, two control groups were studied: HIV negative adults selected based on lifestyle and demographic factors (Co-morBidity in Relation to AIDS, or COBRA) and unselected age-matched donors from a blood bank. Despite long-term ART (median of 12.2 years), HIV-infected adults had lower CD4+ T-cell counts and higher CD8+ T-cell counts compared to well-matched HIV-negative COBRA participants. The proportion of CD38+HLA-DR+ and PD-1+ CD4+ T-cells was higher in HIV-positive cohort compared to the two HIV-negative cohorts. The proportion CD57+ and CD27-CD28- cells of both CD4+ and CD8+ T-cells in HIV-positives was higher compared to unselected adults (blood bank) as reported before but this difference was not apparent in comparison with well-matched HIV-negative COBRA participants. Multiple regression analysis showed that the presence of an increased proportion of terminally differentiated T cells was strongly associated with CMV infection. Compared to appropriately selected HIV-negative controls, HIV-positive individuals on ART with long-term suppressed viraemia exhibited incomplete immune recovery and increased immune activation/exhaustion. CMV infection rather than treated HIV infection appears to have more consistent effects on measures of terminal differentiation of T cells.

Background The 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. Methods Two 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. Results PLWH 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 %). Conclusions Different 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.