Cost-effectiveness of increased HIV testing among MSM in The Netherlands Objectives: To assess the cost-effectiveness of increased consistent HIV testing among MSM in the Netherlands. Methods: Among MSM testing at sexually transmitted infection clinics in the Netherlands in 2014–2015, approximately 20% tested consistently every 6 months. We examined four scenarios with increased percentage of MSM testing every 6 months: a small and a moderate increase among all MSM; a small and a moderate increase only among MSM with at least 10 partners in the preceding 6 months. We used an agent-based model to calculate numbers of HIV infections and AIDS cases prevented with increased HIV testing. These numbers were used in an economic model to calculate costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) due to increased testing, over 2018–2027, taking a healthcare payer perspective. Results: A small increase in the percentage testing every 6 months among all MSM resulted in 490 averted HIV infections and an average ICER of €27 900/QALY gained. A moderate increase among all MSM, resulted in 1380 averted HIV infections and an average ICER of €36 700/QALY gained. Both were not cost-effective, with a €20 000 willingness-to-pay threshold. Increasing the percentage testing every 6 months only among MSM with at least 10 partners in the preceding 6 months resulted in less averted HIV infections than increased testing among all MSM, but was on average cost-saving. Conclusion: Increased HIV testing can prevent considerable numbers of new HIV infections among MSM, but may be cost-effective only if targeted at high-risk individuals, such as those with many partners.

IL-27 posttranslationally regulates Y-box binding protein-1 to inhibit HIV-1 replication in human CD4+ T cells Objectives: IL-27 is known as an antiviral cytokine that inhibits HIV, hepatitis C virus, and other viruses. We have previously demonstrated that, IL-27 posttreatment after HIV-infection inhibits viral replication in primary CD4+ T cells. Design: Here, we evaluated the anti-HIV effect of IL-27 pretreatment in CD4+ T cells from healthy donors prior to HIV infection with HIVNL4.3 or vesicular stomatitis virus G glycoprotein (VSV-G)-pseudotyped HIV-luciferase virus (HIV-LUC-V). Methods: IL-27-treated CD4+ T cells were infected with HIVNL4.3 or HIV-LUC-V and assessed the anti-HIV effect. HIV infection was monitored by p24 antigen ELISA or luciferase assay. HIV fusion/entry and uncoating were determined by BlaM-Vpr assay and HIV fate of capsid and/or HIV Entry/Uncoating assay based on core-packaged RNA availability and Translation assay, respectively. HIV proviral copy number was determined by real-time PCR. Gene expression profile from IL-27-pretreated CD4+ T cells was determined using Genechip array. Posttranslational modification of global proteins from IL-27-pretreated CD4+ T cells was determined by a combination of 2-dimensional difference-in-gel-electrophoresis (2D-DIG), western-blot and protein mass spectrometry. Results: IL-27 pretreatment inhibited HIVNL4.3 and HIV-LUC-V infection in CD4+ T cells. HIV copy assay demonstrated that IL-27-treatment suppressed an early step of reverse transcription during HIV infection. A combination of 2D-DIG-electrophoresis and western blot assays demonstrated that IL-27-treatment induces a change in posttranslational modification of Y box binding protein-1 (YB-1). Overexpression of domain negative YB-1 mutants illustrated that a residue Lysine at 118 plays a key role in supporting HIV infection in CD4+ T cells. Conclusion: IL-27-pretreatment inhibits HIV-1 infection by suppressing an HIV-reverse transcription product formation/uncoating step by suppressing the acetylation of YB-1 in primary CD4+ T cells.

Distinct inflammatory profiles in HIV-infected individuals under antiretroviral therapy using cannabis, cocaine or cannabis plus cocaine Objectives: To evaluate the effects of cannabis and/or cocaine use on inflammatory, oxidative stress status and circulating monocyte subsets in HIV-infected individuals under antiretroviral therapy. Design: Soluble CD14 (sCD14), intestinal fatty acid-binding protein (IFABP), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8, IL-10, C-reactive protein (CRP) and oxidative stress markers were examined. The monocyte subsets and their activation and cytokine production by peripheral blood mononuclear cells (PBMCs) of HIV-1 infected individuals upon lipopolysaccharide (LPS)-stimulation were also investigated. Methods: sCD14, IFABP, TNF-α, IL-6, IL-8 and IL-10 levels were evaluated using ELISA, CRP by turbidimetry; lipid peroxidation (TBARS) spectrofluometrically and total thiol levels by using 5–5′-dithio-bis (2-nitrobenzoic acid) reagent. Monocyte subsets and activation were assessed by flow cytometry. Results: All HIV-infected drug user groups showed higher sCD14 levels compared with HIV+ nondrug users. IFABP was increased in HIV+ drug-users in relation to healthy individuals. Cannabis use lowered the percentages of inflammatory, nonclassical, activated-classic and activated-inflammatory monocytes. Cocaine users showed increased plasmatic TNF-α and TBARS levels, decreased thiols content and lower activated-classic and inflammatory-monocyte percentages. Cannabis-plus-cocaine use increased CRP, IL-8 and IL-6/IL-10 ratio, but decreased thiol content, and inflammatory and activated-classic monocyte percentages. PBMCs of cannabis and cannabis-plus-cocaine users showed low-potential cytokine production either spontaneously or under LPS-stimulation. Conclusion: In HIV infection, the use of cannabis induces predominantly an anti-inflammatory profile. The use of cocaine and cannabis-plus-cocaine showed a mixed pro-inflammatory and anti-inflammatory profile, with predominance of inflammatory status. Further studies are required to better understand the action of these drugs in HIV infection.

Imaging correlates of the blood–brain barrier disruption in HIV-associated neurocognitive disorder and therapeutic implications Objective: HIV-associated neurocognitive disorders (HANDs) in the context of suppressive combination antiretroviral therapy (cART) still occur. We explored the role of blood–brain barrier (BBB) disruption in the pathogenesis of HAND in the context of fully suppressive cART using dynamic contrast enhanced perfusion (DCE-P) MRI. DCE-P is a new MRI technique that measures capillary permeability as an indicator for BBB integrity. We hypothesized that virally suppressed incident HAND would be associated with an impaired BBB as determined by DCE-P. Design: A cross sectional study. Methods: K-trans, a metric derivative of DCE-P, was obtained from different regions of the brain in a cohort of 20 patients with HAND who were virally suppressed in both cerebrospinal fluid (CSF) and blood compared with CSF and blood markers of neuroinflammation as well as with neurometabolites derived from magnetic resonance (MR) spectroscopy. Results: The K-trans data showed significantly impaired BBB in HAND patients when compared with the controls in the regions of the basal ganglia and anterior frontal white matter (both P < 0.0001). CSF neopterin and CSF/serum albumin ratio correlated positively with K-trans but not with blood levels. Conclusion: This study indicates that HAND in the context of viral suppression is associated with BBB disruption and the DCE MR derived K-trans metric is a very sensitive parameter to identify the BBB disruption. The finding of region-specific BBB disruption rather than globally and the lack of correlation with blood markers of neuroinflammation suggest that HIV and not systemic inflammation is driving the BBB disturbance and that the BBB disruption is a consequence of HIV already in the brain as opposed to HIV first causing BBB disruption then brain disease.

Coronary atherosclerosis characteristics in HIV-infected patients on long-term antiretroviral therapy: insights from coronary computed tomography–angiography Objective: The aim of the study was to assess coronary artery disease (CAD) characteristics by coronary computed tomography–angiography (CCTA) in individuals with HIV infection on long-term antiretroviral therapy (ART) Design: Retrospective case-controlled matched cohort study. Methods: Sixty-nine HIV-positive patients who underwent 128-slice dual source CCTA (mean age 54.9 years, 26.1% women) with mean 17.8 ± 9.4 years of HIV infection and a mean duration on ART of 13 ± 7.3 years were propensity score-matched (1 : 1) for age, sex, BMI, and five cardiovascular risk factors with 69 controls. CCTA was evaluated for stenosis severity [according to Coronary Artery Disease – Reporting and Data System (CAD-RADS)], total plaque burden [segment involvement score (SIS) and mixed-noncalcified plaque burden (G-score)]. As inflammatory biomarkers, high-risk plaque (HRP) features (napkin-ring sign, low-attenuation plaque, spotty calcification, positive remodeling), perivascular fat attenuation index (FAI), and ectatic coronary arteries were assessed. Results: CAD-RADS was higher in HIV-positive participants as compared with controls (2.21 ± 1.4 vs. 1.69 ± 1.5, P = 0.031). A higher prevalence of CAD and G-score (P = 0.043 and P = 0.003) was found. HRP prevalence [23 (34.3%) vs. 8 (12.1%); P = 0.002] and the number of HRP (36 vs. 10, P < 0.001) were higher in HIV-positive individuals. A perivascular FAI greater than −70 Hounsfield units was present in 27.8% of HRP. Ectatic coronary arteries were found in 10 (14.5%) HIV-positive persons vs. 0% in controls (P = 0.003). Conclusion: Noncalcified and HRP burden in HIV-infected individuals on long-term ART is higher and associated with higher cardiovascular risk. Moreover, HIV-positive individuals displayed a higher stenosis severity (CAD-RADS) and more ectatic coronary arteries compared with the control group.

Double dissociation of HIV and substance use disorder effects on neurocognitive tasks dependent on striatal integrity Objective: Substance use is common among individuals infected with HIV, yet whether neurocognitive effects of HIV can be distinguished from more nonspecific effects of drug dependence and associated comorbidities is not known. Design: Cross-sectional observational study of neurocognitive function among HIV-infected and uninfected individuals with and without substance use disorders (SUDs). Methods: We compared the performance of 458 (31% HIV-infected) substance-dependent individuals (SDIs) and 90 individuals (23% HIV-infected) with no history of SUDs on measures of delay discounting and probability learning, tasks, which are differentially sensitive to addictive processes and HIV serostatus, respectively. Results: In factorial analyses of covariance adjusted for age, years of education, and sex, we found that SDIs showed significantly higher rates of delay discounting, regardless of HIV serostatus (P < 0.05). Conversely, HIV-infected individuals performed significantly more poorly on probability learning compared with uninfected groups, regardless of SUD history (P < 0.05). Conclusion: Theory-driven cognitive neuropsychological tasks may have the capacity to detect neurocognitive effects of HIV not attributable solely to substance use; evidence from functional neuroimaging studies with more selective neurocognitive probes will be critical for hypothesis testing and mapping underlying brain systems more precisely.

Risk factors and impact of patterns of co-occurring comorbidities in people living with HIV Aims: To assess associations of comorbidity patterns observed in people living with HIV (PLWH) with risk factors and health outcomes. Methods: Common patters of comorbidities in PLWH participating in the Pharmacokinetic and Clinical Observations in People Over Fifty study were determined using principal component analysis and a severity score for each pattern was derived. Associations between each pattern's severity score and risk factors were assessed using median regression. The independent associations of patterns’ severity scores with self-reported physical and mental health (SF-36 summary scores) were assessed using linear regression, with functional impairment (Lawton IADL < 8) and hospitalization in last year using logistic regression and with number of general practitioner visits using Poisson regression. Results: A total of 1073 PLWH were analysed: 85.2% male, median (interquartile range) age 52 (47–59) years, 98% on therapy. Duration of HIV was associated with higher severity in 4/6 of patterns: cardiovascular diseases, mental health problems, metabolic disorders and chest/other infections (all P ≤ 0.001). Prior AIDS was associated with higher severity scores for the same patterns and for the pattern of cancers (P < 0.001). The pattern of cardiovascular diseases was associated with poorer physical health (P = 0.02), higher risk of functional impairment (P = 0.02) and hospitalization (P < 0.001) and with higher number of general practitioner visits (P < 0.001). Severity of mental health (all P < 0.001) and of chest/other infections patterns negatively affected all the five health outcomes. Conclusion: Common patterns of comorbidities seen in PLWH appear to have different risk factors and to differently affect health outcomes. These findings may assist the development of targeted intervention to prevent, treat and manage the increasingly prevalent multimorbidity in PLWH.

Performance of Cepheid Xpert HIV-1 viral load plasma assay to accurately detect treatment failure Background: Coverage of viral load testing remains low with only half of the patients in need having adequate access. Alternative technologies to high throughput centralized machines can be used to support viral load scale-up; however, clinical performance data are lacking. We conducted a meta-analysis comparing the Cepheid Xpert HIV-1 viral load plasma assay to traditional laboratory-based technologies. Methods: Cepheid Xpert HIV-1 and comparator laboratory technology plasma viral load results were provided from 13 of the 19 eligible studies, which accounted for a total of 3790 paired data points. We used random effects models to determine the accuracy and misclassification at various treatment failure thresholds (detectable, 200, 400, 500, 600, 800 and 1000 copies/ml). Results: Thirty percent of viral load test results were undetectable, while 45% were between detectable and 10 000 copies/ml and the remaining 25% were above 10 000 copies/ml. The median Xpert viral load was 119 copies/ml and the median comparator viral load was 157 copies/ml, while the log10 bias was 0.04 (0.02–0.07). The sensitivity and specificity to detect treatment failure were above 95% at all treatment failure thresholds, except for detectable, at which the sensitivity was 93.33% (95% confidence interval: 88.2–96.3) and specificity was 80.56% (95% CI: 64.6–90.4). Conclusion: The Cepheid Xpert HIV-1 viral load plasma assay results were highly comparable to laboratory-based technologies with limited bias and high sensitivity and specificity to detect treatment failure. Alternative specimen types and technologies that enable decentralized testing services can be considered to expand access to viral load.

A 24-week pilot study of dual maintenance therapy with raltegravir and lamivudine Background: There is an increasing interest in two-drug regimens. We hypothesized that maintenance therapy with raltegravir and lamivudine would keep HIV-1 suppressed and be well tolerated. Methods: Virally suppressed HIV-1-infected adults without previous viral failures or known resistance mutations to integrase inhibitors or 3TC/FTC or chronic hepatitis B were randomized 2 : 1 to switch to fixed-dose combination 150 mg lamivudine/300 mg raltegravir twice daily or to continue therapy. Primary outcome was the proportion of patients free of therapeutic failure (defined as viral failure, change in treatment for any reason, consent withdrawal, loss to follow-up or death) at week 24. Secondary outcomes were changes in laboratory, body composition, sleep quality, adherence, and adverse effects. Results: There were 75 patients included: men 78%; median age 50 years; median CD4+ 622/μl. At week 24, 7 (9%) patients had therapeutic failure: raltegravir and lamivudine 2 (4%) vs. control 5 (20%). The difference in proportions of therapeutic failures raltegravir and lamivudine minus control was −0.159 (95% confidence interval: −0.353 to −0.012). There was a trend to more weight gain with raltegravir and lamivudine, but no significant changes in other secondary outcomes. Sixty-four percent of patients in each arm had at least one adverse effect. Two (6%) patients in control arm and 4 (7%) patients in raltegravir and lamivudine arm had severe adverse effects. Conclusion: This pilot study suggests that switching to raltegravir along with lamivudine in patients with viral suppression maintains efficacy and is well tolerated. A larger study of longer duration is required to confirm these findings.

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand Objective: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. Design: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. Methods: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1–10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. Results: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and −1.2 (IQR: −2.3 to −0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20–0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21–1.78) years later in those starting with HAZ less than −3 compared with HAZ at least −1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than −1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least −1, there was no association with age. Girls and boys who initiated ART with HAZ at least −1 maintained a similar height to the WHO reference mean. Conclusion: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least −1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age.