Is increased hepatitis C virus case-finding combined with current or 8-week to 12-week direct-acting antiviral therapy cost-effective in UK prisons? A prevention benefit analysis

UNLABELLED: Prisoners have a high prevalence of hepatitis C virus (HCV), but case-finding may not have been cost-effective because treatment often exceeded average prison stay combined with a lack of continuity of care. We assessed the cost-effectiveness of increased HCV case-finding and treatment in UK prisons using short-course therapies. A dynamic HCV transmission model assesses the cost-effectiveness of doubling HCV case-finding (achieved through introducing opt-out HCV testing in UK pilot prisons) and increasing treatment in UK prisons compared to status quo voluntary risk-based testing (6% prison entrants/year), using currently recommended therapies (8-24 weeks) or interferon (IFN)-free direct-acting antivirals (DAAs; 8-12 weeks, 95% sustained virological response, £3300/week). Costs (British pounds, £) and health utilities (quality-adjusted life years) were used to calculate mean incremental cost-effectiveness ratios (ICERs). We assumed 56% referral and 2.5%/25% of referred people who inject drugs (PWID)/ex-PWID treated within 2 months of diagnosis in prison. PWID and ex-PWID or non-PWID are in prison an average 4 and 8 months, respectively. Doubling prison testing rates with existing treatments produces a mean ICER of £19,850/quality-adjusted life years gained compared to current testing/treatment and is 45% likely to be cost-effective under a £20,000 willingness-to-pay threshold. Switching to 8-week to 12-week IFN-free DAAs in prisons could increase cost-effectiveness (ICER £15,090/quality-adjusted life years gained). Excluding prevention benefit decreases cost-effectiveness. If >10% referred PWID are treated in prison (2.5% base case), either treatment could be highly cost-effective (ICER<£13,000). HCV case-finding and IFN-free DAAs could be highly cost-effective if DAA cost is 10% lower or with 8 weeks' duration. CONCLUSIONS: Increased HCV testing in UK prisons (such as through opt-out testing) is borderline cost-effective compared to status quo voluntary risk-based testing under a £20,000 willingness to pay with current treatments but likely to be cost-effective if short-course IFN-free DAAs are used and could be highly cost-effective if PWID treatment rates were increased. (Hepatology 2016;63:1796-1808)

Human TSCM cell dynamics in vivo are compatible with long-lived immunological memory and stemness.

Adaptive immunity relies on the generation and maintenance of memory T cells to provide protection against repeated antigen exposure. It has been hypothesised that a self-renewing population of T cells, named stem cell-like memory T (TSCM) cells, are responsible for maintaining memory. However, it is not clear if the dynamics of TSCM cells in vivo are compatible with this hypothesis. To address this issue, we investigated the dynamics of TSCM cells under physiological conditions in humans in vivo using a multidisciplinary approach that combines mathematical modelling, stable isotope labelling, telomere length analysis, and cross-sectional data from vaccine recipients. We show that, unexpectedly, the average longevity of a TSCM clone is very short (half-life < 1 year, degree of self-renewal = 430 days): far too short to constitute a stem cell population. However, we also find that the TSCM population is comprised of at least 2 kinetically distinct subpopulations that turn over at different rates. Whilst one subpopulation is rapidly replaced (half-life = 5 months) and explains the rapid average turnover of the bulk TSCM population, the half-life of the other TSCM subpopulation is approximately 9 years, consistent with the longevity of the recall response. We also show that this latter population exhibited a high degree of self-renewal, with a cell residing without dying or differentiating for 15% of our lifetime. Finally, although small, the population was not subject to excessive stochasticity. We conclude that the majority of TSCM cells are not stem cell-like but that there is a subpopulation of TSCM cells whose dynamics are compatible with their putative role in the maintenance of T cell memory

A discrete choice experiment to assess people living with HIV’s (PLWHIV’s) preferences for GP or HIV clinic appointments

Objectives: To understand which aspects of general practitioner (GP) and HIV clinic appointments people living with HIV (PLWHIV) most value when seeking advice for new health problems. Methods: A discrete choice experiment using a convenience sample of people diagnosed with HIV. Participants were recruited from 14 general HIV clinics in the South East of England between December 2014 and April 2015. ORs were calculated using conditional logit (CLOGIT) and latent class models (LCMs). Results: A total of 1106 questionnaires were returned. Most participants were male (85%), white (74%) and were men who have sex with men (69%). The CLOGIT analysis showed people particularly valued shorter appointment waiting times (ORs between 1.52 and 3.62, p<0.001 in all instances). The LCM analysis showed there were two distinct classes, with 59% and 41% of respondents likely to be in each. The first class generally preferred GP to HIV clinic appointments and particularly valued ‘being seen quickly’. For example, they had strong preferences for shorter appointment waiting times and longer GP opening hours. People in the second class also valued shorter waiting times, but they had a strong general preference for HIV clinic rather than GP appointments. Conclusions: PLWHIV value many aspects of care for new health problems, particularly short appointment waiting times. However, they appear split in their general willingness to engage with GPs

CCR8 Expression Defines Tissue-Resident Memory T Cells in Human Skin

Human skin harbors two major T cell compartments of equal size that are distinguished by expression of the chemokine receptor CCR8. In vitro studies have demonstrated that CCR8 expression is regulated by TCR engagement and the skin tissue microenvironment. To extend these observations, we examined the relationship between CCR8+ and CCR8− skin T cells in vivo. Phenotypic, functional, and transcriptomic analyses revealed that CCR8+ skin T cells bear all the hallmarks of resident memory T cells, including homeostatic proliferation in response to IL-7 and IL-15, surface expression of tissue localization (CD103) and retention (CD69) markers, low levels of inhibitory receptors (programmed cell death protein 1, Tim-3, LAG-3), and a lack of senescence markers (CD57, killer cell lectin-like receptor subfamily G member 1). In contrast, CCR8− skin T cells are heterogeneous and comprise variable numbers of exhausted (programmed cell death protein 1+), senescent (CD57+, killer cell lectin-like receptor subfamily G member 1+), and effector (T-bethi, Eomeshi) T cells. Importantly, conventional and high-throughput sequencing of expressed TCR β-chain (TRB) gene rearrangements showed that these CCR8-defined populations are clonotypically distinct, suggesting unique ontogenies in response to separate antigenic challenges and/or stimulatory conditions. Moreover, CCR8+ and CCR8− skin T cells were phenotypically stable in vitro and displayed similar levels of telomere erosion, further supporting the likelihood of a nonlinear differentiation pathway. On the basis of these results, we propose that long-lived memory T cells in human skin can be defined by the expression of CCR8

The pentameric complex drives immunologically covert cell -cell transmission of wild-type human cytomegalovirus

Human cytomegalovirus (HCMV) strains that have been passaged in vitro rapidly acquire mutations that impact viral growth. These laboratory-adapted strains of HCMV generally exhibit restricted tropism, produce high levels of cell-free virus, and develop susceptibility to natural killer cells. To permit experimentation with a virus that retained a clinically relevant phenotype, we reconstructed a wild-type (WT) HCMV genome using bacterial artificial chromosome technology. Like clinical virus, this genome proved to be unstable in cell culture; however, propagation of intact virus was achieved by placing the RL13 and UL128 genes under conditional expression. In this study, we show that WT-HCMV produces extremely low titers of cell-free virus but can efficiently infect fibroblasts, epithelial, monocyte-derived dendritic, and Langerhans cells via direct cell–cell transmission. This process of cell–cell transfer required the UL128 locus, but not the RL13 gene, and was significantly less vulnerable to the disruptive effects of IFN, cellular restriction factors, and neutralizing antibodies compared with cell-free entry. Resistance to neutralizing antibodies was dependent on high-level expression of the pentameric gH/gL/gpUL128–131A complex, a feature of WT but not passaged strains of HCMV

Exploring the putative role of kallikrein-6, calpain-1 and cathepsin-D in the proteolytic degradation of α-synuclein in multiple system atrophy

AIMS: There is evidence that accumulation of α-synuclein (α-syn) in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) results from impaired removal of α-syn rather than its overproduction. Kallikrein-6 (KLK6), calpain-1 (CAPN1) and cathepsin-D (CTSD) are among a small number of proteases that cleave α-syn and are dysregulated in PD and DLB. Our aim in this study was to determine whether protease activity is altered in another α-synucleinopathy, multiple system atrophy (MSA), and might thereby modulate the regional distribution of α-syn accumulation. METHODS: mRNA and protein level and/or activity of KLK6, CAPN1 and CTSD were measured and assessed in relation to α-syn load in multiple brain regions (posterior frontal cortex, caudate nucleus, putamen, occipital cortex, pontine base and cerebellar white matter), in MSA (n = 20) and age-matched post-mortem control tissue (n = 20). RESULTS: CTSD activity was elevated in MSA in the pontine base and cerebellar white matter. KLK6 and CAPN1 levels were elevated in MSA in the putamen and cerebellar white matter. However, the activity or level of these proteolytic enzymes did not correlate with the regional distribution of α-syn. CONCLUSIONS: Accumulation of α-syn in MSA is not due to reduced activity of the proteases we have studied. We suggest that their upregulation is likely to be a compensatory response to increased α-syn in MSA. This article is protected by copyright. All rights reserved

Association between health-related quality of life and menopausal status and symptoms in women living with HIV aged 45-60 years in England: An analysis of the PRIME study

OBJECTIVES: The aim of this study was to compare the health-related quality of life between mid-life women with HIV and the general population and to investigate the association between health-related quality of life and menopausal (1) status and (2) symptoms among women with HIV. METHODS: Cross-sectional data of women with HIV aged 45-60 years from the Positive Transitions Through the Menopause Study. Health-related quality of life was assessed using the Euroqol questionnaire with utility scores categorizing health as perfect (score = 1.00), sub-optimal (0.75-0.99) or poor (< 0.75). Scores were compared between Positive Transitions Through the Menopause study participants and women (aged 45-59 years) from the Health Survey for England. Associations between health-related quality of life and menopausal status/symptoms in Positive Transitions Through the Menopause participants were assessed using a multivariable two-part regression model, the results of which are combined to produce a single marginal effect. RESULTS: In total, 813 women from the Positive Transitions Through the Menopause study were included (median age 49 (interquartile range: 47-53) years); the majority were of Black African ethnicity (72.2%). Overall, 20.9%, 43.7% and 35.3% of women were pre-, peri- and post-menopausal, respectively, and 69.7% experienced mild/moderate/severe menopausal symptoms. Approximately, 40% reported perfect health, 22.1% sub-optimal health and 39.0% poor health, similar to women from the Health Survey for England (perfect health: 36.9%, sub-optimal health: 25.2%, poor health: 37.9%). In multivariable models, we found an association between health-related quality of life and peri-menopausal status (marginal effect: 0.07 (0.02, 0.12)); however, the association with post-menopausal status was attenuated (marginal effect: 0.01 (-0.05, 0.06)). There remained a strong association between lower utility scores and moderate (marginal effect: 0.16 (0.11, 0.20)) and severe (marginal effect: 0.32 (0.27, 0.39)) menopausal symptoms. CONCLUSION: There were no differences in health-related quality of life between women with HIV (Positive Transitions Through the Menopause participants) and women from the Health Survey for England dataset. Among Positive Transitions Through the Menopause participants, health-related quality of life was reduced in peri-menopausal women and those with increasingly severe menopausal symptoms. Our findings highlight the importance of proactive assessment of menopausal status and symptoms to optimize health-related quality of life in women living with HIV as they reach mid-life and beyond

Prospective association of social circumstance, socioeconomic, lifestyle and mental health factors with subsequent hospitalisation over 6–7 year follow up in people living with HIV

Background: Predictors of hospitalisation in people with HIV (PLHIV) in the contemporary treatment era are not well understood. / Methods: This ASTRA sub-study used clinic data linkage and record review to determine occurrence of hospitalisations among 798 PLHIV from baseline questionnaire (February to December 2011) until 1 June 2018. Associations of baseline social circumstance, socioeconomic, lifestyle, mental health, demographic and clinical factors with repeated all-cause hospitalisation from longitudinal data were investigated using Prentice-Williams-Peterson models. Associations were also assessed in 461 individuals on antiretroviral therapy (ART) with viral load ≤50 copies/ml and CD4 count ≥500 cells/ µl. / Findings: Rate of hospitalisation was 5.8/100 person-years (95% CI: 5.1–6.5). Adjusted for age, demographic group and time with diagnosed HIV, the following social circumstance, socioeconomic, lifestyle and mental health factors predicted hospitalisation: no stable partner (adjusted hazard ratio (aHR)=1.59; 95% CI=1.16–2.20 vs living with partner); having children (aHR=1.50; 1.08–2.10); non-employment (aHR=1.56; 1.07–2.27 for unemployment; aHR=2.39; 1.70–3.37 for sick/disabled vs employed); rented housing (aHR=1.72; 1.26–2.37 vs homeowner); not enough money for basic needs (aHR=1.82; 1.19–2.78 vs enough); current smoking (aHR=1.39; 1.02–1.91 vs never); recent injection-drug use (aHR=2.11; 1.30–3.43); anxiety symptoms (aHRs=1.39; 1.01–1.91, 2.06; 1.43–2.95 for mild and moderate vs none/minimal); depressive symptoms (aHRs=1.67; 1.17–2.38, 1.91; 1.30–2.78 for moderate and severe vs none/minimal); treated/untreated depression (aHRs=1.65; 1.03–2.64 for treated depression only, 1.87; 1.39–2.52 for depressive symptoms only; 1.53; 1.05–2.24; for treated depression and depressive symptoms, versus neither). Associations were broadly similar in those with controlled HIV and high CD4. / Interpretation: Social circumstance, socioeconomic disadvantage, adverse lifestyle factors and poorer mental health are strong predictors of hospitalisation in PLHIV, highlighting the need for targeted interventions and care. / Funding: British HIV Association (BHIVA) Research Award (2017); SMR funded by a PhD fellowship from the Royal Free Charity

Sexual risk reduction interventions for patients attending sexual health clinics: a mixed-methods feasibility study

Background: Sexually transmitted infections (STIs) continue to represent a major public health challenge. There is evidence that behavioural interventions to reduce risky sexual behaviours can reduce STI rates in patients attending sexual health (SH) services. However, it is not known if these interventions are effective when implemented at scale in SH settings in England. Objectives: The study had two main objectives: 1. develop and pilot a package of evidence-based sexual risk reduction interventions that can be delivered through SH services; 2. assess the feasibility of conducting a randomised controlled trial (RCT) to determine effectiveness against usual care. Design: The project was a multi-stage mixed methods study, with developmental and pilot RCT phases. Preparatory work included a systematic review; analysis of national surveillance data, and development of a triage algorithm; interviews and surveys with SH staff and patients to identify, select and adapt interventions. A pilot cluster RCT was planned for eight SH clinics; the intervention would be offered in four clinics, with qualitative and process evaluation to assess feasibility and acceptability. Four clinics acted as controls; in all clinics, participants would be consented to a 6-week follow-up STI screen. Setting: SH clinics in England. Participants: Young people (aged 16-25 years old) and men who have sex with men. Intervention: A three-part intervention package: 1. triage tool to score patients as high or low risk of STI infection using routine data; 2. a study-designed webpage with tailored sexual health information for all patients, regardless of risk; 3. a brief one-to-one session based on motivational interviewing for high risk patients. Main outcome measures: The three outcomes were: acceptability of the intervention to patients and SH providers; feasibility of delivering the interventions within existing resources; and feasibility of obtaining follow-up data on STI diagnoses (primary outcome in a full trial). Results: We identified 33 relevant trials from the systematic review, including: videos, peer support, digital, and brief one-to-one sessions. Patients and SH providers showed preferences for one-to-one and digital interventions, and providers indicated these intervention types could feasibly be implemented in their settings. There were no appropriate digital interventions that could be adapted in time for the pilot; therefore, we created a placeholder for the purposes of the pilot. The intervention package was piloted in two SH settings, rather than the planned four. Several barriers were found to intervention implementation, including a lack of trained staff time and clinic space. The intervention package was theoretically acceptable, but we observed poor engagement. We recruited patients from six clinics for the follow-up, rather than eight. The completion rate for follow-up was lower than anticipated (16% versus 46%). Limitations: Fewer clinics were included in the pilot than planned limiting the ability to make strong conclusions on RCT feasibility. Conclusion: We were unable to conclude whether a definitive RCT would be feasible due to challenges in implementation of a pilot, but have laid the groundwork for future research in the area