Publications by authors named "Ross Harris"

72 Publications

Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study.

Lancet Infect Dis 2021 Aug 27. Epub 2021 Aug 27.

COVID-19 National Epidemiology Cell, Public Health England, London, UK.

Background: The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.

Methods: This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.

Findings: Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17-43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32-3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08-1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47-8·05] and for hospital admission or emergency care attendance 1·58 [0·69-3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29-4·16] and 1·43 [1·04-1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low.

Interpretation: This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.

Funding: Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.
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http://dx.doi.org/10.1016/S1473-3099(21)00475-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397301PMC
August 2021

The impact of direct-acting antivirals on hepatitis C viraemia among people who inject drugs in England; real-world data 2011-2018.

J Viral Hepat 2021 Oct 29;28(10):1452-1463. Epub 2021 Jul 29.

National Infection Service, Public Health England, London, UK.

Direct-acting antiviral (DAA) therapy for anybody with viraemic HCV infection has been scaled-up in England since 2017. To assess early impacts, we investigated trends in, and factors associated with, HCV viraemia among people who inject drugs (PWID). We also examined trends in self-reported treatment access. Bio-behavioural data from an annual, national surveillance survey of PWID (2011-2018) estimated trends in viraemic prevalence among HCV antibody-positive PWID. Multivariable logistic regression identified characteristics independently associated with viraemia. Trends in treatment access were examined for PWID with known infection. Between 2011 and 2016, viraemic prevalence among antibody-positive PWID remained stable (2011, 57.7%; 2016, 55.8%) but decreased in 2017 (49.4%) and 2018 (50.4%) (both p < 0.001). After adjustment for demographic and behavioural characteristics, there remained significant reduction in viraemia in 2017 (adjusted odds ratio [aOR] 0.79, 95% CI 0.65-0.94) and 2018 (aOR 0.79, 95% CI 0.66-0.93) compared to 2016. Other factors associated with viraemia were male gender (aOR 1.68, 95% CI 1.53-1.86), geographical region, injecting in past year (aOR 1.26, 95% CI 1.13-1.41), imprisonment (aOR 1.14, 95% CI 1.04-1.31) and homelessness (aOR 1.17, 95% CI 1.04-1.31). Among non-viraemic PWID with known infection, the proportion reporting ever receiving treatment increased in 2017 (28.7%, p < 0.001) and 2018 (38.9%, p < 0.001) compared to 2016 (14.5%). In conclusion, there has been a small reduction in HCV viraemia among antibody-positive PWID in England since 2016, alongside DAA scale-up, and some indication that treatment access has improved in the same period. Population-level monitoring and focus on harm reduction is critical for achieving and evaluating elimination.
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http://dx.doi.org/10.1111/jvh.13575DOI Listing
October 2021

Risk of hospital admission for patients with SARS-CoV-2 variant B.1.1.7: cohort analysis.

BMJ 2021 06 15;373:n1412. Epub 2021 Jun 15.

MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.

Objective: To evaluate the relation between diagnosis of covid-19 with SARS-CoV-2 variant B.1.1.7 (also known as variant of concern 202012/01) and the risk of hospital admission compared with diagnosis with wild-type SARS-CoV-2 variants.

Design: Retrospective cohort analysis.

Setting: Community based SARS-CoV-2 testing in England, individually linked with hospital admission data.

Participants: 839 278 patients with laboratory confirmed covid-19, of whom 36 233 had been admitted to hospital within 14 days, tested between 23 November 2020 and 31 January 2021 and analysed at a laboratory with an available TaqPath assay that enables assessment of S-gene target failure (SGTF), a proxy test for the B.1.1.7 variant. Patient data were stratified by age, sex, ethnicity, deprivation, region of residence, and date of positive test.

Main Outcome Measures: Hospital admission between one and 14 days after the first positive SARS-CoV-2 test.

Results: 27 710 (4.7%) of 592 409 patients with SGTF variants and 8523 (3.5%) of 246 869 patients without SGTF variants had been admitted to hospital within one to 14 days. The stratum adjusted hazard ratio of hospital admission was 1.52 (95% confidence interval 1.47 to 1.57) for patients with covid-19 infected with SGTF variants, compared with those infected with non-SGTF variants. The effect was modified by age (P<0.001), with hazard ratios of 0.93-1.21 in patients younger than 20 years with versus without SGTF variants, 1.29 in those aged 20-29, and 1.45-1.65 in those aged ≥30 years. The adjusted absolute risk of hospital admission within 14 days was 4.7% (95% confidence interval 4.6% to 4.7%) for patients with SGTF variants and 3.5% (3.4% to 3.5%) for those with non-SGTF variants.

Conclusions: The results suggest that the risk of hospital admission is higher for people infected with the B.1.1.7 variant compared with wild-type SARS-CoV-2, likely reflecting a more severe disease. The higher severity may be specific to adults older than 30 years.
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http://dx.doi.org/10.1136/bmj.n1412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204098PMC
June 2021

On the Sensitivity and Specificity of Postmortem Upper Respiratory Tract Testing for SARS-CoV-2.

J Infect Dis 2021 08;224(3):389-394

National COVID-19 Epidemiology Cell, Public Health England, London, United Kingdom.

Background: Postmortem testing can improve our understanding of the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) if sufficiently sensitive and specific.

Methods: We investigated the postmortem sensitivity and specificity of reverse transcriptase polymerase chain reaction (PCR) testing on upper respiratory swabs using a dataset of everyone tested for SARS-CoV-2 before and after death in England, 1 March to 29 October 2020. We analyzed sensitivity in those with a positive test before death by time to postmortem test. We developed a multivariate model and conducted time-to-negativity survival analysis. For specificity, we analyzed those with a negative test in the week before death.

Results: Postmortem testing within a week after death had a sensitivity of 96.8% if the person had tested positive within a week before death. There was no effect of age, sex, or specimen type on sensitivity, but individuals with coronavirus disease 2019 (COVID-19)-related codes on their death certificate were 5.65 times more likely to test positive after death (95% confidence interval, 2.31-13.9). Specificity was 94.2%, increasing to 97.5% in individuals without COVID-19 on the death certificate.

Conclusion: Postmortem testing has high sensitivity (96.8%) and specificity (94.2%) if performed within a week after death and could be a useful diagnostic tool.
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http://dx.doi.org/10.1093/infdis/jiab270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194530PMC
August 2021

Changes in characteristics and case-severity in patients hospitalised with influenza A (H1N1) pdm09 infection between two epidemic waves-England, 2009-2010.

Influenza Other Respir Viruses 2021 09 4;15(5):599-607. Epub 2021 May 4.

Public Health England, London, UK.

Background: During 2009-2010, pandemic influenza A (H1N1) pdm09 virus (pH1N1) infections in England occurred in two epidemic waves. Reasons for a reported increase in case-severity during the second wave are unclear.

Methods: We analysed hospital-based surveillance for patients with pH1N1 infections in England during 2009-2010 and linked national data sets to estimate ethnicity, socio-economic status and death within 28 days of admission. We used multivariable logistic regression to assess whether changes in demographic, clinical and management characteristics of patients could explain an increase in ICU admission or death, and accounted for missing values using multiple imputation.

Results: During the first wave, 54/960 (6%) hospitalised patients required intensive care and 21/960 (2%) died; during the second wave 143/1420 (10%) required intensive care and 55/1420 (4%) died. In a multivariable model, during the second wave patients were less likely to be from an ethnic minority (OR 0.33, 95% CI 0.26-0.42), have an elevated deprivation score (OR 0.75, 95% CI 0.68-0.83), have known comorbidity (OR 0.78, 95% CI 0.63-0.97) or receive antiviral therapy ≤2 days before onset (OR 0.72, 95% CI 0.56-0.92). Increased case-severity during the second wave was not explained by changes in demographic, clinical or management characteristics.

Conclusions: Monitoring changes in patient characteristics could help target interventions during multiple waves of COVID-19 or a future influenza pandemic. To understand and respond to changes in case-severity, surveillance is needed that includes additional factors such as admission thresholds and seasonal coinfections.
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http://dx.doi.org/10.1111/irv.12863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404053PMC
September 2021

Serological surveillance of SARS-CoV-2: Six-month trends and antibody response in a cohort of public health workers.

J Infect 2021 05 22;82(5):162-169. Epub 2021 Mar 22.

Immunisation and Countermeasures Division, PHE Colindale, National Infection Service, 61 Colindale Avenue, London NW9 5EQ, UK; Paediatric Infectious Diseases Research Group (PIDRG), St. Georges University of London (SGUL), London, UK. Electronic address:

Background: Antibody waning after SARS-CoV-2 infection may result in reduction in long-term immunity following natural infection and vaccination, and is therefore a major public health issue. We undertook prospective serosurveillance in a large cohort of healthy adults from the start of the epidemic in England.

Methods: Clinical and non-clinical healthcare workers were recruited across three English regions and tested monthly from March to November 2020 for SARS-CoV-2 spike (S) protein and nucleoprotein (N) antibodies using five different immunoassays. In positive individuals, antibody responses and long-term trends were modelled using mixed effects regression.

Findings: In total, 2246 individuals attended 12,247 visits and 264 were seropositive in ≥ 2 assays. Most seroconversions occurred between March and April 2020. The assays showed > 85% agreement for ever-positivity, although this changed markedly over time. Antibodies were detected earlier with Abbott (N) but declined rapidly thereafter. With the EuroImmun (S) and receptor-binding domain (RBD) assays, responses increased for 4 weeks then fell until week 12-16 before stabilising. For Roche (N), responses increased until 8 weeks, stabilised, then declined, but most remained above the positive threshold. For Roche (S), responses continued to climb over the full 24 weeks, with no sero-reversions. Predicted proportions sero-reverting after 52 weeks were 100% for Abbott, 59% (95% credible interval 50-68%) Euroimmun, 41% (30-52%) RBD, 10% (8-14%) Roche (N) < 2% Roche (S).

Interpretation: Trends in SARS-CoV-2 antibodies following infection are highly dependent on the assay used. Ongoing serosurveillance using multiple assays is critical for monitoring the course and long-term progression of SARS-CoV-2 antibodies.
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http://dx.doi.org/10.1016/j.jinf.2021.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982645PMC
May 2021

Persistence of SARS-CoV-2 N-Antibody Response in Healthcare Workers, London, UK.

Emerg Infect Dis 2021 04 18;27(4):1155-1158. Epub 2021 Mar 18.

Prospective serosurveillance of severe acute respiratory syndrome coronavirus 2 in 1,069 healthcare workers in London, UK, demonstrated that nucleocapsid antibody titers were stable and sustained for <12 weeks in 312 seropositive participants. This finding was consistent across demographic and clinical variables and contrasts with reports of short-term antibody waning.
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http://dx.doi.org/10.3201/eid2704.204554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007325PMC
April 2021

Effectiveness and outcomes of air travel-related TB incident follow-up: a systematic review.

Eur Respir J 2021 05 6;57(5). Epub 2021 May 6.

Institute for Global Health, University College London, London, UK.

The World Health Organization (WHO) recommends following up passengers after possible exposure to a case of infectious tuberculosis (TB) during air travel. This is time-consuming and difficult, and increasingly so with higher numbers each year of flights and passengers to and from countries with high TB endemicity. This paper systematically reviews the literature on contact tracing investigations after a plane exposure to active pulmonary TB. Evidence for in-flight transmission was assessed by reviewing the positive results of contacts without prior risk factors for latent TB.A search of Medline, EMBASE, BIOSIS, Cochrane Library and Database of Systematic Reviews was carried out, with no restrictions on study design, index case characteristics, duration of flight or publication date.In total, 22 papers were included, with 469 index cases and 15 889 contacts. Only 26.4% of all contacts identified completed screening after exposure. The yield of either a single positive tuberculin skin test (TST) or a TST conversion attributable to in-flight transmission was between 0.19% (95% CI 0.13%-0.27%) and 0.74% (95% CI 0.61%-0.88%) of all contacts identified (0.00%, 95% CI 0.00%-0.00% and 0.13%, 95% CI 0.00%-0.61% in random effects meta-analysis). The main limitation of this study was heterogeneity of reporting.The evidence behind the criteria for initiating investigations is weak and it has been widely demonstrated that active screening of contacts is labour-intensive and unlikely to be effective. Based on our findings, formal comprehensive contact tracing may be of limited utility following a plane exposure.
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http://dx.doi.org/10.1183/13993003.00013-2020DOI Listing
May 2021

Estimating the prevalence of problem drug use from drug-related mortality data.

Addiction 2020 12 9;115(12):2393-2404. Epub 2020 Jun 9.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background And Aims: Indirect estimation methods are required for estimating the size of populations where only a proportion of individuals are observed directly, such as problem drug users (PDUs). Capture-recapture and multiplier methods are widely used, but have been criticized as subject to bias. We propose a new approach to estimating prevalence of PDU from numbers of fatal drug-related poisonings (fDRPs) using linked databases, addressing the key limitations of simplistic 'mortality multipliers'.

Methods: Our approach requires linkage of data on a large cohort of known PDUs to mortality registers and summary information concerning additional fDRPs observed outside this cohort. We model fDRP rates among the cohort and assume that rates in unobserved PDUs are equal to rates in the cohort during periods out of treatment. Prevalence is estimated in a Bayesian statistical framework, in which we simultaneously fit regression models to fDRP rates and prevalence, allowing both to vary by demographic factors and the former also by treatment status.

Results: We report a case study analysis, estimating the prevalence of opioid dependence in England in 2008/09, by gender, age group and geographical region. Overall prevalence was estimated as 0.82% (95% credible interval = 0.74-0.94%) of 15-64-year-olds, which is similar to a published estimate based on capture-recapture analysis.

Conclusions: Our modelling approach estimates prevalence from drug-related mortality data, while addressing the main limitations of simplistic multipliers. This offers an alternative approach for the common situation where available data sources do not meet the strong assumptions required for valid capture-recapture estimation. In a case study analysis, prevalence estimates based on our approach were surprisingly similar to existing capture-recapture estimates but, we argue, are based on a much more objective and justifiable modelling approach.
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http://dx.doi.org/10.1111/add.15111DOI Listing
December 2020

Completeness of tuberculosis (TB) notification: inventory studies and capture-recapture analyses, six European Union countries, 2014 to 2016.

Euro Surveill 2020 03;25(12)

Department of Pulmonology and Tuberculosis, University Medical Centre Groningen (UMCG), Groningen, the Netherlands.

BackgroundProgress towards the World Health Organization's End TB Strategy is monitored by assessing tuberculosis (TB) incidence, often derived from TB notification, assuming complete case detection and reporting. This assumption is unlikely to hold in many settings, including European Union (EU) countries.AimWe aimed to assess observed and estimated completeness of TB notification through inventory studies and capture-recapture (CRC) methodology in six EU countries: Croatia, Denmark, Finland, the Netherlands, Portugal Slovenia.MethodsWe performed record linkage, case ascertainment and CRC analyses of data collected retrospectively from at least three national TB-related registers in each country between 2014 and 2016.ResultsObserved completeness of TB notification by inventory studies was 73.9% in Croatia, 98.7% in Denmark, 83.6% in Finland, 81.6% in the Netherlands, 85.8% in Portugal and 100% in Slovenia. Subsequent CRC analysis estimated completeness of TB notification to be 98.4% in Denmark, 76.5% in Finland and 77.0% in Portugal. In Croatia, CRC analyses produced implausible results while in the Netherlands and Slovenia, it was methodologically considered not meaningful.ConclusionInventory studies and CRC methodology suggest a TB notification completeness between 73.9% and 100% in the six EU countries. Mandatory reporting by clinicians and laboratories, and cross-checking of registers, strongly contributes to accurate notification rates, but hospital episode registers likely contain a considerable proportion of false-positive TB records and are thus less useful. Further strengthening routine surveillance to count TB cases, i.e. incidence, accurately by employing record-linkage of high-quality TB registers should make CRC studies obsolete in EU countries.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.12.1900568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118341PMC
March 2020

Cost-Effectiveness of One-Time Birth Cohort Screening for Hepatitis C as Part of the National Health Service Health Check Program in England.

Value Health 2019 11 19;22(11):1248-1256. Epub 2019 Aug 19.

The National Institute for Health Research Health Protection Research Unit in Blood Borne and Sexually Transmitted Infections at University College London, England, UK; Population Health Sciences, Bristol Medical School, University of Bristol, England, UK; The National Institute for Health Research Health Protection Research Unit in Evaluation of Interventions, England, UK.

Background And Objectives: Birth cohort screening for the hepatitis C virus (HCV) has been implemented in the US, but there is little evidence of its cost-effectiveness in England. We aim to evaluate the cost-effectiveness of one-time HCV screening for individuals born between 1950 and 1979 as part of the National Health Service health check in England, a health check for adults aged 40 to 74 years in primary care.

Methods: A Markov model was developed to analyze add-on HCV testing to the National Health Service health check for individuals in birth cohorts between 1950 and 1979, versus current background HCV testing only, over a lifetime horizon. The model used data from a back-calculation model of the burden of HCV in England, sentinel surveillance of HCV testing, and published literature. Results are presented from a health service perspective in pounds in 2017, as incremental cost-effectiveness ratios per quality-adjusted life years gained.

Results: The base-case incremental cost-effectiveness ratios ranged from £7648 to £24 434, and £18 681 to £46 024, across birth cohorts when considering 2 sources of HCV transition probabilities. The intervention is most likely to be cost-effective for those born in the 1970s, and potentially cost-effective for those born from 1955 to 1969. The model results were most sensitive to the source of HCV transition probabilities, the probability of referral and receiving treatment, and the HCV prevalence among testers. The maximum value of future research across all birth cohorts was £11.3 million at £20 000 per quality-adjusted life years gained.

Conclusion: Birth cohort screening is likely to be cost-effective for younger birth cohorts, although considerable uncertainty exists for other birth cohorts. Further studies are warranted to reduce uncertainty in cost-effectiveness and consider the acceptability of the intervention.
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http://dx.doi.org/10.1016/j.jval.2019.06.006DOI Listing
November 2019

Evaluating the population impact of hepatitis C direct acting antiviral treatment as prevention for people who inject drugs (EPIToPe) - a natural experiment (protocol).

BMJ Open 2019 09 24;9(9):e029538. Epub 2019 Sep 24.

Glasgow Caledonian University, Glasgow, UK.

Introduction: Hepatitis C virus (HCV) is the second largest contributor to liver disease in the UK, with injecting drug use as the main risk factor among the estimated 200 000 people currently infected. Despite effective prevention interventions, chronic HCV prevalence remains around 40% among people who inject drugs (PWID). New direct-acting antiviral (DAA) HCV therapies combine high cure rates (>90%) and short treatment duration (8 to 12 weeks). Theoretical mathematical modelling evidence suggests HCV treatment scale-up can prevent transmission and substantially reduce HCV prevalence/incidence among PWID. Our primary aim is to generate empirical evidence on the effectiveness of HCV 'Treatment as Prevention' (TasP) in PWID.

Methods And Analysis: We plan to establish a natural experiment with Tayside, Scotland, as a single intervention site where HCV care pathways are being expanded (including specialist drug treatment clinics, needle and syringe programmes (NSPs), pharmacies and prison) and HCV treatment for PWID is being rapidly scaled-up. Other sites in Scotland and England will act as potential controls. Over 2 years from 2017/2018, at least 500 PWID will be treated in Tayside, which simulation studies project will reduce chronic HCV prevalence among PWID by 62% (from 26% to 10%) and HCV incidence will fall by approximately 2/3 (from 4.2 per 100 person-years (p100py) to 1.4 p100py). Treatment response and re-infection rates will be monitored. We will conduct focus groups and interviews with service providers and patients that accept and decline treatment to identify barriers and facilitators in implementing TasP. We will conduct longitudinal interviews with up to 40 PWID to assess whether successful HCV treatment alters their perspectives on and engagement with drug treatment and recovery. Trained peer researchers will be involved in data collection and dissemination. The primary outcome - chronic HCV prevalence in PWID - is measured using information from the Needle Exchange Surveillance Initiative survey in Scotland and the Unlinked Anonymous Monitoring Programme in England, conducted at least four times before and three times during and after the intervention. We will adapt Bayesian synthetic control methods (specifically the Causal Impact Method) to generate the cumulative impact of the intervention on chronic HCV prevalence and incidence. We will use a dynamic HCV transmission and economic model to evaluate the cost-effectiveness of the HCV TasP intervention, and to estimate the contribution of the scale-up in HCV treatment to observe changes in HCV prevalence. Through the qualitative data we will systematically explore key mechanisms of TasP real world implementation from provider and patient perspectives to develop a manual for scaling up HCV treatment in other settings. We will compare qualitative accounts of drug treatment and recovery with a 'virtual cohort' of PWID linking information on HCV treatment with Scottish Drug treatment databases to test whether DAA treatment improves drug treatment outcomes.

Ethics And Dissemination: Extending HCV community care pathways is covered by ethics (ERADICATE C, ISRCTN27564683, Super DOT C Trial clinicaltrials.gov: NCT02706223). Ethical approval for extra data collection from patients including health utilities and qualitative interviews has been granted (REC ref: 18/ES/0128) and ISCRCTN registration has been completed (ISRCTN72038467). Our findings will have direct National Health Service and patient relevance; informing prioritisation given to early HCV treatment for PWID. We will present findings to practitioners and policymakers, and support design of an evaluation of HCV TasP in England.
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http://dx.doi.org/10.1136/bmjopen-2019-029538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773339PMC
September 2019

Data linkage to monitor hepatitis C-associated end-stage liver disease and hepatocellular carcinoma inpatient stays in England.

J Viral Hepat 2020 01 3;27(1):20-27. Epub 2019 Oct 3.

National Infection Service, Public Health England, London, UK.

Persons with chronic hepatitis C (HCV) infection are at increased risk of end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC). The impact of hepatitis treatment scale-up and elimination strategies on ESLD and HCC incidence is a critical measure of progress towards WHO targets. Data from national laboratory surveillance of HCV diagnoses were linked to inpatient care records in Hospital Episode Statistics (HES). For persons first diagnosed with HCV between 1998 and 2016, we describe the characteristics of those with ESLD and HCC and estimate incidence. Of persons diagnosed with HCV between 1998 and 2016 (104 674), 9.1% (9525) had an admission for ESLD and 2.5% (2610) for HCC. The majority of persons with ESLD and HCC were male (70.7% and 82.7%) and of white ethnicity (89.9% and 82.7%). Crude incidence of ESLD and HCC admission was 10.4 and 3.2 per 1000 person-years, respectively. When compared to 2011-2013, incidence of ESLD and HCC admissions in 2014-2017 were lower (ESLD incidence rate ratio [IRR]: 0.81; 95% Confidence interval [CI]: 0.76-0.86; HCC IRR: 0.90; 95% CI: 0.82-1.00, P = .045). Data linkage showed considerable underreporting of HCV in HES coding for ESLD and HCC (16.0% and 11.3%, respectively). In conclusion, we found a decline in incidence of ESLD and HCC-related inpatient admissions since 2011-2013. Linked analysis is required for the continued monitoring of ESLD and HCC inpatient incidence. However, HES data quality issues around completeness of identifiers contribute to uncertainty in linkage and may limit our ability to robustly monitor progress towards WHO elimination goals.
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http://dx.doi.org/10.1111/jvh.13203DOI Listing
January 2020

Effectiveness of pre-entry active tuberculosis and post-entry latent tuberculosis screening in new entrants to the UK: a retrospective, population-based cohort study.

Lancet Infect Dis 2019 11 27;19(11):1191-1201. Epub 2019 Aug 27.

National Institute for Health Research Health Protection Research Unit in Respiratory Infections, National Heart and Lung Institute, Imperial College London, London, UK; Tuberculosis Unit, TARGET, National Infection Service, Public Health England, London, UK.

Background: Evaluating interventions that might lead to a reduction in tuberculosis in high-income countries with a low incidence of the disease is key to accelerate progress towards its elimination. In such countries, migrants are known to contribute a large proportion of tuberculosis cases to the burden. We assessed the effectiveness of screening for active tuberculosis before entry to the UK and for latent tuberculosis infection (LTBI) post-entry for reduction of tuberculosis in new-entrant migrants to the UK. Additionally, we investigated the effect of access to primary care on tuberculosis incidence in this population.

Methods: We did a retrospective, population-based cohort study of migrants from 66 countries who were negative for active tuberculosis at pre-entry screening between Jan 1, 2011, and Dec 31, 2014, and eligible for LTBI screening. We used record linkage to track their first contact with primary care, uptake of LTBI screening, and development of active tuberculosis in England, Wales, and Northern Ireland. To assess the effectiveness of the pre-entry screening programme, we identified a control group of migrants who were not screened for active tuberculosis using the specific code for new entrants to the UK registering in primary care within the National Health Service patient registration data system. Our primary outcome was development of active tuberculosis notified to the National Enhanced Tuberculosis Surveillance System.

Findings: Our cohort comprised 224 234 migrants who were screened for active tuberculosis before entry to the UK and a control group of 118 738 migrants who were not. 103 990 (50%) migrants who were screened for active tuberculosis registered in primary care; all individuals in the control group were registered in primary care. 1828 tuberculosis cases were identified during the cohort time, of which 31 were prevalent. There were 26 incident active tuberculosis cases in migrants with no evidence of primary care registration, and 1771 cases in the entire cohort of migrants who registered in primary care (n=222 728), giving an incidence rate of 174 (95% CI 166-182) per 100 000 person-years. 672 (1%) of 103 990 migrants who were screened for active tuberculosis went on to develop tuberculosis compared with 1099 (1%) of 118 738 not screened for active tuberculosis (incidence rate ratio [IRR] 1·49, 95% CI 1·33-1·67; p<0·0001). 2451 (1%) of the 222 728 migrants registered in primary care were screened for LTBI, of whom 421 (17%) tested positive and 1961 (80%) tested negative; none developed active tuberculosis within the observed time period. Migrants settling in the least deprived areas had a decreased risk of developing tuberculosis (IRR 0·74, 95% CI 0·62-0·89; p=0·002), and time from UK arrival to primary care registration of 1 year or longer was associated with increased risk of active tuberculosis (2·96, 2·59-3·38; p<0·0001).

Interpretation: Pre-entry tuberculosis screening, early primary care registration, and LTBI screening are strongly and independently associated with a lower tuberculosis incidence in new-entrant migrants.

Funding: National Institute for Health Research (NIHR) Health Protection Research Unit in Respiratory Infections and NIHR Imperial Biomedical Research Centre.
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http://dx.doi.org/10.1016/S1473-3099(19)30260-9DOI Listing
November 2019

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

Eur Respir J 2019 10 10;54(4). Epub 2019 Oct 10.

Institute for Global Health, University College London, London, UK.

Introduction: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance.

Methods: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence).

Results: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42).

Conclusions: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations.
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http://dx.doi.org/10.1183/13993003.00982-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785706PMC
October 2019

Mortality rates among individuals diagnosed with hepatitis C virus (HCV); an observational cohort study, England, 2008 to 2016.

Euro Surveill 2019 Jul;24(30)

The National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Blood Borne and Sexually Transmitted Infections at University College London, United Kingdom.

BackgroundMonitoring trends in mortality for individuals diagnosed with hepatitis C virus (HCV) infection are important as we expand treatment and move towards World Health Organization elimination targets.AimTo estimate mortality rates for individuals aged ≥ 15 years diagnosed with HCV infection in England 2008-16.MethodsAn observational cohort study whereby death certificate information was linked to the Sentinel Surveillance of Blood Borne Virus Testing in England. Age-sex standardised mortality rates (ASMR) for individuals diagnosed with HCV infection (2008-16) were calculated and compared to the general population.ResultsOf 43,895 individuals with HCV infection, 2,656 (6.3%) died. All-cause ASMRs were 2,834.2 per 100,000 person years (PY), 2.3 times higher than in the general population. In individuals aged 30-69 years, all-cause mortality rates were 1,768.9 per 100,000 PY among individuals with HCV, 4.7 times higher than in the general population. ASMRs had not decreased between 2010 (2,992) and 2016 (2,340; p=0.10), with no change from 2014 (p = 0.058). ASMRs were 441.0 times higher for hepatitis, 34.4 times higher for liver cancer, 8.1 times higher for end stage liver disease and 6.4 times higher for external causes than in the general population.ConclusionsMortality was higher in individuals with diagnosed HCV infection compared to the general population, highlighting health inequalities. There is a need to improve HCV diagnosis, engagement in care and treatment rates. The high mortality from external causes highlights the importance of integrated health and social care strategies and addressing the needs of this vulnerable population.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.30.1800695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668288PMC
July 2019

Seroprevalence and demographic factors associated with hepatitis B, hepatitis C and HIV infection from a hospital emergency department testing programme, London, United Kingdom, 2015 to 2016.

Euro Surveill 2019 Jul;24(27)

Queen Mary University of London, London, United Kingdom.

BackgroundProgress towards HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) elimination requires local prevalence estimates and linkage to care (LTC) of undiagnosed or disengaged cases.AimWe aimed to estimate seroprevalence, factors associated with positive blood-borne virus (BBV) serology and numbers needed to screen (NNS) to detect a new BBV diagnosis and achieve full LTC from emergency department (ED) BBV testing.MethodsDuring a 9-month programme in an ED in east London, England, testing was offered to adult attendees having a full blood count (FBC). We estimated factors associated with positive BBV serology using logistic regression and NNS as the inverse of seroprevalence. Estimates were weighted to the age, sex and ethnicity of the FBC population.ResultsOf 6,211 FBC patients tested, 217 (3.5%) were positive for at least one BBV. Weighted BBV seroprevalence was 4.2% (95% confidence interval (CI): 3.6-4.9). Adjusted odds ratios (aOR) of positive BBV serology were elevated among patients that were: male (aOR: 2.7; 95% CI: 1.9-3.9), 40-59 years old (aOR: 1.9; 95% CI: 1.4-2.7), of Black British/Black other ethnicity (aOR: 1.8; 95% CI: 1.2-2.8) or had no fixed address (aOR: 2.9; 95% CI: 1.5-5.5). NNS to detect a new BBV diagnosis was 154 (95% CI: 103-233) and 135 (95% CI: 93-200) to achieve LTC.ConclusionsThe low NNS suggests routine BBV screening in EDs may be worthwhile. Those considering similar programmes should use our findings to inform their assessments of anticipated public health benefits.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.27.1800377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628754PMC
July 2019

Monitoring the hepatitis C epidemic in England and evaluating intervention scale-up using routinely collected data.

J Viral Hepat 2019 05 28;26(5):541-551. Epub 2019 Feb 28.

Statistics Modelling and Economics Department, National Infection Service, Public Health England, London, UK.

In England, 160 000 individuals were estimated to be chronically infected with hepatitis C virus (HCV) in 2005 and the burden of severe HCV-related liver disease has increased steadily for the past 15 years. Direct-acting antiviral treatments can clear infection in most patients, motivating HCV elimination targets. However, the current burden of HCV is unknown and new methods are required to monitor progress. We employed a Bayesian back-calculation approach, combining data on severe HCV-related liver disease and disease progression, to reconstruct historical HCV incidence and estimate current prevalence in England. We explicitly modelled infections occurring in people who inject drugs, the key risk group, allowing information on the size of this population and surveillance data on HCV prevalence to inform recent incidence. We estimated that there were 143 000 chronic infections in 2015 (95% credible interval 123 000-161 000), with 34% and 54% in those with recent and past injecting drug use, respectively. Following the planned scale-up of new treatments, chronic infections were predicted to fall to 113 400 (94 900-132 400) by the end of 2018 and to 89 500 (71 300-108 600) by the end of 2020. Numbers developing severe HCV-related liver disease were predicted to fall by at least 24% from 2015 to 2020. Thus, we describe a coherent framework to monitor progress using routinely collected data, which can be extended to incorporate additional data sources. Planned treatment scale-up is likely to achieve 2020 WHO targets for HCV morbidity, but substantial efforts will be required to ensure that HCV testing and patient engagement are sufficiently high.
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http://dx.doi.org/10.1111/jvh.13063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518935PMC
May 2019

Antimicrobial stewardship: an evaluation of structure and process and their association with antimicrobial prescribing in NHS hospitals in England.

J Antimicrob Chemother 2019 04;74(4):1143-1152

Reference Microbiology, National Infection Service, Public Health England, 61 Colindale Avenue, London, UK.

Background: Rigorous antimicrobial stewardship programmes (ASPs) are an essential strategy against antimicrobial resistance.

Objectives: To evaluate and score ASPs in acute English NHS hospitals and determine association of ASP scores with antimicrobial prescribing.

Methods: ASP structure and process were evaluated through an online survey in 148/152 acute hospitals in 2017. Scores were assigned to quality indicators based on resource- and labour-intensiveness, and their association with total and modified WHO-categorized 'Access', 'Watch' and 'Reserve' (AwaRe) prescribing was analysed.

Results: The survey response rate was 97% with 78% of trusts submitting antimicrobial prescribing data. Over 80% of ASPs contained stewardship teams, policies and access to outpatient parenteral antimicrobial therapy, whilst less than 50% scored well for leadership or funding. High process performance was observed for antimicrobial pre-authorization, prescribing review and feedback, restricted susceptibility reporting, antimicrobial consumption monitoring, adherence to guidelines and junior doctor training. Low process attainment included education of senior prescribers and lack of resistance surveillance data distribution. Between 2016 and 2017, there was no difference in total trust prescribing (P = 0.117) although carbapenem prescribing fell (incidence rate ratio = 0.93, 95% CI 0.88-0.98) in non-teaching hospitals; 'Watch' prescribing also increased for specialist hospitals (OR = 1.10, 95% CI 1.01-1.20), as did 'Reserve' category prescribing in teaching (OR = 1.58, 95% CI 1.23-3.02) and specialist hospitals (OR = 3.09, 95% CI 2.02-4.74). A high process score was associated with lower 'Reserve' prescribing (OR = 0.82, 95% CI 0.67-1.01).

Conclusions: All responding trusts had established ASPs. The association of a scoring system with total and 'AWaRe' prescribing to assess effectiveness of ASPs merits further study.
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http://dx.doi.org/10.1093/jac/dky538DOI Listing
April 2019

Mortality risk factors for listeriosis - A 10 year review of non-pregnancy associated cases in England 2006-2015.

J Infect 2019 03 5;78(3):208-214. Epub 2018 Dec 5.

Reference Microbiology Services, National Infection Service, Public Health England, 61 Colindale Avenue, London NW9 5EQ, United Kingdom; Gastrointestinal Infections Department, National Infection Service, Public Health England, 61 Colindale Avenue, London NW9 5EQ, United Kingdom. Electronic address:

LISTERIOSIS: is a foodborne illness that can result in septicaemia, Central Nervous System (CNS) disease, foetal loss and death in high risk patients.

Objectives: To analyse the demographic trends, clinical features and treatment of non-perinatal listeriosis cases over a ten year period and identify mortality-associated risk factors.

Methods: Reported laboratory-confirmed non-pregnancy associated cases of listeriosis between 2006 and 2015 in England were included and retrospectively analysed. Multivariate logistic regression analysis was performed to determine independent risk factors for mortality.

Results: 1357/1683 reported cases met the inclusion criteria. Overall all-cause mortality was 28.7%; however, mortality rates declined from 42.1% to 20.2%. Septicaemia was the most common presentation 69.5%, followed by CNS involvement 22.4%. CNS presentations were significantly associated with age < 50 years, and septicaemia with older age. Age > 80 years (OR 3.32 95% CI 1.92-5.74), solid-organ malignancy (OR 3.42 95% CI 2.29-5.11), cardiovascular disease (OR 3.30 95% CI 1.64-6.63), liver disease (OR 4.61 95% CI 2.47-8.61), immunosuppression (OR 2.12 95% CI 1.40-3.21) and septicaemia (OR 1.60 95% CI 1.17-2.20) were identified as independent mortality risk factors.

Conclusions: High risk groups identified in this study should be the priority focus of future public health strategies aimed at reducing listeriosis incidence and mortality.
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http://dx.doi.org/10.1016/j.jinf.2018.11.007DOI Listing
March 2019

A comparison of two biological markers of recent hepatitis C virus (HCV) infection: implications for the monitoring of interventions and strategies to reduce HCV transmission among people who inject drugs.

Euro Surveill 2018 11;23(47)

Faculty of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom.

BackgroundMonitoring hepatitis C virus (HCV) incidence is important for assessing intervention impact. Longitudinal studies of people who inject drugs (PWID), using repeated biological tests, are costly; alternatively, incidence can be estimated using biological markers of recent infection in cross-sectional studies.AimWe aimed to compare incidence estimates obtained from two different biological markers of recent infection in a cross-sectional study to inform monitoring approaches for HCV elimination strategies.MethodSamples from an unlinked anonymous bio-behavioural survey of PWID were tested for two recent infection markers: HCV RNA with anti-HCV negative ('RNA') and low-avidity anti-HCV with HCV RNA present ('avidity'). These two markers were used separately and in combination to estimate HCV incidence.ResultsBetween 2011 and 2013, 2,816 anti-HIV-negative PWID (25% female) who had injected during the preceding year were either HCV-negative or had one of the two markers of recent infection: 57 (2.0%) had the RNA marker and 90 (3.2%) the avidity marker. The two markers had similar distributions of risk and demographic factors. Pooled estimated incidence was 12.3 per 100 person-years (pyrs) (95% credible interval: 8.8-17.0) and not significantly different to avidity-only (p = 0.865) and RNA-only (p = 0.691) estimates. However, the RNA marker is limited by its short duration before anti-HCV seroconversion and the avidity marker by uncertainty around its duration.ConclusionBoth markers have utility in monitoring HCV incidence among PWID. When HCV transmission is high, one marker may provide an accurate estimate of incidence; when it is low or decreasing, a combination may be required.
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http://dx.doi.org/10.2807/1560-7917.ES.2018.23.47.1700635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341939PMC
November 2018

Epidemiology and Outcomes of Nontyphoidal Bacteremias from England, 2004 to 2015.

J Clin Microbiol 2019 01 2;57(1). Epub 2019 Jan 2.

Tuberculosis, Acute Respiratory, Gastrointestinal, Emerging/Zoonotic Infections, and Travel and Migrant Health Division, National Infection Service, Public Health England, London, United Kingdom

Nontyphoidal (NTS) bacteremia causes hospitalization and high morbidity and mortality. We linked Gastrointestinal Bacteria Reference Unit (GBRU) data to the Hospital Episode Statistics (HES) data set to study the trends and outcomes of NTS bacteremias in England between 2004 and 2015. All confirmed NTS isolates from blood from England submitted to GBRU between 1 January 2004 and 31 December 2015 were deterministically linked to HES records. Adjusted odds ratios (AOR), proportions, and confidence intervals (CI) were calculated to describe differences in age, sex, antibiotic resistance patterns, and serotypes over time. Males, neonates, and adults above 65 years were more likely to have NTS bacteremia (AOR, 1.54 [95% CI, 1.46 to 1.67]; 2.57 [95% CI, 1.43 to 4.60]; and 3.56 [95% CI, 3.25 to 3.90], respectively). Proportions of bacteremia increased from 1.41% in 2004 to 2.67% in 2015. Thirty-four percent of all blood isolates were resistant to a first-line antibiotic, and 1,397 (56%) blood isolates were linked to an HES record. Of the patients with NTS bacteremia, 969 (69%) had a cardiovascular condition and 155 (12%) patients died, out of which 120 (77%) patients were age 65 years and above. NTS bacteremia mainly affects older people with comorbidities placing them at increased risk of prolonged hospital stay and death. Resistance of invasive NTS to first-line antimicrobial agents appeared to be stable in England, but the emergence of resistance to last-resort antibiotics, such as colistin, requires careful monitoring.
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http://dx.doi.org/10.1128/JCM.01189-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322475PMC
January 2019

Reduction in tuberculosis incidence in the UK from 2011 to 2015: a population-based study.

Thorax 2018 08 19;73(8):769-775. Epub 2018 Apr 19.

Respiratory Diseases Department, National Infection Service, Public Health England, London, UK.

Background: Following nearly two decades of increasing tuberculosis in the UK, TB incidence decreased by 32% from 2011 to 2015. Explaining this reduction is crucial to informing ongoing TB control efforts.

Methods: We stratified TB cases notified in the UK and TB cases averted in the UK through pre-entry screening (PES) between 2011 and 2015 by country of birth and time since arrival. We used population estimates and migration data to establish denominators, and calculated incidence rate ratios (IRRs) between 2011 and 2015. We calculated the contribution of changing migrant population sizes, PES and changes in TB rates to the reduction in TB notifications.

Results: TB IRRs fell in all non-EU migrant and UK-born populations between 2011 and 2015 (0.61; 95%  CI 0.59 to 0.64 and 0.78; 0.73 to 0.83 respectively), with the greatest decrease in recent non-EU migrants (0.54; 0.48 to 0.61). 61.9% of the reduction in TB notifications was attributable to decreases in TB rates, 33.4% to a fall in the number of recent/mid-term non-EU migrants and 11.4% to PES. A small increase in notifications in EU-born migrants offset the reduction by 6.6%.

Conclusions: Large decreases in TB rates in almost all populations accounted for the majority of the reduction in TB notifications, providing evidence of the impact of recent interventions to improve UK TB control. The particularly large decrease in TB rates in recent non-EU migrants provides evidence of the effectiveness of screening interventions that target this population. These findings will inform ongoing improvements to TB control.
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http://dx.doi.org/10.1136/thoraxjnl-2017-211074DOI Listing
August 2018

Relationship between socioeconomic status and gastrointestinal infections in developed countries: A systematic review and meta-analysis.

PLoS One 2018 23;13(1):e0191633. Epub 2018 Jan 23.

NIHR Health Protection Research Unit in Gastrointestinal Infections, Liverpool, United Kingdom.

Background: The association between socioeconomic status (SES) and health is well-documented; however limited evidence on the relationship between SES and gastrointestinal (GI) infections exists, with published studies producing conflicting results. This systematic review aimed to assess the association between SES and GI infection risk, and explore possible sources of heterogeneity in effect estimates reported in the literature.

Methods: MEDLINE, Scopus, Web of Science and grey literature were searched from 1980 to October 2015 for studies reporting an association between GI infections and SES in a representative population sample from a member-country of the Organisation for Economic Co-operation and Development. Harvest plots and meta-regression were used to investigate potential sources of heterogeneity such as age; level of SES variable; GI infection measurement; and predominant mode of transmission. The protocol was registered on PROSPERO: CRD42015027231.

Results: In total, 6021 studies were identified; 102 met the inclusion criteria. Age was identified as the only statistically significant potential effect modifier of the association between SES and GI infection risk. For children, GI infection risk was higher for those of lower SES versus high (RR 1.51, 95% CI;1.26-1.83), but there was no association for adults (RR 0.79, 95% CI;0.58-1.06). In univariate analysis, the increased risk comparing low and high SES groups was significantly higher for pathogens spread by person-to-person transmission, but lower for environmental pathogens, as compared to foodborne pathogens.

Conclusions: Disadvantaged children, but not adults, have greater risk of GI infection compared to their more advantaged counterparts. There was high heterogeneity and many studies were of low quality. More high quality studies are needed to investigate the association between SES and GI infection risk, and future research should stratify analyses by age and pathogen type. Gaining further insight into this relationship will help inform policies to reduce inequalities in GI illness in children.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191633PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779704PMC
February 2018

Clonality, virulence and antimicrobial resistance of enteroaggregative Escherichia coli from Mirzapur, Bangladesh.

J Med Microbiol 2017 Oct 25;66(10):1429-1435. Epub 2017 Sep 25.

Centre for Food and Water Borne Diseases, International Centre for Diarrhoeal Disease Research, Bangladesh.

Purpose: This study investigates the virulence and antimicrobial resistance in association with common clonal complexes (CCs) of enteroaggregative Escherichia coli (EAEC) isolated from Bangladesh. The aim was to determine whether specific CCs were more likely to be associated with putative virulence genes and/or antimicrobial resistance.

Methodology: The presence of 15 virulence genes (by PCR) and susceptibility to 18 antibiotics were determined for 151 EAEC isolated from cases and controls during an intestinal infectious disease study carried out between 2007-2011 in the rural setting of Mirzapur, Bangladesh (Kotloff KL, Blackwelder WC, Nasrin D, Nataro JP, Farag TH et al.Clin Infect Dis 2012;55:S232-S245). These data were then analysed in the context of previously determined serotypes and clonal complexes defined by multi-locus sequence typing.

Results: Overall there was no association between the presence of virulence or antimicrobial resistance genes in isolates of EAEC from cases versus controls. However, when stratified by clonal complex (CC) one CC associated with cases harboured more virulence factors (CC40) and one CC harboured more resistance genes (CC38) than the average. There was no direct link between the virulence gene content and antibiotic resistance. Strains within a single CC had variable virulence and resistance gene content indicating independent and multiple gene acquisitions over time.

Conclusion: In Bangladesh, there are multiple clonal complexes of EAEC harbouring a variety of virulence and resistance genes. The emergence of two of the most successful clones appeared to be linked to either increased virulence (CC40) or antimicrobial resistance (CC38), but increased resistance and virulence were not found in the same clonal complexes.
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http://dx.doi.org/10.1099/jmm.0.000594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845566PMC
October 2017

Treatment of Latent Tuberculosis Infection: An Updated Network Meta-analysis.

Ann Intern Med 2017 Aug 1;167(4):248-255. Epub 2017 Aug 1.

From Institute for Global Health, University College London; Public Health England; and Royal Free London National Health Service Foundation Trust, London, United Kingdom, and European Centre for Disease Prevention and Control, Stockholm, Sweden.

Background: Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI.

Purpose: To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children.

Data Sources: PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied.

Study Selection: Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB).

Data Extraction: 2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol.

Data Synthesis: The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy.

Limitation: Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies.

Conclusion: Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin.

Primary Funding Source: U.K. National Institute for Health Research. (PROSPERO: CRD42016037871).
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http://dx.doi.org/10.7326/M17-0609DOI Listing
August 2017

Evaluating 17 years of latent tuberculosis infection screening in north-west England: a retrospective cohort study of reactivation.

Eur Respir J 2017 07 27;50(1). Epub 2017 Jul 27.

Institute of Inflammation, University of Manchester, Manchester, UK.

Approximately 72% of tuberculosis (TB) cases in England occur among non-UK born individuals, mostly as a result of reactivation of latent TB infection (LTBI). Programmatic LTBI screening is a key intervention of the TB strategy for England. This article reviews the results of a long-standing LTBI screening initiative in England.A retrospective cohort was created through probabilistic linkage between LTBI screening data and national TB case notifications. Screened persons were followed until they died, became a case, emigrated or until cohort-end. TB incidence rates and rate ratios (IRR) were calculated.97 out of 1820 individuals screened for LTBI were reported to have active TB. Crude incidence rates among LTBI-positive, treatment-naïve individuals were 4.1 and 2.3 per 100 person-years in the QuantiFERON and tuberculin skin test cohorts, respectively. Among the QuantiFERON cohort, Poisson regression showed that LTBI positivity (IRR 22.6, 95% CI 6.8-74.6) and no chemoprophylaxis increased the probability of becoming a TB case (IRR 0.17, 95% CI 0.05-0.6).We found high TB rates in LTBI-positive, treatment-naïve individuals and a strong association between no treatment and becoming a TB case, demonstrating feasibility and effectiveness of LTBI screening and providing important policy lessons for LTBI screening in England and beyond.
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http://dx.doi.org/10.1183/13993003.02505-2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540676PMC
July 2017

Respiratory symptoms in people living with HIV and the effect of antiretroviral therapy: a systematic review and meta-analysis.

Thorax 2017 04 24;72(4):355-366. Epub 2016 Oct 24.

Departments of HIV and Respiratory Medicine, Royal Free London NHS Foundation trust, London, UK.

Background: Antiretroviral therapy (ART) has significantly altered the pattern of acute and chronic HIV-related disease. However, it is not clear what this means in terms of respiratory symptoms. We sought to investigate the association between HIV status and respiratory symptoms and how these have changed with the availability of ART.

Methods: We searched Cochrane, Medline and Embase databases for studies published between 1946 and August 2015 comparing the prevalence of respiratory symptoms in populations with and without HIV infection. We undertook random effects meta-analysis of the main symptoms reported. We studied heterogeneity and completed sensitivity analyses and funnel plots.

Results: From 5788 unique references identified, 24 papers provided relevant data: 18 documented the prevalence of cough and 11 examined the prevalence of breathlessness among other symptoms reported. Compared with the HIV negative, people living with HIV (PLWH) were more likely to have respiratory symptoms with pooled ORs for the prevalence of cough of 3.05 (95% CI 2.24 to 4.16) in resource-limited populations without access to ART; 2.18 (1.56 to 3.18) in resource-rich populations without access to ART and 1.11 (0.99 to 1.24) in resource-rich populations with access to ART. In resource-rich settings, although the availability of ART was associated with a reduction in the difference between HIV-positive and HIV-negative individuals, PLWH were more likely to report breathlessness, OR 1.39 (95% CI 1.11 to 1.73).

Conclusions: Respiratory symptoms are more common in PLWH than controls. This association persists although at a reduced level in populations with access to ART.
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http://dx.doi.org/10.1136/thoraxjnl-2016-208657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520276PMC
April 2017

Enhanced surveillance of HIV-1 drug resistance in recently infected MSM in the UK.

J Antimicrob Chemother 2017 01 14;72(1):227-234. Epub 2016 Oct 14.

Virus Reference Department, National Infection Service, Public Health England, London, UK

Objectives: To determine the prevalence of inferred low-frequency HIV-1 transmitted drug resistance (TDR) in MSM in the UK and its predicted effect on first-line therapy.

Methods: The HIV-1 pol gene was amplified from 442 newly diagnosed MSM identified as likely recently infected by serological avidity testing in 2011-13. The PCR products were sequenced by next-generation sequencing with a mutation frequency threshold of >2% and TDR mutations defined according to the 2009 WHO surveillance drug resistance mutations list.

Results: The majority (75.6%) were infected with subtype B and 6.6% with rare complex or unique recombinant forms. At a mutation frequency threshold of >20%, 7.2% (95% CI 5.0%-10.1%) of the sequences had TDR and this doubled to 15.8% (95% CI 12.6%-19.6%) at >2% mutation frequency (P < 0.0001). The majority (26/42, 62%) of low-frequency variants were against PIs. The most common mutations detected at >20% and 2%-20% mutation frequency differed for each drug class, these respectively being: L90M (n = 7) and M46IL (n = 10) for PIs; T215rev (n = 9) and D67GN (n = 4) for NRTIs; and K103N (n = 5) and G190E (n = 2) for NNRTIs. Combined TDR was more frequent in subtype B than non-B (OR = 0.38; 95% CI = 0.17-0.88; P = 0.024) and had minimal predicted effect on recommended first-line therapies.

Conclusions: The data suggest differences in the types of low-frequency compared with majority TDR variants that require a better understanding of the origins and clinical significance of low-frequency variants. This will better inform diagnostic and treatment strategies.
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http://dx.doi.org/10.1093/jac/dkw404DOI Listing
January 2017
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