Effects of Second Dose of SARS-CoV-2 Vaccination on Household Transmission, England.

A single SARS-CoV-2 vaccine dose reduces onward transmission from case-patients. We assessed the potential effects of receiving 2 doses on household transmission for case-patients in England and their household contacts. We used stratified Cox regression models to calculate hazard ratios (HRs) for contacts becoming secondary case-patients, comparing contacts of 2-dose vaccinated and unvaccinated index case-patients. We controlled for age, sex, and vaccination status of case-patients and contacts, as well as region, household composition, and relative socioeconomic condition based on household location. During the Alpha-dominant period, HRs were 0.19 (0.13-0.28) for contacts of 2-dose BNT162b2-vaccinated case-patients and 0.54 (0.41-0.69) for contacts of 2-dose Ch4dOx1-vaccinated case-patients; during the Delta-dominant period, HRs were higher, 0.74 (0.72-0.76) for BNT162b2 and 1.06 (1.04-1.08) for Ch4dOx1. Reduction of onward transmission was lower for index case-patients who tested positive ≥2 months after the second dose of either vaccine.

Effectiveness of nationwide programmatic testing and treatment for latent tuberculosis infection in migrants in England: a retrospective, population-based cohort study.

BACKGROUND: In low-incidence countries, tuberculosis mainly affects migrants, mostly resulting from reactivation of latent tuberculosis infection (LTBI) acquired in high-incidence countries before migration. A nationwide primary care-based LTBI testing and treatment programme for migrants from high-incidence countries was therefore established in high tuberculosis incidence areas in England. We aimed to assess the effectiveness of this programme. METHODS: We did a retrospective, population-based cohort study of migrants who registered in primary care between Jan 1, 2011, and Dec 31, 2018, in 55 high-burden areas with programmatic LTBI testing and treatment. Eligible individuals were aged 16-35 years, born in a high-incidence country, and had entered England in the past 5 years. Individuals who tested interferon-γ release assay (IGRA)-negative were advised about symptoms of tuberculosis, whereas those who tested IGRA-positive were clinically assessed to rule out active tuberculosis and offered preventive therapy. The primary outcome was incident tuberculosis notified to the national Enhanced Tuberculosis Surveillance system. FINDINGS: Our cohort comprised 368 097 eligible individuals who had registered in primary care, of whom 37 268 (10·1%) were tested by the programme. 1446 incident cases of tuberculosis were identified: 166 cases in individuals who had IGRA testing (incidence 204 cases [95% CI 176-238] per 100 000 person-years) and 1280 in individuals without IGRA testing (82 cases [77-86] per 100 000 person-years). Overall, in our primary analysis including all diagnosed tuberculosis cases, a time-varying association was identified between LTBI testing and treatment and lower risk of incident tuberculosis (hazard ratio [HR] 0·76 [95% CI 0·63-0·91]) when compared with no testing. In stratified analysis by follow-up period, the intervention was associated with higher risk of tuberculosis diagnosis during the first 6 months of follow-up (9·93 [7·63-12·9) and a lower risk after 6 months (0·57 [0·41-0·79]). IGRA-positive individuals had higher risk of tuberculosis diagnosis than IGRA-negative individuals (31·9 [20·4-49·8]). Of 37 268 migrants who were tested, 6640 (17·8%) were IGRA-positive, of whom 1740 (26·2%) started preventive treatment. LTBI treatment lowered the risk of tuberculosis: of 135 incident cases in the IGRA-positive cohort, seven cases were diagnosed in the treated group (1·87 cases [95% CI 0·89-3·93] per 1000 person-years) and 128 cases were diagnosed in the untreated group (10·9 cases [9·16-12·9] per 1000 person-years; HR 0·14 [95% CI 0·06-0·32]). INTERPRETATION: A low proportion of eligible migrants were tested by the programme and a small proportion of those testing positive started treatment. Despite this, programmatic LTBI testing and treatment of individuals migrating to a low-incidence region is effective at diagnosing active tuberculosis earlier and lowers the long-term risk of progression to tuberculosis. Increasing programme participation and treatment rates for those testing positive could substantially impact national tuberculosis incidence. FUNDING: National Institute for Health Research Health Protection Research Unit in Respiratory Infections.

Epidemiology of HIV infection and associated behaviours among people who inject drugs in England, Wales, and Northern Ireland: Nearly 40 years on.

INTRODUCTION: People who inject drugs are at high risk of blood-borne infections. We describe the epidemiology of HIV among people who inject drugs in England, Wales, and Northern Ireland (EW&NI) since 1981. METHODS: National HIV surveillance data were used to describe trends in diagnoses (1981-2019), prevalence (1990-2019), and behaviours (1990-2019) among people who inject drugs aged ≥15 years in EW&NI. HIV care and treatment uptake were assessed among those attending in 2019. RESULTS: Over the past four decades, the prevalence of HIV among people who inject drugs in EW&NI remained low (range: 0.64%-1.81%). Overall, 4978 people who inject drugs were diagnosed with HIV (3.2% of cases). Diagnoses peaked at 234 in 1987, decreasing to 78 in 2019; the majority were among white men born in the UK/Europe (90%), though the epidemic diversified over time. Late diagnosis (CD4 <350 cells/µl) was common (2010-2019: 52% [429/832]). Of those who last attended for HIV care in 2019, 97% (1503/1550) were receiving HIV treatment and 90% (1375/1520) had a suppressed viral load (<200 copies/ml). HIV testing uptake has steadily increased among people who inject drugs (32% since 1990). However, in 2019, 18% (246/1404) of those currently injecting reported never testing. The proportion of people currently injecting reporting sharing needles/syringes decreased from 1999 to 2012, before increasing to 20% (288/1426) in 2019, with sharing of any injecting equipment at 37% (523/1429). CONCLUSION: The HIV epidemic among people who inject drugs in EW&NI has remained relatively contained compared with in other countries, most likely because of the prompt implementation of an effective national harm reduction programme. However, risk behaviours and varied access to preventive interventions among people who inject drugs indicate the potential for HIV outbreaks.

Household transmission of COVID-19 cases associated with SARS-CoV-2 delta variant (B.1.617.2): national case-control study.

BACKGROUND: The SARS-CoV-2 Delta variant (B.1.617.2), first detected in India, has rapidly become the dominant variant in England. Early reports suggest this variant has an increased growth rate suggesting increased transmissibility. This study indirectly assessed differences in transmissibility between the emergent Delta variant compared to the previously dominant Alpha variant (B.1.1.7). METHODS: A matched case-control study was conducted to estimate the odds of household transmission (≥ 2 cases within 14 days) for Delta variant index cases compared with Alpha cases. Cases were derived from national surveillance data (March to June 2021). One-to-two matching was undertaken on geographical location of residence, time period of testing and property type, and a multivariable conditional logistic regression model was used for analysis. FINDINGS: In total 5,976 genomically sequenced index cases in household clusters were matched to 11,952 sporadic index cases (single case within a household). 43.3% (n=2,586) of cases in household clusters were confirmed Delta variant compared to 40.4% (n= 4,824) of sporadic cases. The odds ratio of household transmission was 1.70 among Delta variant cases (95% CI 1.48-1.95, p <0.001) compared to Alpha cases after adjusting for age, sex, ethnicity, index of multiple deprivation (IMD), number of household contacts and vaccination status of index case. INTERPRETATION: We found evidence of increased household transmission of SARS-CoV-2 Delta variant, potentially explaining its success at displacing Alpha variant as the dominant strain in England. With the Delta variant now having been detected in many countries worldwide, the understanding of the transmissibility of this variant is important for informing infection prevention and control policies internationally.

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.

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.

Antibody persistence and neutralising activity in primary school students and staff: Prospective active surveillance, June to December 2020, England.

BACKGROUND: Prospective, longitudinal SARS-CoV-2 sero-surveillance in schools across England was initiated after the first national lockdown, allowing comparison of child and adult antibody responses over time. METHODS: Prospective active serological surveillance in 46 primary schools in England tested for SARS-CoV-2 antibodies during June, July and December 2020. Samples were tested for nucleocapsid (N) and receptor binding domain (RBD) antibodies, to estimate antibody persistence at least 6 months after infection, and for the correlation of N, RBD and live virus neutralising activity. FINDINGS: In June 2020, 1,344 staff and 835 students were tested. Overall, 11.5% (95%CI: 9.4-13.9) and 11.3% (95%CI: 9.2-13.6; p = 0.88) of students had nucleoprotein and RBD antibodies, compared to 15.6% (95%CI: 13.7-17.6) and 15.3% (95%CI: 13.4-17.3; p = 0.83) of staff. Live virus neutralising activity was detected in 79.8% (n = 71/89) of nucleocapsid and 85.5% (71/83) of RBD antibody positive children. RBD antibodies correlated more strongly with neutralising antibodies (rs=0.7527; p<0.0001) than nucleocapsid antibodies (rs=0.3698; p<0.0001). A median of 24.4 weeks later, 58.2% (107/184) participants had nucleocapsid antibody seroreversion, compared to 20.9% (33/158) for RBD (p<0.001). Similar seroreversion rates were observed between staff and students for nucleocapsid (p = 0.26) and RBD-antibodies (p = 0.43). Nucleocapsid and RBD antibody quantitative results were significantly lower in staff compared to students (p = 0.028 and <0.0001 respectively) at baseline, but not at 24 weeks (p = 0.16 and p = 0.37, respectively). INTERPRETATION: The immune response in children following SARS-CoV-2 infection was robust and sustained (>6 months) but further work is required to understand the extent to which this protects against reinfection.

Trends in undiagnosed HIV prevalence in England and implications for eliminating HIV transmission by 2030: an evidence synthesis model.

BACKGROUND: A target to eliminate HIV transmission in England by 2030 was set in early 2019. This study aimed to estimate trends from 2013 to 2019 in HIV prevalence, particularly the number of people living with undiagnosed HIV, by exposure group, ethnicity, gender, age group, and region. These estimates are essential to monitor progress towards elimination. METHODS: A Bayesian synthesis of evidence from multiple surveillance, demographic, and survey datasets relevant to HIV in England was used to estimate trends in the number of people living with HIV, the proportion of people unaware of their HIV infection, and the corresponding prevalence of undiagnosed HIV. All estimates were stratified by exposure group, ethnicity, gender, age group (15-34, 35-44, 45-59, or 60-74 years), region (London, or outside of London) and year (2013-19). FINDINGS: The total number of people living with HIV aged 15-74 years in England increased from 83 500 (95% credible interval 80 200-89 600) in 2013 to 92 800 (91 000-95 600) in 2019. The proportion diagnosed steadily increased from 86% (80-90%) to 94% (91-95%) during the same time period, corresponding to a halving in the number of undiagnosed infections from 11 600 (8300-17 700) to 5900 (4400-8700) and in undiagnosed prevalence from 0·29 (0·21-0·44) to 0·14 (0·11-0·21) per 1000 population. Similar steep declines were estimated in all subgroups of gay, bisexual, and other men who have sex with men and in most subgroups of Black African heterosexuals. The pace of reduction was less pronounced for heterosexuals in other ethnic groups and people who inject drugs, particularly outside London; however, undiagnosed prevalence in these groups has remained very low. INTERPRETATION: The UNAIDS target of diagnosing 90% of people living with HIV by 2020 was reached by 2016 in England, with the country on track to achieve the new target of 95% diagnosed by 2025. Reductions in transmission and undiagnosed prevalence have corresponded to large scale-up of testing in key populations and early diagnosis and treatment. Additional and intensified prevention measures are required to eliminate transmission of HIV among the communities that have experienced slower declines than other subgroups, despite having very low prevalences of HIV. FUNDING: UK Medical Research Council and Public Health England.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.