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BackgroundDespite progress in TB control in low-burden countries like England and Wales, there are still diagnostic delays. Molecular testing and/or whole-genome sequencing (WGS) provide more rapid diagnosis but their cost-effectiveness is relatively unexplored in low-burden settings.MethodsAn integrated transmission-dynamic health economic model is used to assess the cost-effectiveness of using WGS to replace culture-based drug-sensitivity testing, versus using molecular testing versus combined use of WGS and molecular testing, for routine TB diagnosis. The model accounts for the effects of faster appropriate treatment in reducing transmission, benefiting health and reducing future treatment costs. Cost-effectiveness is assessed using incremental net benefit (INB) over a 10-year horizon with a quality-adjusted life-year valued at £20 000, and discounting at 3.5% per year.ResultsWGS shortens the time to drug sensitivity testing and treatment modification where necessary, reducing treatment and hospitalisation costs, with an INB of £7.1 million. Molecular testing shortens the time to TB diagnosis and treatment. Initially, this causes an increase in annual costs of treatment, but averting transmissions and future active TB disease subsequently, resulting in cost savings and health benefits to achieve an INB of £8.6 million (GeneXpert MTB/RIF) or £11.1 million (Xpert-Ultra). Combined use of Xpert-Ultra and WGS is the optimal strategy we consider, with an INB of £16.5 million.ConclusionRoutine use of WGS or molecular testing is cost-effective in a low-burden setting, and combined use is the most cost-effective option. Adoption of these technologies can help low-burden countries meet the WHO End TB Strategy milestones, particularly the UK, which still has relatively high TB rates.

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.

Background The incidence of TB has doubled in the last 20 years in London. A better understanding of risk groups for recent transmission is required to effectively target interventions. We investigated the molecular epidemiological characteristics of TB cases to estimate the proportion of cases due to recent transmission, and identify predictors for belonging to a cluster. Methods The study population included all culture-positive TB cases in London residents, notified between January 2010 and December 2012, strain typed using 24-loci multiple interspersed repetitive units-variable number tandem repeats. Multivariable logistic regression analysis was performed to assess the risk factors for clustering using sociodemographic and clinical characteristics of cases and for cluster size based on the characteristics of the first two cases. Results There were 10 147 cases of which 5728 (57%) were culture confirmed and 4790 isolates (84%) were typed. 2194 (46%) were clustered in 570 clusters, and the estimated proportion attributable to recent transmission was 34%. Clustered cases were more likely to be UK born, have pulmonary TB, a previous diagnosis, a history of substance abuse or alcohol abuse and imprisonment, be of white, Indian, black-African or Caribbean ethnicity. The time between notification of the first two cases was more likely to be

INTRODUCTION: Consensus on the best treatment regimens for patients with isoniazid-resistant TB is limited; global treatment guidelines differ. We undertook a systematic review and meta-analysis using mixed-treatment comparisons methodology to provide an up-to-date summary of randomised controlled trials (RCTs) and relative regimen efficacy.METHODS: Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Extracted data were inputted into fixed-effects and random-effects models. ORs for all possible network comparisons and hierarchical rankings for different regimens were obtained.RESULTS: 12 604 records were retrieved and 118 remained postextraction, representing 59 studies-27 standalone and 32 with multiple papers. In comparison to a baseline category that included the WHO-recommended regimen for countries with high levels of isoniazid resistance (rifampicin-containing regimens using fewer than three effective drugs at 4 months, in which rifampicin was protected by another effective drug at 6 months, and rifampicin was taken for 6 months), extending the duration of rifampicin and increasing the number of effective drugs at 4 months lowered the odds of unfavourable outcomes (treatment failure or the lack of microbiological cure; relapse post-treatment; death due to TB) in a fixed-effects model (OR 0.31 (95% credible interval 0.12-0.81)). In a random-effects model all estimates crossed the null.CONCLUSIONS: Our systematic review and network meta-analysis highlight a regimen category that may be more efficacious than the WHO population level recommendation, and identify knowledge gaps where data are sparse.SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42014015025.

BACKGROUND: TB remains a major public health concern, even in low-incidence countries like the USA and the UK. Over the last two decades, cases of TB reported in the USA have declined, while they have increased substantially in the UK. We examined factors associated with this divergence in TB trends between the two countries.METHODS: We analysed all cases of TB reported to the US and UK national TB surveillance systems from 1 January 2000 through 31 December 2011. Negative binominal regression was used to assess potential demographic, clinical and risk factor variables associated with differences in observed trends.FINDINGS: A total of 259,609 cases were reported. From 2000 to 2011, annual TB incidence rates declined from 5.8 to 3.4 cases per 100,000 in the USA, whereas in the UK, TB incidence increased from 11.4 to 14.4 cases per 100,000. The majority of cases in both the USA (56%) and the UK (64%) were among foreign-born persons. The number of foreign-born cases reported in the USA declined by 15% (7731 in 2000 to 6564 in 2011) while native-born cases fell by 54% (8442 in 2000 to 3883 in 2011). In contrast, the number of foreign-born cases reported in the UK increased by 80% (3380 in 2000 to 6088 in 2011), while the number of native-born cases remained largely unchanged (2158 in 2000 to 2137 in 2011). In an adjusted negative binomial regression model, significant differences in trend were associated with sex, age, race/ethnicity, site of disease, HIV status and previous history of TB (pINTERPRETATION: To achieve TB elimination in the UK, a re-evaluation of current TB control policies and practices with a focus on foreign-born are needed. In the USA, maintaining and strengthening control practices are necessary to sustain the progress made over the last 20 years.

Background In response to rising TB notification rates in England, universal strain typing was introduced in 2010. We evaluated the acceptability, effectiveness and cost-effectiveness of the TB strain typing service (TB-STS). Methods We conducted a mixed-methods evaluation using routine laboratory, clinic and public health data. We estimated the effect of the TB-STS on detection of false positive Mycobacterium tuberculosis diagnoses (2010–2012); contact tracing yield (number of infections or active disease per pulmonary TB case); and diagnostic delay. We developed a deterministic age-structured compartmental model to explore the effectiveness of the TB-STS, which informed a cost-effectiveness analysis. Results Semi-structured interviews explored user experience. Strain typing identified 17 additional false positive diagnoses. The TB-STS had no significant effect on contact tracing yield or diagnostic delay. Mathematical modelling suggested increasing the proportion of infections detected would have little value in reducing TB incidence in the white UK-born population. However, in the non-white UK-born and non-UK-born populations, over 20 years, if detection of latent infection increases from 3% to 13% per year, then TB incidence would decrease by 11%; reducing diagnostic delay by one week could lead to 25% reduction in incidence. The current TB-STS was not predicted to be cost-effective over 20 years (£95 628/quality-adjusted life-years). Interviews found people had mixed experiences, but identified broader benefits, of the TB-STS. Conclusions To reduce costs, improve efficiency and increase effectiveness, we recommend changes to the TB-STS, including discontinuing routine cluster investigations and focusing on reducing diagnostic delay across the TB programme. This evaluation of a complex intervention informs the future of strain typing in the era of rapidly advancing technologies.

Background Interferon gamma release assays (IGRAs) are the first new diagnostic tests for latent tuberculosis (TB) infection (LTBI) since the century-old tuberculin skin test (TST). They are cell-mediated immune-based blood tests that have revolutionised LTBI diagnosis and are increasingly recommended by national guidelines. Objectives With the rapid expansion of the IGRA evidence-base in recent years, the limitations of IGRA and uncertainties in clinical interpretation of IGRA results have increasingly come into focus. In LTBI diagnosis these include: prognostic power of IGRAs relative to TST for quantifying risk of progression to active disease, false-negative rates in immunocompromised patients, the clinical meaning of IGRA reversion and the significance of the size of IGRA response. Furthermore, the role of IGRAs in the diagnostic work-up of active TB is unclear, and there is little evidence supporting use of the tests in anti-TB treatment monitoring. Methodological approach On-going large prospective longitudinal clinical endpoint cohort studies of active and latent TB will tackle some of the uncertainties regarding IGRAs. Here we discuss clinical practice and guidance in light of the current uncertainties, based on existing evidence. Conclusions and impact Current and planned clinical research will fill the gaps in the evidence-base, narrowing the areas of uncertainty and informing future policy. Translational research into next-generation IGRAs and new T cell-based diagnostic platforms will likely overcome the limitations of current IGRAs in the near future.

Background In July 2008 a case of smear-positive pulmonary tuberculosis (TB) in a white UK-born nursery teacher was notified in London. The case had been symptomatic for 9 months while working in the nursery. The outbreak is described and the protective effect of BCG vaccination against latent Mycobacterium tuberculosis infection as measured by an interferon gamma release assay (IGRA) is assessed. Methods Screening by chest X-ray and IGRA of nursery children, staff and their contacts was conducted using a ‘stone-in-the pond’ approach. Information was collected on various factors including BCG vaccination status, and data were analysed using multivariable logistic regression. Results Overall, 168 children, 31 staff members and 57 other adults associated with the nursery were screened for TB. There were 12 cases of active TB and 43 cases of latent TB (72% children). 37.5% (95% CI 18% to 56%) and 40% (95% CI 30% to 50%) had a positive IGRA among teachers and children, respectively. 42% of children and 60% of adults were BCG vaccinated. In the adjusted analysis, BCG vaccination showed a significant protective effect against M tuberculosis infection in children (OR 0.25, 95% CI 0.09 to 0.69) and being taught by the index case was associated with acquiring TB infection (OR 18.91, 95% CI 4.43 to 80.79). A vaccine effectiveness of 66% was calculated, implying that 21 of the 32 infections could have been avoided if all children had been vaccinated with BCG. Conclusions This outbreak shows extensive transmission of TB among very young children. BCG seems to have a protective effect against TB infection as assessed by positive IGRA in this cohort.

Extrapulmonary tuberculosis appears to be increasing in England and Wales. The trends in extrapulmonary tuberculosis and factors associated with these trends were examined.National tuberculosis surveillance data from 1999-2006 for England and Wales were used, including demographic, clinical and laboratory information. Trends in the proportion of tuberculosis cases with extrapulmonary disease were investigated using the chi(2) trend test and associated factors using logistic regression.Among all the cases of tuberculosis, the proportion with extrapulmonary disease increased from 48% in 1999 (2717 cases) to 53% in 2006 (4205 cases, p0.001). Regression analysis showed that the rise in extrapulmonary disease was associated with an increase in the proportion of non-UK born cases (odds ratio 2.7, 95% CI 2.6 to 2.8). A more than threefold increase was observed in the proportion of all tuberculosis cases with miliary tuberculosis from 0.7% of all cases (38 cases) to 2.2% (180 cases, p0.001). This rise was not associated with changes in place of birth or in any of the other risk factors identified.The proportion of cases with extrapulmonary disease has increased over the study period. To a large extent this is due to an increasing proportion of non-UK born cases. Reasons for the rise in miliary tuberculosis require further investigation. Clinicians should have a higher index of clinical suspicion of extrapulmonary tuberculosis in non-UK born cases.

Background: The emergence of multidrug-resistant tuberculosis (MDRTB) and extensively drug-resistant tuberculosis (XDRTB) is a threat to global tuberculosis control. Limited information is, however, available on the outcome of XDRTB cases. This study describes the susceptibility to second- and third-line antituberculosis drugs among MDRTB cases and treatment outcome of identified XDRTB cases. Method: The results of second-line antituberculosis drug susceptibility tests in the UK between January 1995 and December 2007 were retrospectively reviewed and clinicians contacted for treatment outcome of XDRTB cases. Participants included all 678 patients with culture-confirmed MDRTB in the UK. The main outcome measures were the proportion of isolates resistant to second-line antituberculosis drugs and treatment outcome for XDRTB cases. Results: Among MDRTB isolates, levels of resistance to amikacin, capreomycin, ciprofloxacin, cycloserine, ethionamide and p-aminosalicylic acid (PAS) were 5.5, 3.4, 5.6, 5.1, 14.0 and 16.7%, respectively. Six XDRTB cases (0.9% of MDR cases) were identified during this period. Two further cases of XDRTB were reported in 2008. Five individuals with XDRTB died of tuberculosis within 3 years of diagnosis and three are still on treatment. Conclusion: Levels of MDRTB remain low, and those of XDRTB very low, in this high income country. The case fatality ratio among XDRTB cases was high despite low levels of HIV co-infection.

Cohort review has been used internationally to support tuberculosis (TB) control. We describe its first use in the UK by a London TB service. Improvements were noted in case management and contact tracing, weaknesses identified and important service changes put in place. Key areas of impact were directly observed therapy (DOT) provision (a greater proportion of cases offered DOT, and in response to low uptake resources diverted to create posts responsible for patient-centred DOT delivery), and contact tracing (more contacts per case screened and assessed). Cohort review enables whole system review and improvement. It has subsequently been adopted across the UK.

BCG uptake among infants in England has not been measured since targeted infant vaccination replaced universal schoolchildren vaccination in 2005, mainly because of the challenges in defining denominators. We estimated uptake between 2006 and 2008 by dividing number of BCG doses administered to infants by number of all live births (where BCG vaccination is universal) or ethnic minority/Eastern Europeans live births (where infant-BCG vaccination is selective). Weighted average uptake was 68% (95% CI 65% to 71%), slightly higher in primary care trusts with universal (72% (95% CI 64% to 80%)) than selective (66% (95% CI 61% to 70%)) policy; and also 13% higher in areas vaccinating in postnatal wards compared with community settings.

Active tuberculosis (TB) in the UK predominantly affects the non-UK born, but is generally not manifest at the time of UK entry. Strategies to detect latent TB infection (LTBI) in this population are, therefore, important. To date, targeted screening has focused on TB risk estimates based on the incidence in the country of origin. Using TB incidence in the UK and migration data, we estimated the numbers needed to be tested and treated for LTBI to prevent one case of TB disease. Numbers were the lowest in Somalian and the highest in South African and Filipino migrants, which contrasts with TB rates in these countries. Targeting screening on the basis of incidence in the UK may thus improve effectiveness.

Cohort review has been used internationally to support tuberculosis (TB) control. We describe its first use in the UK by a London TB service. Improvements were noted in case management and contact tracing, weaknesses identified and important service changes put in place. Key areas of impact were directly observed therapy (DOT) provision (a greater proportion of cases offered DOT, and in response to low uptake resources diverted to create posts responsible for patient-centred DOT delivery), and contact tracing (more contacts per case screened and assessed). Cohort review enables whole system review and improvement. It has subsequently been adopted across the UK.

Interferon gamma release assays (IGRAs) are the first new diagnostic tests for latent tuberculosis (TB) infection (LTBI) since the century-old tuberculin skin test (TST). They are cell-mediated immune-based blood tests that have revolutionised LTBI diagnosis and are increasingly recommended by national guidelines.With the rapid expansion of the IGRA evidence-base in recent years, the limitations of IGRA and uncertainties in clinical interpretation of IGRA results have increasingly come into focus. In LTBI diagnosis these include: prognostic power of IGRAs relative to TST for quantifying risk of progression to active disease, false-negative rates in immunocompromised patients, the clinical meaning of IGRA reversion and the significance of the size of IGRA response. Furthermore, the role of IGRAs in the diagnostic work-up of active TB is unclear, and there is little evidence supporting use of the tests in anti-TB treatment monitoring.On-going large prospective longitudinal clinical endpoint cohort studies of active and latent TB will tackle some of the uncertainties regarding IGRAs. Here we discuss clinical practice and guidance in light of the current uncertainties, based on existing evidence.Current and planned clinical research will fill the gaps in the evidence-base, narrowing the areas of uncertainty and informing future policy. Translational research into next-generation IGRAs and new T cell-based diagnostic platforms will likely overcome the limitations of current IGRAs in the near future.

UK guidelines advise testing for latent tuberculosis infection (LTBI) in people with known HIV. Both National Institute for Health and Care Excellence (NICE) 2011 and 2016, and British HIV Association (BHIVA) guidelines use targeted testing, in comparison to those from other countries, notably the United States. None of these have been compared for cost-effectiveness in a contemporary HIV population. We sought to determine the cost-effectiveness of each UK guideline from an NHS perspective, plus alternatives, using prospective data. All patients with a new HIV diagnosis attending an ambulatory HIV clinic, plus a sample of those with known HIV were approached; and offered a symptom questionnaire, chest radiograph (CXR), tuberculin skin test (TST), blood interferon gamma release assay (IGRA) and induced sputum for mycobacterial culture (IS). The uptake and results were used to calculate the cost-effectiveness of thirty different testing strategies using univariate, multivariate and probabilistic sensitivity analyses (PSA). 219 subjects, representative of the total clinic population, took part. 73% were male, 28% black African and 95% on antiretroviral therapy (ART). During testing, 2 cases (0.9%) of subclinical TB and 14 (6%) of LTBI were detected. Half the patients with LTBI completed preventive treatment. Over a median of 28 months follow up, no new cases of active TB were identified. When compared to no testing, only three of the thirty strategies were below the maximum NICE threshold for cost-effectiveness 20/100,000 (‘middle incidence’, MI) cost £25,218/QALY and £32,410/QALY using TST alone or IGRA alone respectively. NICE, BHIVA, or more extensive strategies, were not cost-effective. (Table) Using PSA, no testing was most likely cost-effective up to £30,000/QALY. In a contemporary HIV population with very high uptake of ART, neither current UK guideline is cost-effective. Testing black Africans, or black Africans and people from middle TB incidence countries appear at best marginally cost-effective. Future UK guidance needs to reflect changing health demographics, improved outcomes for people in HIV care, and clinical pragmatism.

WHO standards for tuberculosis (TB) control require monitoring and evaluation of TB control programmes. In London, TB rates have stabilised at 44 per 100,000 since 2005. In 38 urban areas outside London with TB rates above the national average, these continued to rise after 2004, to 28 per 100,000 in 2008 (15% increase). London has the highest proportion of TB cases in certain risk groups, but these are increasing rapidly outside London. Many TB control efforts focus on the capital, but with rates rising elsewhere in the country, this strategy is likely to fail in the long term.

We read with interest the editorial by Moore-Gillon et al ,1 which advocated a more comprehensive system of immigrant screening/treatment for latent tuberculosis infection (LTBI) as a means of augmenting tuberculosis (TB) control in the UK. A recent comprehensive, national evaluation of local TB services/primary care organisations(PCOs) in the UK, which provides key insights into UK screening practices,2 found that the existing …

Introduction The incidence of nontuberculous mycobacteria (NTM) isolation from humans is increasing worldwide. In England, Wales and Northern Ireland (EW and NI) the reported rate of NTM more than doubled between 1996 and 2006. It is unclear if this trend has continued. We present an updated analysis with national NTM data from 2007 to 2012. Methods All individuals with culture positive NTM isolates between 2007–2012 reported to Public Health England by the five mycobacterial reference laboratories serving EW and NI, were included. The annual incidence of NTM was calculated based on the year of the first positive NTM isolate from each individual. Results 21,024 individuals had NTM culture positive samples. Over the study period the incidence rose from 5.57 (n = 3126) to 7.63 (n = 4454) per 100,000 population. The majority were male (57%) and older (71% >50 years of age). 77% of individuals had a pulmonary isolate – and here the incidence increased from 3.97 to 6.05 per 100,000 population between 2007 and 2012. In those with extra-pulmonary samples it remained stable at 1.61 per 100,000 population. In patients Table 1 indicates the seven most frequently reported organisms; M. avium-intracellulare (MAI) accounted for 35% of isolates (75% in people >50 years). 78% of these were from pulmonary samples. 42% of M. abscessus isolates were in patients 60 years. Conclusion The incidence of NTM has continued to rise since the last national survey. This represents an almost ten-fold increase since 1995. The majority of these are pulmonary isolates (in particular MAI). Possible explanations include greater awareness amongst clinicians leading to increased sampling, improvements in laboratory techniques for speciation or laboratory reporting practices. However, such a large increase most likely reflects a genuine rise in NTM infection in the population. Given this change in culture confirmation, it is imperative that a comprehensive clinical database is set up to provide national monitoring of clinically significant infections, and establish the true burden of disease present in EW and NI.

Background Information on recurrent tuberculosis can provide an indication of the effectiveness of tuberculosis services and identify patients who are most vulnerable. The objective of this study was to estimate the incidence of, and investigate risk factors for, recurrent episodes of tuberculosis in England and Wales. Methods Episodes of recurrent tuberculosis were identified among prospectively collected records of tuberculosis cases reported to the Health Protection Agency between 1998 and 2005. An episode of recurrent tuberculosis was defined as a re-notified case in the same patient after at least 12 months from the date of the initial notification. To estimate incidence, follow-up time was calculated for all cases until re-notification or censure. Multivariable Cox proportionate hazard models were used to determine hazard ratios (HR) for recurrence of tuberculosis and investigate the risk associated with clinical, demographic and microbiological factors. Results Five hundred and eighty-eight recurrent tuberculosis events were identified among 53 214 cases reported between 1998 and 2005, a rate of 4.1 (95% CI 3.8 to 4.5) episodes per 1000 person years of follow-up. Factors independently associated with a greater risk of recurrent tuberculosis were HIV co-infection (HR 1.64, 95% CI 1.13 to 2.38) and belonging to a South Asian ethnic group (HR 1.54, 95% CI 1.23 to 1.93). Conclusion Tuberculosis recurrence is uncommon in England and Wales despite the absence of a universal directly observed treatment policy. The identification of HIV co-infection as a risk factor for recurrent tuberculosis is consistent with findings elsewhere. The higher risk among South Asians, however, requires further investigation.

In 1998, the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) published recommendations standardising the evaluation of tuberculosis treatment outcome in Europe. These guidelines fail to account for clinically appropriate alterations in the management of patients.To evaluate tuberculosis treatment outcome in England, Wales and Northern Ireland by redefining the outcome criteria and investigate factors associated with unsuccessful treatment outcome 12 months after notification.This was a prospective analysis of a cohort of patients diagnosed in England, Wales and Northern Ireland and reported to the Enhanced Tuberculosis Surveillance system in 2001 and 2002. Proportions of success and failure were calculated based on a new set of criteria following discussion with clinicians treating tuberculosis cases. Logistic regression was used to study risk factors for unsuccessful treatment outcome.13 048 cases were notified in the study period. Of the 2676 that were identified as new sputum smear positive pulmonary cases, 2209 (82.5%) had treatment outcome data reported. Using the WHO/IUATLD criteria, 76.8% were classified as successful. In contrast, applying the new criteria, the success rate was 87.5%. This rate exceeds the 85% success target set by the WHO. Risk factors for unsuccessful treatment outcome included male sex (OR 1.27; 95% CI 1.08 to 1.49), being elderly (p trend0.001), having pulmonary tuberculosis (OR 1.28; 95% CI 1.08 to 1.53) and having resistance to any antituberculosis drug (OR 1.90; 95% CI 1.44 to 2.52).The proportion of tuberculosis cases with a successful treatment outcome exceeded the target of 85% success rate based on the modified outcome categories. Although the tuberculosis treatment outcome criteria set by WHO/IUATLD appear to be clear, they mix measures of process and outcome. Further refinement may be necessary in low incidence high income countries, especially those with a high mortality among the elderly.

BACKGROUND: Previous studies have estimated the prevalence of tuberculosis and HIV infection in population subgroups in the UK. This study was undertaken to describe recent trends in the proportion of individuals with HIV infection among reported cases of tuberculosis in England and Wales, and to review the implications for clinical and public health care. METHODS: A population-based matching study using national surveillance databases was used to investigate all persons aged 15 years and over reported with a diagnosis of tuberculosis to the Health Protection Agency in England and Wales in 1999-2003. Record linkage was used to match the national tuberculosis and HIV/AIDS surveillance databases to identify all cases of tuberculosis and determine the proportion of patients with tuberculosis co-infected with HIV. The distribution and characteristics of the cases were determined and the trend examined by year. RESULTS: Of 30,670 cases of tuberculosis reported in England and Wales between 1999 and 2003, an estimated 1743 (5.7%) were co-infected with HIV. There was a year on year increase in the proportion from 3.1% (169/5388) in 1999 to 8.3% (548/6584) in 2003 (p for trend

Introduction India accounts for more than one-fifth of the total global tuberculosis (TB) incidence. In response, the Revised National TB Control Program (RNTCP) of India has supported the decentralisation of service delivery with encouragement of active community participation. Operation ASHA is an international NGO that offers TB services to slum populations – a group that have proven difficult historically to engage. It employs a unique treatment approach involving community-based providers and biometric data registration to support adherence. We report treatment outcome for patients with presumed drug-susceptible tuberculosis managed by Op ASHA within Delhi’s slum districts. Methods Retrospective, observational cohort study focusing on patients within 14 southern Delhi slum districts started on treatment according to RNTCP guidelines between 1.4.2012 and 31.3.2013. Demographic and clinical information were systematically recorded. Patients still on treatment by the end of October 2013 were excluded from analysis. Successful outcomes were defined as bacteriologically confirmed cure or treatment completion. Adverse outcomes were: treatment default, conversion to MDR-TB treatment, treatment failure or death. Results 1217 patients were started on treatment. 29% were aged Conclusions The model of care achieves the WHO target for treatment completion of 85% in a population considered very high risk of failure under traditional TB programmes. Future work needs to focus on the factors that result in adverse outcomes, in particular for the key patient population with infectious pulmonary TB.

Tuberculosis (TB) remains a problem in the UK, and almost three-quarters of active TB cases occur in the non-UK born. Most of these are likely infected abroad and strategies to detect latent TB in this population are being considered. We investigated how soon after arrival into the UK certain groups developed TB and the implications of this for numbers needed to screen and treat. Numbers of migrants arriving in 2005 from the top 6 countries of origin (of TB cases) were obtained from the Labour Force Survey (LFS). National TB surveillance (ETS) provided information on active cases from these countries. Estimates of interferon γ release assay (IGRA) positive cases (20%–28%), IGRA sensitivity (84%), and efficacy (65%) and completeness (85%) of chemoprophylaxis were obtained from Pareek et al. (Lancet ID 2011). The Abstract S39 table 1 shows numbers needed to screen and treat to prevent one case of TB developing in the UK in the 5 years after arrival. Numbers were relatively low, especially for Bangladesh and Somalia. The Abstract S39 table 1 also shows time between diagnosis and entry into the UK, which varied between countries of the Indian Subcontinent and sub-Saharan Africa and changed over time. While 45% of cases born in India had been in the country more than 10 years prior to arrival in 2000–2004, this was 32% in 2005–2009. Conversely, 57% of cases born in Zimbabwe were diagnosed within 2 years of arrival in 2000–2004, decreasing to 15% in 2005–2009. The relatively low numbers needed to treat among migrants from these high burden countries provide support for new guidance to expand latent infection treatment. The observed trends and differences in time since entry reflect underlying migration patterns, with higher but decreasing levels of migration from sub-Saharan Africa and an established and ongoing migrant population from the Indian Subcontinent. A more detailed analysis of migration patterns and its impact on UK cases of TB is warranted.

Background Although many randomised controlled trials (RCTs) and systematic reviews of treatment for latent tuberculosis (TB) infection (LTBI) have been conducted, previous analyses have not been able directly compare all utilised regimens. To address this we systematically searched for RCTs of LTBI treatment, then used a Bayesian network approach, which allows indirect head-to-head comparisons, to determine the most efficacious regimens at preventing active TB and those that caused the fewest adverse events. Methods PubMed, EMBASE and Web of Science were systematically mined using a search strategy developed to find RCTs of LTBI treatment. Animal studies, non-RCTs, and RCTs without at least one of our two endpoints were excluded. No language restrictions were made. Extracted data were inputted into a full random effects mixed treatment compartment model, based on code by Ades, Welton and Lu, and implemented in WinBUGS. Odds ratios for all possible comparisons in the network and hierarchical rankings for the different treatments were obtained from the model with point estimates taken as the median of the posterior distribution and 95% credibility intervals (CrI) from the appropriate percentiles. Study quality was individually assessed. Results 1,344 publications were generated by our search strategy, of which 52 fitted our criteria. 31 studies contained extractable data on adverse events and 44 on the development of active TB. 14 regimens were compared; an extract of the full results is presented (Table 1). Conclusion Our Bayesian approach allows a novel, integrated, overview of the comparative efficacy and safety of different LTBI regimens, as well as a clear identification of the knowledge gaps where inference is difficult due to sparse data. The results of our study can therefore be used to inform guidelines and plan vital future LTBI treatment RCTs.

Introduction Tuberculosis (TB) rates in the UK are amongst the highest in Western Europe and HIV-TB co-infection (HIV-TB) contributes significantly to the burden of TB in the UK. Globally, HIV-TB is associated with significant morbidity and mortality, in particular where there is delayed diagnosis. Analysis of setting-specific survival can inform local healthcare policy. Here we report the outcome of individuals diagnosed with HIV in the UK, with particular emphasis on TB co-infection.Methodology We examined deaths among a retrospective national cohort of adults (15 years +) diagnosed with HIV infection between 2000–2008 linked to the national TB databases and death records from the Office of National Statistics to mid-2010. Hazard ratios (HR) estimates using uni- and multi-variable Cox regression modelling were calculated to compare all-cause and AIDS-specific mortality by key demographic and clinical markers.Results A total of 1,880 (4.3%) deaths were observed among 44,050 HIV-diagnosed adults during 149,663 person-years of follow-up. 3,188 (7.2%) adults developed TB and HIV-TB cases accounted for 341 (18.1%) of all deaths of whom 270 (79.2%) were late presenters (CD4

Background Diabetes is associated with an increased risk of tuberculosis disease, but it is unclear whether a similar association exists between diabetes and latent tuberculosis infection (LTBI). Methods The ongoing UK PREDICT (Prognostic Evaluation of Diagnostic IGRAs Consortium) cohort study aims to recruit 10,000 participants to assess the predictive values of interferon gamma release assays (IGRAs) for the development of active TB in recent entrants to the UK and contacts of active TB cases. We used a nested case-control design within the first 5000 recruits in this cohort, to investigate the association between diabetes and LTBI. Participants in PREDICT provide demographic, medical and social information, including any history of diabetes. LTBI is detected using the two commercially available IGRAs, Quantiferon Gold In-Tube and TSpot. TB . Cases were individuals who tested positive on either or both IGRAs; controls were negative on both assays (or negative on one and indeterminate on the other). Logistic regression was used to estimate odds ratios and adjust for potential confounders. Assuming a 5% diabetes prevalence, 1084 cases and 3252 controls would allow the detection of a 1.5-fold increase of LTBI with 80% power and 5% error. Results Overall, 1388/4730 (29%) had a positive IGRA. 286/4730 (6%) reported a history of diabetes. Amongst diabetic participants, 168 used insulin and/or oral hypoglycaemic medications and 25 reported control through diet alone (1 participant was being monitored only and for 92 the level of control was unknown). Univariate analysis found an association between diabetes and LTBI (OR = 1.45 [95% CI 1.13–1.86], p = 0.003). After adjustment for age, this association was no longer apparent (OR = 1.15 [95% CI 0.88–1.50], p = 0.30). Adjustment for other variables in addition to age (sex, ethnicity, birthplace outside the UK, previous contact with a TB case, or previous TB diagnosis) did not substantially change the estimated age-adjusted OR relating diabetes to LTBI. Similar results were obtained when the analysis was restricted to contacts . Conclusions In the current PREDICT cohort, diabetes does not appear to be associated with LTBI after adjustment for age. The relationship between diabetes and TB disease observed elsewhere may reflect an increased risk of disease rather than infection.

Since its creation by Dr Karel Styblo, the cohort review (CR) principle of systematically analysing treatment outcome of every notified TB case and contact investigation in a brief, timely, structured manner, has been implemented widely outside of the UK—with impressive results. In 2010, North Central London (NCL) TB service adopted the concept, trained staff members and put in practice CR. Given the resource implications that our service faced already, plus the potential for its introduction to result in an increased staff workload, we undertook a survey of how CR was perceived and the impact it had on those involved in its use. After four rounds of CR (12 months from introduction), an anonymous on-line survey was sent to NCL staff members plus external participants and observers who had attended at least one review. The survey explored participant9s personal and institutional response to the organisation, impact and outcome of CR9s introduction. It was sent to 88 individuals. 72 (82%) completed the 10 min online questionnaire. Over 95% felt that CR identified gaps in service, most frequently: collaboration with other TB services (69%), patient care (63%), collaboration with allied services (51%) and service organisation (45%). Just over a third felt that CR highlighted training needs, especially for contact tracing. 70% reported changes to their way of working—in particular altering practice in response to apparent weaknesses in their approach to contact tracing. 86% felt that CR led to improvement in the speed of interventions, better data quality and enhanced professional relations. A small number of staff noted negative consequences which largely reflected increase in initial work load. Cohort review has enhanced our service provision. It is well received by local staff as well as external participants & observers. Our data are encouraging; and we hope will assist in promoting roll out to other parts of the country.

Background Tuberculosis (TB) and HIV/AIDS are global public health problems with considerable mutual interaction. Data on national TB-HIV co-infection trends are essential to plan and evaluate TB-HIV control measures. We compared the burden of co-infection and how this is monitored in surveillance systems in England with the rest of Europe. Methods A systematic search of academic and grey literature identifying studies reporting data on TB-HIV co-infection in EU/EEA countries. A questionnaire survey among EU/EEA countries9 TB surveillance leads, regarding surveillance methods, data and proportion of cases tested for HIV. For England, Wales and Northern Ireland, cases reported to Enhanced Tuberculosis Surveillance matched to national HIV/AIDS case reports. Results A total of 55 papers were identified providing estimates on the proportion of TB patients co-infected with HIV. From 30 EU/EEA countries 25 TB questionnaires were returned. This gave prevalence data for 23 countries. In England, the prevalence of HIV co-infection among TB patients rose from 5% in 2000 to 8% in 2005, with a peak at 9% in 2003–2004. These figures are at the higher end of what is observed in Europe. France, Iceland and Portugal (11–15%) had higher co-infection levels, while similar levels were found for Estonia and Malta (9%). Very low levels were reported from central European countries (0–1%). A rise in co-infection levels was seen in Estonia, Latvia, Lithuania, the UK and Belgium, while decreases were seen in Spain and Portugal. The burden was higher in countries reporting high levels of HIV testing and countries with a higher HIV burden. Information on TB patients9 HIV status was collected in 19/25 TB surveillance systems responding to the survey. While 17 countries rely on clinician reporting, in England and Finland, data are obtained by matching to national HIV/AIDS surveillance data due to confidentiality concerns. Conclusion Levels of TB-HIV co-infection vary widely across EU countries, with the UK being at the higher end. Our data suggest that TB-HIV surveillance appears patchy and needs strengthening to better inform control policies and clinical practice.

Background Radiographic screening for pulmonary tuberculosis is used in high risk groups in many countries. There are no published reports of the sensitivity and specificity of this technique in an operational setting with high screening throughput. A Department of Health screening programme has used mobile digital chest radiography to identify pulmonary tuberculosis amongst homeless people, problem drug users and prisoners in London since April 2005. We aimed to use data from this programme and from national tuberculosis surveillance to establish the sensitivity and specificity of mobile digital X-ray screening for the identification of pulmonary tuberculosis. Methods Data collected on those screened for the period March 2005 to March 2010 were collated. Abnormal radiographs were classified as: 1) suspected active tuberculosis; 2) signs of old inactive tuberculosis; 3) other suspicious findings that warrant further investigation (eg, possible cancer); 4) abnormal but no further investigation required; 5) normal. Demographic data from those screened were matched to the national tuberculosis surveillance database using probabilistic algorithms. Duplicates within the screening database (ie, persons having been screened more than once) were removed using the same algorithms. To calculate sensitivity and specificity all those who were referred with suspected active tuberculosis were classified as ‘screen positive’ with all others classified as ‘screen negative’. The gold standard comparator was a notification of pulmonary tuberculosis within the four months after screening. Non-pulmonary cases of tuberculosis were also excluded. Results 39 225 individuals were screened during the study period, 75% were male and the median age was 36 (IQR 27–45). 430 of those screened were referred with suspected active tuberculosis for further investigation. Matching of the screening data to surveillance data identified 44 screened individuals who were notified with pulmonary tuberculosis within 4 months of screening, 36 of these were screen positive. Based on these results, sensitivity was 82% (95% CI 67.3 to 91.8%) and specificity 99.3% (95% CI 99.1 to 99.3%) (see Abstract S6 Table 1). Conclusion High throughput mobile digital radiographic screening for pulmonary tuberculosis has high sensitivity and specificity in high risk groups and should be considered as a key tool for active case finding in these populations.