H Lucy Thomas

Assessment of Mycobacterium tuberculosis transmission in Oxfordshire, UK, 2007-12, with whole pathogen genome sequences: an observational study.

Summary Background Patients born outside the UK have contributed to a 20% rise in the UK’s tuberculosis incidence since 2000, but their effect on domestic transmission is not known. Here we use whole-genome sequencing to investigate the epidemiology of tuberculosis transmission in an unselected population over 6 years. Methods We identified all residents with Oxfordshire postcodes with a Mycobacterium tuberculosis culture or a clinical diagnosis of tuberculosis between Jan 1, 2007, and Dec 31, 2012, using local databases and checking against the national Enhanced Tuberculosis Surveillance database. We used Illumina technology to sequence all available M tuberculosis cultures from identified cases. Sequences were clustered by genetic relatedness and compared retrospectively with contact investigations. The first patient diagnosed in each cluster was defined as the index case, with links to subsequent cases assigned first by use of any epidemiological linkage, then by genetic distance, and then by timing of diagnosis. Findings Although we identified 384 patients with a diagnosis of tuberculosis, country of birth was known for 380 and we sequenced isolates from 247 of 269 cases with culture-confirmed disease. 39 cases were genomically linked within 13 clusters, implying 26 local transmission events. Only 11 of 26 possible transmissions had been previously identified through contact tracing. Of seven genomically confirmed household clusters, five contained additional genomic links to epidemiologically unidentified non-household members. 255 (67%) patients were born in a country with high tuberculosis incidence, conferring a local incidence of 109 cases per 100 000 population per year in Oxfordshire, compared with 3·5 cases per 100 000 per year for those born in low-incidence countries. However, patients born in the low-incidence countries, predominantly UK, were more likely to have pulmonary disease (adjusted odds ratio 1·8 [95% CI 1·2–2·9]; p=0·009), social risk factors (4·4 [2·0–9·4]; p<0·0001), and be part of a local transmission cluster (4·8 [1·6–14·8]; p=0·006). Interpretation Although inward migration has contributed to the overall tuberculosis incidence, our findings suggest that most patients born in high-incidence countries reactivate latent infection acquired abroad and are not involved in local onward transmission. Systematic screening of new entrants could further improve tuberculosis control, but it is important that health care remains accessible to all individuals, especially high-risk groups, if tuberculosis control is not to be jeopardised.

Does antiretroviral therapy reduce HIV-associated tuberculosis incidence to background rates? A national observational cohort study from England, Wales, and Northern Ireland

BACKGROUND Whether the incidence of tuberculosis in HIV-positive people receiving long-term antiretroviral therapy (ART) remains above background population rates is unclear. We compared tuberculosis incidence in people receiving ART with background rates in England, Wales, and Northern Ireland. METHODS We analysed a national cohort of HIV-positive individuals linked to the national tuberculosis register. Tuberculosis incidence in the HIV-positive cohort (2007-11) was stratified by ethnic origin and time on ART and compared with background rates (2009). Ethnic groups were defined as follows: the black African group included all individuals of black African origin, including those born in the UK and overseas; the white ethnic group included all white individuals born in the UK and overseas; the south Asian group included those of Indian, Pakistani, and Bangladeshi origin, born in the UK and overseas; and the other ethnic group included all other ethnic origins, including black Afro-Caribbeans. FINDINGS The HIV-positive cohort comprised 79 919 individuals, in whom there were 1550 incident cases in 231 664 person-years of observation (incidence 6·7 cases per 1000 person-years). Incidence of tuberculosis in the HIV-positive cohort was 13·6 per 1000 person-years in black Africans and 1·7 per 1000 person-years in white individuals. Incidence of tuberculosis during long-term ART (≥5 years) in black Africans with HIV was 2·4 per 1000 person-years, similar to background rates of 1·9 per 1000 person-years in this group (rate ratio 1·2, 95% CI 0·96-1·6; p=0·083); but in white individuals with HIV on long-term ART the incidence of 0·5 per 1000 person-years was higher than the background rate of 0·04 per 1000 person-years (rate ratio 14·5, 9·4-21·3; p<0·0001). The increased incidence relative to background in white HIV-positive individuals persisted when analysis was restricted to person-time accrued on ART with CD4 counts of at least 500 cells per μL and when white HIV-positive individuals born abroad were excluded. INTERPRETATION Tuberculosis incidence is unacceptably high irrespective of HIV status in black Africans. In white individuals with HIV, tuberculosis incidence is significantly higher than background rates in white people despite long-term ART. Expanded testing and treatment for latent tuberculosis infection to all HIV-infected adults, irrespective of ART status and CD4 cell count, might be warranted. FUNDING Public Health England.

A collaborative strategy to tackle tuberculosis in England

312 www.thelancet.com Vol 385 January 24, 2015 The UK has the second highest rate of tuberculosis among western European countries. Tuberculosis clinics in London manage more cases a year than those in all other western European capital cities put together. Rates of tuberculosis are now nearly fi ve times higher in the UK than in the USA. Lack of progress with tuberculosis control in the UK does not just represent a risk to domestic public health, but also an international embarrassment with examples of cases acquired in the UK leading to infections in other low-incidence countries. In recognition of this unacceptable trend, Public Health England has led a coalition of stakeholders to develop a forum, the national Tuberculosis Oversight Group, where innovation and good practice are shared between local, regional, and national health leaders. These discussions have led to local changes, with several areas establishing tuberculosis control boards and systematic cohort review, and the identifi cation of tuberculosis as a major priority for Public Health England. However, the implementation of improved tuberculosis control measures has not been universal, and there is still unacceptable variation in the quality of clinical and public health measures across England. A collaborative strategy to tackle tuberculosis in England There are some limitations to the study. First, the subtle eff ects of the HMGCR variants meant that the investigators had to use large numbers of cases and controls, and the associations between the variants and type 2 diabetes are not statistically beyond reproach—more cases and controls would help confi rm the fi ndings. Second, we cannot be certain that the variants operate directly and solely through the HMGCR gene, although there is some evidence that these variants alter splicing of HMGCR transcripts. Finally, genetic studies are not completely exempt from the confounders and biases of epidemiological studies—survival and index event biases can aff ect genetic studies, and further work with larger numbers of incident cases would provide more reassurance that the genetic associations with type 2 diabetes are real. However, the associations with body-mass index seem to be statistically robust and provide a mechanism downstream of the HMGCoA-reductase eff ect (increased body-mass index leading to increased insulin resistance, and to increased diabetes). In summary, Swerdlow and colleagues have used naturally occurring human genetic variation to provide another piece of evidence about the side-eff ects of statins, but have not cast any doubt on the evidence that the benefi ts of statins vastly outweigh their risks.

Epidemiology of Mycobacterium bovis Disease in Humans in England, Wales, and Northern Ireland, 2002-2014

Despite slightly increased cases in these areas, human infection with this cattle pathogen remains rare.

An evaluation of tuberculosis contact investigations against national standards

Background Contact tracing is a key element in Englands 2015 collaborative TB strategy, although proposed indicators of successful contact tracing remain undescribed. Methods We conducted descriptive and multivariable analyses of contact tracing of TB cases in London between 1 July 2012 and 31 December 2015 using cohort review data from Londons TB Register, identifying characteristics associated with improved indicators and yield. Results Of the pulmonary TB cases notified, 60% (2716/4561) had sufficient information for inclusion. Of these, 91% (2481/2716) had at least 1 contact (median: 4/case (IQR: 2–6)) identified, with 86% (10 251/11 981) of these contacts evaluated. 4.1% (177/4328), 1.3% (45/3421) and 0.70% (51/7264) of evaluated contacts of pulmonary smear-positive, pulmonary smear-negative and non-pulmonary cases, respectively, had active disease. Cases who were former prisoners or male were less likely to have at least one contact identified than those never imprisoned or female, respectively. Cases diagnosed at clinics with more directly observed therapy or social workers were more likely to have one or more contacts identified. Contacts screened at a different clinic to their index case or of male index cases were less likely to be evaluated than those screened at the same clinic or of women, respectively; yield of active disease was similar by sex. 10% (490/4850) of evaluated child contacts had latent TB infection. Conclusions These are the first London-wide estimates of TB contact tracing indicators which are important for monitoring the strategys success and informing risk assessment of index cases. Understanding why differences in indicators occur between groups could improve contact tracing outcomes.

Incidence and risk factors for drug intolerance and association with incomplete treatment for tuberculosis: analysis of national case registers for England, Wales and Northern Ireland, 2001–2010

Anti-tuberculosis drug regimens are efficacious, but drug intolerance can be severe and may impact on treatment completion rates. The Enhanced Tuberculosis Surveillance (ETS) system is a case register of all new notifications of tuberculosis in England, Wales and Northern Ireland. We conducted a cohort study to estimate the incidence of, and risk factors for, drug intolerance reported through ETS between 2001 and 2010 and to assess its relationship with treatment non-completion. Reports of drug intolerance were found for 868/67 547 (1.28%) patients in the cohort, and important risk factors were female sex, older age, later case report year and white ethnicity. Drug intolerance was associated with an approximate fivefold increased odds of treatment non-completion (p<0.001). These results highlight the need for better-tolerated drug regimens and close case management of patients at risk of drug intolerance to improve treatment completion rates and contribute to more effective disease control.

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

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.

Acquired Resistance to Antituberculosis Drugs in England, Wales, and Northern Ireland, 2000–2015

Among tuberculosis (TB) patients, acquired resistance to anti-TB drugs represents a failure in the treatment pathway. To improve diagnosis and care for patients with drug-resistant TB, we examined the epidemiology and risk factors associated with acquired drug resistance during 2000–2015 among TB patients in England, Wales, and Northern Ireland. We found acquired resistance in 0.2% (158/67,710) of patients with culture-confirmed TB. Using multivariate logistic regression, we identified the following factors associated with acquired drug resistance: having pulmonary disease; initial resistance to isoniazid, rifampin, or both; a previous TB episode; and being born in China or South Africa. Treatment outcomes were worse for patients with than without acquired resistance. Although acquired resistance is rare in the study area, certain patient groups are at higher risk. Identifying these patients and ensuring that adequate resources are available for treatment may prevent acquisition of resistance, thereby limiting transmission of drug-resistant strains of mycobacteria.

Injecting drug use predicts active tuberculosis in a national cohort of people living with HIV

Objectives: Tuberculosis (TB) is common in people living with HIV, leading to worse clinical outcomes including increased mortality. We investigated risk factors for developing TB following HIV diagnosis. Design: Adults aged at least 15 years first presenting to health services for HIV care in England, Wales or Northern Ireland from 2000 to 2014 were identified from national HIV surveillance data and linked to TB surveillance data. Methods: We calculated incidence rates for TB occurring more than 91 days after HIV diagnosis and investigated risk factors using multivariable Poisson regression. Results: A total of 95 003 adults diagnosed with HIV were followed for 635 591 person-years; overall incidence of TB was 344 per 100 000 person-years (95% confidence interval 330–359). TB incidence was high for people who acquired HIV through injecting drugs [PWID; men 876 (696–1104), women 605 (365–945)] and black Africans born in high TB incidence countries [644 (612–677)]. The adjusted incidence rate ratio for TB amongst PWID was 4.79 (3.35–6.85) for men and 6.18 (3.49–10.93) for women, compared with MSM. The adjusted incidence rate ratio for TB in black Africans from high-TB countries was 4.27 (3.42–5.33), compared with white UK-born individuals. Lower time-updated CD4+ cell count was associated with increased rates of TB. Conclusion: PWID had the greatest risk of TB; incidence rates were comparable with those in black Africans from high TB incidence countries. Most TB cases in PWID were UK-born, and likely acquired TB through transmission within the United Kingdom. Earlier HIV diagnosis and quicker initiation of antiretroviral therapy should reduce TB incidence in these populations.

Should NICE reconsider the 2016 UK guidelines on TB contact tracing? A cost-effectiveness analysis of contact investigations in London

Background In January 2016, clinical TB guidance in the UK changed to no longer recommend screening contacts of non-pulmonary, non-laryngeal (ETB) index cases. However, no new evidence was cited for this change, and there is evidence that screening these contacts may be worthwhile. The objective of this study was to estimate the cost-effectiveness of screening contacts of adult ETB cases and adult pulmonary or laryngeal TB (PTB) cases in London, UK. Methods We carried out a cross-sectional analysis of data collected on TB index cases and contacts in the London TB register and an economic evaluation using a static model describing contact tracing outcomes. Incremental cost-effectiveness ratios (ICERs) were calculated using no screening as the baseline comparator. All adult TB cases (≥15 years old) in London from 2012 to 2015, and their contacts, were eligible (2465/5084 PTB and 2559/6090 ETB index cases were included). Results Assuming each contact with PTB infects one person/month, the ICER of screening contacts of ETB cases was £78 000/quality-adjusted life-years (QALY) (95% CI 39 000 to 140 000), and screening contacts of PTB cases was £30 000/QALY (95% CI 18 000 to 50 000). The ICER of screening contacts of ETB cases was £30 000/QALY if each contact with PTB infects 3.4 people/month. Limitations of this study include the use of self-reported symptomatic periods and lack of knowledge about onward transmission from PTB contacts. Conclusions Screening contacts of ETB cases in London was almost certainly not cost-effective at any conventional willingness-to-pay threshold in England, supporting recent changes to National Institute for Health and Care Excellence national guidelines.