Dominik Zenner

Treatment of Latent Tuberculosis Infection: A Network Meta-analysis

BACKGROUND Effective treatment of latent tuberculosis infection (LTBI) is an important component of TB elimination programs. Promising new regimens that may be more effective are being introduced. Because few regimens can be directly compared, network meta-analyses, which allow indirect comparisons to be made, strengthen conclusions. PURPOSE To determine the most efficacious regimen for preventing active TB with the lowest likelihood of adverse events to inform LTBI treatment policies. DATA SOURCES PubMed, EMBASE, and Web of Science up to 29 January 2014; clinical trial registries; and conference abstracts. STUDY SELECTION Randomized, controlled trials that evaluated LTBI treatment in humans and recorded at least 1 of 2 prespecified end points (preventing active TB or hepatotoxicity), without language or date restrictions. DATA EXTRACTION Data from eligible studies were independently extracted by 2 investigators according to a standard protocol. DATA SYNTHESIS Of the 1516 articles identified, 53 studies met the inclusion criteria. Data on 15 regimens were available; of 105 possible comparisons, 42 (40%) were compared directly. Compared with placebo, isoniazid for 6 months (odds ratio [OR], 0.64 [95% credible interval {CrI}, 0.48 to 0.83]) or 12 months or longer (OR, 0.52 [CrI, 0.41 to 0.66]), rifampicin for 3 to 4 months (OR, 0.41 [CrI, 0.18 to 0.86]), and rifampicin-isoniazid regimens for 3 to 4 months (OR, 0.52 [CrI, 0.34 to 0.79]) were efficacious within the network. LIMITATIONS The risk of bias was unclear for many studies across various domains. Evidence was sparse for some comparisons, particularly hepatotoxicity. CONCLUSION Comparison of different LTBI treatment regimens showed that various therapies containing rifamycins for 3 months or more were efficacious at preventing active TB, potentially more so than isoniazid alone. Regimens containing rifamycins may be effective alternatives to isoniazid monotherapy. PRIMARY FUNDING SOURCE None.

The impact of migration on tuberculosis epidemiology and control in high-income countries: a review.

Tuberculosis (TB) causes significant morbidity and mortality in high-income countries with foreign-born individuals bearing a disproportionate burden of the overall TB case burden in these countries. In this review of tuberculosis and migration we discuss the impact of migration on the epidemiology of TB in low burden countries, describe the various screening strategies to address this issue, review the yield and cost-effectiveness of these programs and describe the gaps in knowledge as well as possible future solutions.The reasons for the TB burden in the migrant population are likely to be the reactivation of remotely-acquired latent tuberculosis infection (LTBI) following migration from low/intermediate-income high TB burden settings to high-income, low TB burden countries.TB control in high-income countries has historically focused on the early identification and treatment of active TB with accompanying contact-tracing. In the face of the TB case-load in migrant populations, however, there is ongoing discussion about how best to identify TB in migrant populations. In general, countries have generally focused on two methods: identification of active TB (either at/post-arrival or increasingly pre-arrival in countries of origin) and secondly, conditionally supported by WHO guidance, through identifying LTBI in migrants from high TB burden countries. Although health-economic analyses have shown that TB control in high income settings would benefit from providing targeted LTBI screening and treatment to certain migrants from high TB burden countries, implementation issues and barriers such as sub-optimal treatment completion will need to be addressed to ensure program efficacy.

Transmission of multidrug-resistant tuberculosis in the UK: a cross-sectional molecular and epidemiological study of clustering and contact tracing.

BACKGROUND Between 2000 and 2012 the number of multidrug-resistant (MDR) tuberculosis cases in the UK increased from 28 per year to 81 per year. We investigated the proportion of MDR tuberculosis cases arising from transmission in the UK and associated risk factors. METHOD We identified patients with MDR tuberculosis notified in England, Wales, and Northern Ireland between Jan 1, 2004, and Dec 31, 2007, by linking national laboratory and surveillance data. Data for laboratory isolates, including drug sensitivities and 24-mycobacterial interspersed repetitive-unit-variable-number tandem repeat (MIRU-VNTR) typing were obtained routinely from the National Tuberculosis Reference laboratories as part of national tuberculosis surveillance. We investigated clusters of cases with indistinguishable MIRU-VNTR profiles to identify epidemiological links. We calculated transmission using the n-1 method and established associated risk factors by logistic regression. We also assessed the likelihood of transmission to additional secondary active tuberculosis cases, identified through conventional contact tracing. FINDINGS 204 patients were diagnosed with MDR tuberculosis in the study period; 189 (92·6%) had an MIRU-VNTR profile. We identified 12 clusters containing 40 individuals and 149 unique strains. The proportion of cases attributable to recent transmission, on the basis of molecular data, was 15% (40 cases clustered-12 clusters/189 with a strain type). The proportion of cases attributable to recent transmission (ie, transmission within the UK) after adjustment for epidemiological links was 8·5% (22 cases with epidemiological links-six clusters/189 cases with a strain type). Being UK born (odds ratio 4·81; 95% CI 2·03-11·36, p=0·0005) and illicit drug use (4·75; 1·19-18·96, p=0·026) were significantly associated with clustering. The most common transmission setting was the household but 21 of 22 of epidemiological links were missed by conventional contact tracing. 13 secondary active tuberculosis cases identified by conventional contact tracing were mostly contacts of patients with MDR tuberculosis from countries of high tuberculosis burden. 11 (85%) of 13 shared the same country of birth as the index case, of whom ten did not share a strain type or drug resistance pattern. INTERPRETATION Transmission of MDR tuberculosis in the UK is low and associated with being UK born or illicit drug use. MIRU-VNTR typing with cluster investigation was more successful at identifying transmission events than conventional contact tracing. Individuals with tuberculosis who have had contact with a known MDR tuberculosis source case from a country of high tuberculosis burden should have drug-sensitivity testing on isolates to ensure appropriate treatment is given. FUNDING Public Health England.

Pre-entry screening programmes for tuberculosis in migrants to low-incidence countries: a systematic review and meta-analysis.

BACKGROUND Several high-income countries have pre-entry screening programmes for tuberculosis. We aimed to establish the yield of pre-entry screening programmes to inform evidence-based policy for migrant health screening. METHODS We searched six bibliographic databases for experimental or observational studies and systematic reviews, which reported data on migrant screening for active or latent tuberculosis by any method before migration to a low-incidence country. Primary outcomes were principal reported screening yield of active tuberculosis, yield of culture-confirmed cases, and yield of sputum smear for acid-fast bacilli cases. Where appropriate, fixed-effects models were used to summarise the yield of pre-entry screening across included studies. FINDINGS We identified 15 unique studies with data for 3 739 266 migrants screened pre-entry for tuberculosis between 1982 and 2010. Heterogeneity was high for all primary outcomes. After stratification by prevalence in country of origin, heterogeneity was reduced for culture-confirmed and smear-confirmed cases. Yield of culture-confirmed cases increased with prevalence in the country of origin, and summary estimates ranged from 19·7 (95% CI 10·3-31·5) cases identified per 100 000 individuals screened in countries with a prevalence of 50-149 cases per 100 000 population to 335·9 (283·0-393·2) per 100 000 in countries with a prevalence of greater than 350 per 100 000 population. INTERPRETATION Targeting high-prevalence countries could result in the highest yield for active disease. Pre-entry screening should be considered as part of a broad package of measures to ensure early diagnosis and effective management of migrants with active tuberculosis, and be integrated with initiatives that address the health needs of migrants. FUNDING Wellcome Trust, UK National Institute for Health Research, Medical Research Council, Public Health England.

Prevalence of and risk factors for active tuberculosis in migrants screened before entry to the UK: a population-based cross-sectional study

BACKGROUND An increasing number of countries with low incidence of tuberculosis have pre-entry screening programmes for migrants. We present the first estimates of the prevalence of and risk factors for tuberculosis in migrants from 15 high-incidence countries screened before entry to the UK. METHODS We did a population-based cross-sectional study of applicants for long-term visas who were screened for tuberculosis before entry to the UK in a pilot programme between Oct 1, 2005, and Dec 31, 2013. The primary outcome was prevalence of bacteriologically confirmed tuberculosis. We used Poisson regression to estimate crude prevalence and created a multivariable logistic regression model to identify risk factors for the primary outcome. FINDINGS 476 455 visa applicants were screened, and the crude prevalence of bacteriologically confirmed tuberculosis was 92 (95% CI 84-101) per 100 000 individuals. After adjustment for age and sex, factors that were strongly associated with an increased risk of bacteriologically confirmed disease at pre-entry screening were self-report of close or household contact with an individual with tuberculosis (odds ratio 11·6, 95% CI 7·0-19·3; p<0·0001) and being an applicant for settlement and dependant visas (1·3, 1·0-1·6; p=0·0203). INTERPRETATION Migrants reporting contact with an individual with tuberculosis had the highest risk of tuberculosis at pre-entry screening. To tackle this disease burden in migrants, a comprehensive and collaborative approach is needed between countries with pre-entry screening programmes, health services in the countries of origin and migration, national tuberculosis control programmes, and international public health bodies. FUNDING Wellcome Trust, Medical Research Council, and UK National Institute for Health Research.

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

Background Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI. Purpose To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children. Data Sources PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied. Study Selection Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB). Data Extraction 2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol. Data Synthesis The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy. Limitation Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies. Conclusion Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin. Primary Funding Source U.K. National Institute for Health Research. (PROSPERO: CRD42016037871).

Impact of TB on the survival of people living with HIV infection in England, Wales and Northern Ireland

Introduction The impact of TB disease on survival in people living with HIV in high resource settings is not well documented in the antiretroviral treatment (ART) era. We calculated TB incidence rates and compared the mortality of persons with and without HIV-TB in a UK HIV cohort in the post-ART era, to determine the impact of HIV-TB on survival in the UK. Methods We linked the national cohort of persons (aged ≥15 years) diagnosed with HIV between 2000 and 2008 in England, Wales and Northern Ireland with the national TB register and deaths from the Office of National Statistics. We compared all-cause and AIDS-specific mortality in patients with and without TB by estimating HRs using Cox regression modelling allowing for potential predictors. Results Overall, 3188 (7.2%) individuals developed TB infection among a cohort of 44 050 HIV-diagnosed persons and 149 663 person-years. The cumulative TB incidence rate was 2.13 per 100 person-years with a spike within the first 6 months after HIV diagnosis. TB coinfected patients comprised 18% of the 1880 deaths during follow-up and 79% of deaths (n=967) in the year following HIV diagnosis. TB coinfection (HR 4.77, 95% CI 4.11 to 5.54) was significantly associated with increased all-cause mortality. Analysis of AIDS-related survival showed similar results. Discussion The unexpected high mortality in patients with HIV-TB in a population with good healthcare access and ART availability highlights the importance of improving active and latent TB case-finding among patients with HIV, and HIV-testing among patients with TB, to ensure appropriate and prompt treatment initiation for both diseases.

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.

Prevention and assessment of infectious diseases among children and adult migrants arriving to the European Union/European Economic Association: a protocol for a suite of systematic reviews for public health and health systems

Introduction The European Centre for Disease Prevention and Control is developing evidence-based guidance for voluntary screening, treatment and vaccine prevention of infectious diseases for newly arriving migrants to the European Union/European Economic Area. The objective of this systematic review protocol is to guide the identification, appraisal and synthesis of the best available evidence on prevention and assessment of the following priority infectious diseases: tuberculosis, HIV, hepatitis B, hepatitis C, measles, mumps, rubella, diphtheria, tetanus, pertussis, poliomyelitis (polio), Haemophilus influenza disease, strongyloidiasis and schistosomiasis. Methods and analysis The search strategy will identify evidence from existing systematic reviews and then update the effectiveness and cost-effectiveness evidence using prospective trials, economic evaluations and/or recently published systematic reviews. Interdisciplinary teams have designed logic models to help define study inclusion and exclusion criteria, guiding the search strategy and identifying relevant outcomes. We will assess the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Ethics and dissemination There are no ethical or safety issues. We anticipate disseminating the findings through open-access publications, conference abstracts and presentations. We plan to publish technical syntheses as GRADEpro evidence summaries and the systematic reviews as part of a special edition open-access publication on refugee health. We are following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols reporting guideline. This protocol is registered in PROSPERO: CRD42016045798.

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.