An open label, randomised controlled trial of rifapentine versus rifampicin based short course regimens for the treatment of latent tuberculosis in England: the HALT LTBI pilot study.

BACKGROUND: Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and isoniazid regimen versus daily rifampicin and isoniazid, both self-administered for 12 weeks. METHODS: An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/isoniazid ('intervention') or a daily combination of rifampicin/isoniazid ('standard'), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded. RESULTS: Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7-91.4), compared with 19 of 25 (76.0%, CI 54.9-90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms. CONCLUSION: In this pilot trial, treatment completion was comparable between the weekly rifapentine/isoniazid and the daily rifampicin/isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment. TRIAL REGISTRATION: The trial was funded by the NIHR, UK and registered with ISRCTN ( 26/02/2013-No.04379941 ).

Discordance in latent tuberculosis (TB) test results in patients with end-stage renal disease.

OBJECTIVES: This natural experiment was designed to assess the impact of exposure to an active case of tuberculosis (TB) on a group of immunosuppressed individuals, with end-stage renal disease over an extended follow-up. STUDY DESIGN: Close contacts of people with sputum smear-positive Mycobacterium tuberculosis are at high risk of infection, particularly immunosuppressed individuals. An infectious TB healthcare worker worked in a renal dialysis unit for a month before diagnosis, with 104 renal dialysis patients, was exposed for ≥8 h. METHODS: Patients were informed and invited for screening 8-10 weeks postexposure. They either underwent standard two-step assessment with tuberculin skin test (TST) and QuantiFERON®-TB Gold (Cellestis GmbH; QFN) interferon-gamma release assay (IGRA) or after consent, enrolled in a study where these two tests were performed simultaneously with T-SPOT®-TB (Oxford Immunotec Ltd; TSPOT). Patients within the study were followed up for 2 years from exposure, with QFN and TSPOT repeated at months 3 and 6 from the first testing. RESULTS: Of 104 exposed individuals, 75 enrolled in the study. There was a high degree of discordance among QFN, TSPOT and TST. This was seen at both the first time point and also over time in subjects who were retested. No patients had active TB at the baseline testing. None received treatment for latent TB infection. Over the following 2 years, no one developed TB disease. CONCLUSION: This study suggests that there is a low risk of progression to active TB in low-incidence countries even in high-risk groups. This plus the degree of the test result discordance emphasises the complexities of managing TB in such settings as it is unclear which of these tests, if any, provides the best diagnostic accuracy.

Increasing incidence of HIV- associated tuberculosis in Romanian injecting drug users.

BACKGROUND: A high prevalence of tuberculosis (TB) among HIV-positive injecting drug users (IDUs) may fuel the TB epidemic in the general population of Romania. We determined the frequency and characteristics of TB in HIV-infected IDUs referred to a national centre. METHODS: Prospective observational cohort study of all newly-diagnosed HIV-positive IDUs admitted to Victor Babes Hospital, Bucharest, between January 2009 and December 2014. Socio-demographics, clinical characteristics and outcomes of HIV/TB co-infected IDUs were compared to HIV-positive IDUs without TB. RESULTS: 170/598 (28.5%) HIV-infected IDUs were diagnosed with TB. The prevalence increased from 12.5% in 2009 to 32.1% in 2014 (P < 0.001). HIV/TB co-infected individuals had lower median CD4 cell counts 75 (vs. 450/mm3 , P < 0.0001) and higher median HIV viral loads 5.6 log10 (vs. 4.9 log10 , P < 0.0001) when presenting to healthcare services. 103/170 (60.6%) HIV/TB co-infected IDUs were diagnosed with pulmonary TB. Resistant Mycobacterium tuberculosis strains were common, with 18/105 (17.1%) of patients having Multi-Drug Resistant (MDR) disease. Higher mortality rate was associated with TB co-infection (P < 0.0001), extra-pulmonary TB (P = 0.0026) and extensively drug resistant TB (P = 0.024). CONCLUSIONS: Tuberculosis (TB) is an increasing problem in HIV-infected IDUs in Romania. Presentation is often with advanced HIV, significant TB drug resistance and consequent outcomes are poor.

Hepatitis C among vulnerable populations: A seroprevalence study of homeless, people who inject drugs and prisoners in London.

Injecting drugs substantially increases the risk of hepatitis C virus (HCV) infection and is common in the homeless and prisoners. Capturing accurate data on disease prevalence within these groups is challenging but is essential to inform strategies to reduce HCV transmission. The aim of this study was to estimate the prevalence of HCV in these populations. We conducted a cross-sectional study between May 2011 and June 2013 in London and, using convenience sampling, recruited participants from hostels for the homeless, drug treatment services and a prison. A questionnaire was administered and blood samples were tested for hepatitis C. We recruited 491 individuals who were homeless (40.7%), 205 drug users (17%) and 511 prisoners (42.3%). Eight per cent of patients (98/1207, 95% CI: 6.7%-9.8%) had active HCV infection and 3% (38/1207, 95% CI: 2.3%-4.3%) past HCV infection. Overall, one quarter (51/205) of people recruited in drug treatment services, 13% (65/491) of people from homeless residential sites and 4% (20/511) prisoners in this study were anti-HCV positive. Seventy-seven of the 136 (56.6%, 95% CI: 47.9%-65%) of HCV infected participants identified had a history of all three risk factors (homelessness, imprisonment and drug use), 27.3% (95% CI: 20.1%-35.6%) had 2 overlapping risk factors, and 15.4% (95% CI: 10.6%-23.7%) one risk factor. Drug treatment services, prisons and homelessness services provide good opportunities for identifying hepatitis C-infected individuals. Effective models need to be developed to ensure case identification in these settings that can lead to an effective treatment and an efficient HCV prevention.

Respiratory health status is impaired in UK HIV-positive adults with virologically suppressed HIV infection.

OBJECTIVES: We sought to evaluate whether people living with HIV (PLWH) using effective antiretroviral therapy (ART) have worse respiratory health status than similar HIV-negative individuals. METHODS: We recruited 197 HIV-positive and 93 HIV-negative adults from HIV and sexual health clinics. They completed a questionnaire regarding risk factors for respiratory illness. Respiratory health status was assessed using the St George's Respiratory Questionnaire (SGRQ) and the Medical Research Council (MRC) breathlessness scale. Subjects underwent spirometry without bronchodilation. RESULTS: PLWH had worse respiratory health status: the median SGRQ Total score was 12 [interquartile range (IQR) 6-25] in HIV-positive subjects vs. 6 (IQR 2-14) in HIV-negative subjects (P < 0.001); breathlessness was common in the HIV-positive group, where 47% compared with 24% had an MRC breathlessness score ≥ 2 (P = 0.001). Eighteen (11%) HIV-positive and seven (9%) HIV-negative participants had airflow obstruction. In multivariable analyses (adjusted for age, gender, smoking, body mass index and depression), HIV infection remained associated with higher SGRQ and MRC scores, with an adjusted fold-change in SGRQ Total score of 1.54 [95% confidence interval (CI) 1.14-2.09; P = 0.005] and adjusted odds ratio of having an MRC score of ≥ 2 of 2.45 (95% CI 1.15-5.20; P = 0.02). Similar findings were obtained when analyses were repeated including only HIV-positive participants with a viral load < 40 HIV-1 RNA copies/mL. CONCLUSIONS: Despite effective ART, impaired respiratory health appears more common in HIV-positive adults, and has a significant impact on health-related quality of life.

What are the most efficacious treatment regimens for isoniazid-resistant tuberculosis? A systematic review and network meta-analysis.

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.

Waist-to-height ratio as a measure of abdominal obesity in southern Chinese and European children and adolescents.

BACKGROUND: Waist-to-height ratio (WHtR), with a 0.5 threshold (WHtR0.5), is regarded as a simple age- and gender-independent criterion of abdominal obesity (AO) and a better predictor than the 90th percentile of waist circumference (WCP90). OBJECTIVE: An analysis of gender and ethnic differences of WHtR and other AO indices between children and adolescents from southern China (HK: Hong-Kong, China) and Europe (LD: Lódz, Poland). SUBJECTS: Two large cross-sectional surveys of children and adolescents aged 7-19 years, one from LD (13 172) and one from HK (14 566). METHODS: The percentile and standardized values of WHtR and other parameters (WC, body mass index (BMI)) were assessed using the LMS method. The WHtR values corresponding to WCP90 and to the BMI definition of global obesity (BMIP95) were evaluated with the polynomial regression model. The compliance of the AO prevalence data, obtained with two criteria (WCP90 vs WHtR0.5) was analyzed using Cohen's kappa index (κC). RESULTS: The WHtR data of Polish subjects were generally higher than those of their HK peers, and the ethic differences increased with age. The WHtR values of HK boys showed a stronger relationship with BMI z-score. WHtR corresponding to WCP90 assumed values <0.5. An application of Cohen's kappa coefficient (κC) to Polish subjects showed either 'substantial' (κC>0.6) or 'almost perfect' (κC>0.8) agreement in the AO prevalence for both criteria (WCP90 and WHtR0.5). For these criteria, either 'fair' (κC <0.4) or 'moderate' (κC<0.6) AO consistency ratings were observed among HK girls. In HK boys, a significant difference in the prevalence of AO was observed, independent of the criterion used. CONCLUSIONS: Our results provide further evidence of the need for developing ethnic-specific WC charts and for recommending that a WHtR cutoff of 0.5 may not be appropriate to predict cardiometabolic risk in children of different ethnic groups.

Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance.

No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.

Managing latent tuberculosis in UK renal transplant units: how does practice compare with published guidance?

Renal transplantation significantly increases the risk of active tuberculosis (TB) in individuals with latent TB infection (LTBI). UK transplant recipients are often born in TB endemic areas. Using a self-completed questionnaire, we evaluated how the 23 UK renal transplant units' LTBI management compared with recently published national guidance. Three-quarters had a management protocol, but only one-third of these were in line with the guidance. Interferon-gamma release assays were rarely used to confirm LTBI. Almost half of the units prescribed LTBI treatment at the wrong dose or duration. We conclude that units should develop local protocols in line with evidence-based guidance. This must be in a format that enables national audit programmes and quality improvement to be routinely performed.

When is an outbreak not an outbreak? Fit, divergent strains of Mycobacterium tuberculosis display independent evolution of drug resistance in a large London outbreak.

OBJECTIVES: To study the evolutionary relationship of Mycobacterium tuberculosis isolates from 13 patients in a large outbreak of isoniazid-resistant tuberculosis in London. METHODS: Genotypic and phenotypic susceptibility tests were performed. Molecular genotyping using restriction fragment length polymorphisms and mycobacterial interspersed repetitive units was carried out. Additionally, the generation times of 13 strains of M. tuberculosis from the outbreak were measured to determine relative fitness. RESULTS: Genotypic and phenotypic susceptibility testing demonstrated variations between isolates. Polymorphisms causing isoniazid resistance varied within clusters of isolates that were indistinguishable by standard genotyping. The measurement of in vitro generation times demonstrated that the fitness of the resistant strains was not significantly different from either wild-type or susceptible isolates in the outbreak, indicating that apparently no fitness cost was associated with the acquisition of drug resistance. CONCLUSIONS: It appears that this outbreak comprised a heterogeneous collection of closely related strains, which appear to exhibit more variation than would usually be associated with a point source outbreak. These strains appear to have evolved by acquisition of additional antimicrobial resistance mutations while remaining competitive. The acquired resistance and retained competitiveness may be partly responsible for the difficulty in controlling the outbreak.

Interferon-γ release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis.

Interferon-γ release assays (IGRAs) are now established for the immunodiagnosis of latent infection with Mycobacterium tuberculosis in many countries. However, the role of IGRAs for the diagnosis of active tuberculosis (TB) remains unclear. Following preferred reporting items for systematic reviews and meta-analyses (PRISMA) and quality assessment of diagnostic accuracy studies (QUADAS) guidelines, we searched PubMed, EMBASE and Cochrane databases to identify studies published in January 2001-November 2009 that evaluated the evidence of using QuantiFERON-TB® Gold in-tube (QFT-G-IT) and T-SPOT.TB® directly on blood or extrasanguinous specimens for the diagnosis of active TB. The literature search yielded 844 studies and 27 met the inclusion criteria. In blood and extrasanguinous fluids, the pooled sensitivity for the diagnosis of active TB was 80% (95% CI 75-84%) and 48% (95% CI 39-58%) for QFT-G-IT, and 81% (95% CI 78-84%) and 88% (confirmed and unconfirmed cases) (95% CI 82-92%) for T-SPOT.TB®, respectively. In blood and extrasanguinous fluids, the pooled specificity was 79% (95% CI 75-82%) and 82% (95% CI 70-91%) for QFT-G-IT, and 59% (95% CI 56-62%) and 82% (95% CI 78-86%) for T-SPOT.TB®, respectively. Although the diagnostic sensitivities of both IGRAs were higher than that of tuberculin skin tests, it was still not high enough to use as a rule out test for TB. Positive evidence for the use of IGRAs in compartments other than blood will require more independent and carefully designed prospective studies.

Large outbreak of isoniazid-monoresistant tuberculosis in London, 1995 to 2006: case-control study and recommendations.

We conducted a case­control study to examine risk factors for isoniazid-monoresistant Mycobacterium tuberculosis in an ongoing outbreak in London. Cases were defined as individuals with an isoniazid-monoresistant strain diagnosed from 1995 to the third quarter of 2006 with an indistinguishable restriction fragment length polymorphism (RFLP) or mycobacterial interspersed repetitive unit (MIRU)-variable number tandem repeats (VNTR) pattern who were resident in or had epidemiological links with London. Controls were all other individuals reported with tuberculosis to the Health Protection Agency London regional epidemiology unit or the HPA London TB Register during 2000 to 2005. Of 293 cases, 153 (52%) were sputum smear-positive compared with 3,266 (18%) of controls. Cases were more likely to be young adults (aged between 15 and 34 years), born in the United Kingdom (OR: 2.4; 95% CI: 1.7­3.4) and of white (OR: 2.9; 95% CI: 1.8­4.8) or black Caribbean (OR: 12.5; 95% CI: 7.7­20.4) ethnicity, a prisoner at the time of diagnosis (OR: 20.2; 95% CI: 6.7­60.6), unemployed (OR: 4.1; 95% CI: 3.0­5.6), or a drug dealer or sex worker (OR: 187.1; 95% CI: 28.4­1,232.3). A total of 113 (39%) of cases used drugs and 54 (18%) were homeless. Completion of treatment gradually improved in cases from 55% among those diagnosed up to the end of 2002 compared with 65% by the end of 2006. Treatment completion increased from 79% to 83% in controls from 2000 to 2005. There are complex social challenges facing many cases in this outbreak that need to be addressed if medical interventions are to be successful.

Limited value of annual tuberculosis symptom reminders for health care workers.

BACKGROUND: (UK) National Institute for Health and Clinical Excellence tuberculosis (TB) guidance (2006) recommends that occupational health services send annual TB symptom reminders to staff at increased risk of occupational TB exposure. AIMS: To evaluate the effectiveness of annual TB symptom reminders. METHODS: Retrospective analysis of returns from 4 years' annual TB symptom reminders compared with numbers of hospital staff diagnosed with active TB in the same time period. RESULTS: There were 405 responses to symptom reminders received during the period studied that represented a response rate of 16%. None of the respondents declared TB symptoms. Twelve staff were diagnosed with active TB over the same period. From their work location, only two of these would have received TB symptom reminders according to local TB policy. CONCLUSIONS: Annual TB symptom reminders as currently used result in little direct benefit.

Determinants of non-adherence to anti-TB treatment in high income, low TB incidence settings: a scoping review.

BACKGROUND: Improving adherence to anti-TB treatment is a public health priority in high-income, low incidence (HILI) regions. We conducted a scoping review to identify reported determinants of non-adherence in HILI settings.METHODS: Key terms related to TB, treatment and adherence were used to search MEDLINE, EMBASE, Web of Science, PsycINFO and CINAHL in June 2019. Quantitative studies examining determinants (demographic, clinical, health systems or psychosocial) of non-adherence to anti-TB treatment in HILI settings were included.RESULTS: From 10,801 results, we identified 24 relevant studies from 10 countries. Definitions and methods of assessing adherence were highly variable, as were documented levels of non-adherence (0.9-89%). Demographic factors were assessed in all studies and clinical factors were frequently assessed (23/24). Determinants commonly associated with non-adherence were homelessness, incarceration, and alcohol or drug misuse. Health system (8/24) and psychosocial factors (6/24) were less commonly evaluated.CONCLUSION: Our review identified some key factors associated with non-adherence to anti-TB treatment in HILI settings. Modifiable determinants such as psychosocial factors are under-evidenced and should be further explored, as these may be better targeted by adherence support. There is an urgent need to standardise definitions and measurement of adherence to more accurately identify the strongest determinants.

Comparison of the yield of infectious virus from clones of human and simian lymphoblastoid lines transformed by Epstein-Barr virus.

Three lymphoblastoid cell lines, of human, squirrel monkey, and marmoset origin, all transformed by the same strain of Epstein-Barr virus (EBV), differed markedly in their content of infectious virus. Single cell clones were obtained from each line to learn whether these differences were dependent upon factors shared by all cells in each line or upon factors present only in a proportion of the total cell population. A total of 17 primary clones were examined: 6 human, 6 squirrel monkey, and 5 marmoset. Cloning efficiency on human placental cell feeder layers varied from 16 to 24%. EBV antiserum, present in the cloning suspension, was shown to neutralize all extracellular virus. 15 of the 17 clones released EBV as measured by the transformation assay. Titers of infectious virus released by daughter clones paralleled titers of virus in the parent line. The median virus titers from human, squirrel monkey, and marmoset clones were respectively 10(1.5), 10(3.0), and 10(4.3) 50% transforming doses per 0.2 ml. The median yield of virus from clones of the three species was, respectively, 4, 96, and 786 transforming units per 1,000 cells containing viral capsid antigen. Two nonproducer clones (one human and one squirrel monkey) did not release infectious virus after treatment with 5'-bromodeoxyuridine, or with X ray followed by co-cultivation with marmoset leukocytes. The nonproducer clones could not be superinfected by biologically active EBV. These results show that differences in production of infectious EBV among the lines tested are reflected in the majority of cells of these lines. The data imply that the mechanism for regulation of the expression of the EBV genome is cellular rather than viral in origin. There are presumably genetic differences among primate species in this regulatory process.

Tumor induction by immunologically activated murine leukemia virus.

A graft-vs.-host reaction (GVHR) was induced in young male CAF(I) and CB6F(1) mice by the administration of BALB/cJ spleen cells. A proportion of such mice subsequently developed lymphoreticular rumors. Cell-free extracts (CFEs) prepared from the reticular tissues of CAF(1) mice killed at intervals after the induction of the GVHR were tested for their capacity to produce the same tumors in a litter of syngeneic mice inoculated at birth. 12 of 29 (41.4%) such extracts were positive, causing lymphoreticular tumors in one or more littermate recipients. The positive CFEs came from donors killed at all stages of the GVHR, from tumor-bearing mice as well as from non-tumor-bearing mice. However, whereas less than 30% of CFEs from mice killed within 12 mo of GVHR induction were oncogenic, the incidence of oncogenic extracts from mice killed 12-15 mo after GVHR induction rose to 75%. None of the CFEs prepared from nine normal uninjected male CAF(1) mice killed between the ages of 8 and 18 mo transmitted tumors to recipients. CFEs prepared from CAF(1) mice with the GVHR were tested for infectious murine leukemia virus (MuLV) using the XC assay and also for complement-fixing (CF) group-specific MuLV antigen. Substantial titers of B-tropic MuLV and CF antigen were detected in at least half the extracts from mice killed 11-14 mo after GVHR induction. During the first few months of GVHR induction, MuLV titers were low and CF antigen was absent. Neither infectious MuLV nor CF antigen were detected in CFEs prepared from normal control mice. Serially passed CFEs originating from a CB6F(1) GVHR-induced RCN caused similar tumors in successive generations of syngeneic recipient mice. These lymphoreticular tumors were shown to contain infectious MuLV, CF MuLV antigen, and C-type particles. These data together provide evidence that MuLV is activated during the GVHR and that it is responsible for the eventual development of lymphoreticular tumors.

Extensively drug-resistant tuberculosis in the UK: 1995 to 2007.

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.