1Chest Clinic, Royal Blackburn Hospital, Blackburn, Lancs, BB2 3HH, UK 2Lancashire Postgraduate School of Medicine, University of Central Lancashire, Preston, Lancs, PR1 2HE, UK 3Manchester University, Oxford Road, Manchester, M13 9PL, UK 4Department of Microbiology, Royal Blackburn Hospital, Blackburn, Lancs, BB2 3HH, UK Received date: 23 Sept 2015; Accepted date: 19 October 2015; Published date: 24 October 2015.

Background: Chest Clinic in Blackburn UK, a high Tuberculosis (TB) incidence area of the United Kingdom. Methods: Retrospective analysis of a prospectively compiled database of TB notifications. The clinical characteristics and management of those cases with isonazid resistance (with or without additional streptomycin resistance) for the years 1989-2008 inclusive is described. Results: 36 patients with proven and 3 with presumed isoniazid resistance were treated, 15 with pulmonary and 21 with non-pulmonary confirmed cultures. 35 patients (92%) were treated with a regimen of nine months rifampicin and ethambutol, supplemented by two months initial pyrazinamide (2RZE/7RE). No clinical or bacteriological relapses occurred. Conclusion: This retrospective cohort study with a minimum of 12 months post treatment follow-up of all cases shows that a nine-month regimen, 2RZE/7RE with careful monitoring can be associated with satisfactory results in the treatment of isoniazid-resistant TB.

SETTING:Blackburn, Hyndburn and Ribble Valley Local Government areas of England and Wales, the former a high tuberculosis (TB) prevalence district. BACKGROUND:The incidence of tuberculosis in new entrants aged 16-34 with positive tuberculin skin tests but normal chest X-rays after initial entry is not definitely known, and was previously estimated from cross-sectional national surveys and derived data for the 2006 and 2011 NICE economic appraisals of new entrant TB screening. METHODS:New entrants aged 16-34 years predominantly from South Asia (India, Pakistan and Bangladesh), with tuberculin tests inappropriately positive for their BCG history were identified for the years 1989-2001 inclusive from a new entrant database. These entrants were compared with the current GP registration database to see if local residence could be confirmed and the local TB notification database to October 2008. Survival analysis was carried out using Kaplan-Meier survival curves and a Cox Regression model. RESULTS:Four hundred and seventy-nine such new entrants with normal initial chest X-rays were identified. Of these 402 (84%) registered with a General Practitioner in East Lancashire for a period of time and could be followed up by this study. The crude incidence density of active TB amongst these individuals with latent disease was 1297 per 100 000 person-years (95% CI; 991-1698 per 100 000 person-years). After 10 and 15 years of follow-up 13.5 and 16.3% of individuals, respectively, had progressed on to active disease. CONCLUSION:This patient-derived, rather than estimated, data shows a minimum risk of TB disease of 16.3% at 15 years. The 2006 NICE economic appraisal, suggested that treatment for latent TB infection (LTBI) was cost-effective when the incidence of clinical TB over 15 years surpassed 18% in these populations. The 2011 NICE economic appraisal reduced this to 12% active TB over 15 years, and showed that at 16% active TB over 15 years a single interferon gamma release assay was the most cost-effective strategy. Further cohort studies are urgently needed to confirm or revise the assumptions behind the 2011 NICE economic appraisal.

BACKGROUND:East Lancashire has had high rates of tuberculosis for 40 years. The ethnically diverse population is predominantly of South Asian and white origin. Drug resistance data from 1960 to 1999 indirectly suggest that no significant inter-ethnic transmission has occurred. This study used mycobacterial interspersed repetitive unit variable number tandem repeat (MIRU-VNTR) fingerprinting to assess clustering within and between ethnic groups.METHODS:All isolates of Mycobacterium tuberculosis from January 2001 to July 2009 from East Lancashire postcode areas were MIRU-VNTR fingerprinted. Clusters of strains with indistinguishable profiles were also assessed epidemiologically, and their MIRU-VNTR profiles compared with the UK M tuberculosis Strain Typing Database.RESULTS:332 strains were typed (63 white patients, and 269 non-white patients). 198 MIRU-VNTR profiles were identified, with 144 profiles occurring only once. The typing clustered 187 strains into 53 clusters indistinguishable at all 12 loci and these were further characterised using the exact tandem repeat loci A, B, and C. The 15 loci clustered 32/63 (50.8%) of white and 110/269 (40.9%) of non-white cases and all but nine clusters were of the same ethnicity. The nine inter-racial clusters were further assessed from an epidemiological and clinical perspective and fingerprinting using nine additional loci. Isolates within two of the clusters were further discriminated using the additional nine loci. However, the additional loci did not further discriminate the isolates in the other seven inter-racial clusters.CONCLUSIONS:MIRU-VNTR fingerprinting indicates that although there is evidence of a high rate of transmission within the South Asian sub-population, the data suggest that there is little inter-ethnic transmission.

背景和目的:调查英格兰和威尔士结核病高发地区外周淋巴结结核患者常规治疗与管理情况,分析英国胸科学会推荐的6个月化疗方案效果.方法:选择1995-2004年诊断为淋巴结结核病例进行分析.结果:共收集100例外周淋巴结结核病例资料,其中男55例,女45例;94例为南亚人;92例为颈部和锁骨上淋巴结结核,5例为腋下淋巴结结核,3例为腹股沟淋巴结结核;49例进行细针抽吸,38例抽到脓液并进行MTB培养,其中27例培养阳性;66例行淋巴结活检术.本组100例中通过培养和组织学同时确诊37例,仅经培养证实29例,仅经组织学证实26例,临床诊断8例.

BACKGROUND: The varied behaviour of tuberculous lymph nodes during TB chemotherapy can cause clinical uncertainty, resulting in prolonged courses of treatment.OBJECTIVES: To investigate whether results in routine practice in Blackburn, a high-incidence tuberculosis (TB) area in England and Wales, replicated the results of the 6-month chemotherapy trial for lymph node TB conducted by the British Thoracic Society.DESIGN: All TB cases managed at the Blackburn Chest Clinic are recorded prospectively. Patients with lymph node TB were identified over a 10-year period.RESULTS: A total of 100 patients with lymph node TB were listed in the database. Fine-needle aspiration was performed in 49 patients, while 66 underwent incisional lymph node biopsy. Culture confirmation was achieved in 60 cases. Sinus and new lymph node development was comparable between our study and the BTS trial. After cessation of treatment, 10 patients developed new/enlarged lymph nodes, but further investigations revealed that only three patients had relapsed TB.CONCLUSION: The varied behaviour of lymph node TB during and after treatment causes clinical uncertainty. Six months of chemotherapy is effective for fully susceptible TB in routine clinical practice in England. Investigation of new signs is important in differentiating patients with relapsed TB from normal varied behaviour.

Table of Contents 1.0 Summary of guidelines 2.0 Introduction 3.0 Aims of TB treatment 4.0 Diagnostic tests 5.0 Type and duration of TB treatment 6.0 Drug–drug interactions 7.0 Overlapping toxicity profiles of antiretrovirals and TB therapy 8.0 Drug absorption 9.0 When to start HAART 10.0 Immune reconstitution inflammatory syndrome (IRIS) 11.0 Directly observed therapy (DOT) 12.0 Management of relapse, treatment failure and drug resistance 13.0 Pregnancy and breast-feeding 14.0 Treatment of latent TB infection – HAART, anti-tuberculosis drugs or both? 15.0 Prevention and control of transmission 16.0 Death and clinico-pathological audit 17.0 Tables 18.0 Key points 19.0 References The guidelines have been extensively revised since the last edition in 2005. Most sections have been amended and tables updated and added. Areas where there is a need for clinical trials or data have been highlighted. The major changes/amendments are: a more detailed discussion of gamma-interferon tests; new guidance on chemopreventative therapy; a complete update of the drug interactions section and tables; an updated section on choice of nonnucleoside reverse transcriptase inhibitor (NNRTI); a revised section on when to start highly active antiretroviral therapy (HAART); a new section on isoniazid resistance and extensively drug-resistant tuberculosis (XDR-TB); guidance on the diagnosis of immune reconstitution inflammatory syndrome (IRIS); new tables for management of adverse reactions. These guidelines have been drawn up to help physicians manage adults with tuberculosis (TB)/HIV coinfection. Recommendations for the treatment of TB in HIV-infected adults are similar to those in HIV-negative adults. However, there are important exceptions which are discussed in this summary. We recommend that coinfected patients are managed by a multidisciplinary team which includes physicians with expertise in the treatment of both TB and HIV infection. We recommend using the optimal anti-tuberculosis regimen. In the majority of cases this will include rifampicin and isoniazid. In the treatment of HIV infection, patients starting HAART have an ever-greater choice of drugs. We recommend that if patients on anti-tuberculosis therapy are starting HAART then antiretrovirals should be chosen to minimize interactions with TB therapy. There will be cases in which the choice of antiretrovirals is limited by intolerance, severe toxicity or genotypic resistance. TB treatment should only be modified when drug interactions with these antiretrovirals do not allow the optimal TB regimen. In some of these cases a longer duration of TB treatment may be necessary. The gold standard for diagnosing TB is microscopy followed by culture and drug sensitivity testing. Molecular diagnostics may be valuable when acid-fast bacilli are seen on smears. Rapid confirmation, by molecular diagnostics, that acid-fast bacilli are not Mycobacterium tuberculosis may avoid unnecessary treatment and infection-control measures. We recommend rapid detection of rifampicin resistance using molecular techniques in patients whose initial assessment (e.g. recent immigrant from an area with a high prevalence of rifampicin-resistant disease) or clinical course suggests multi-drug-resistant TB (MDR-TB). These molecular tests should be used as an adjunct to standard laboratory techniques. HIV-infected individuals with latent TB infection are much more likely to progress to active TB than HIV-uninfected people. Detection and treatment of latent TB infection is therefore important, although diagnosis can be difficult. TSTs/interferon-γ release assays (IGRAs) are used to detect latent infection. They are not recommended as a diagnostic tool in suspected active TB as they only reflect previous mycobacterial exposure. Tuberculin skin testing is less useful in patients with HIV infection compared with HIV-uninfected patients, especially at low CD4 cell counts. IGRAs are newer blood assays derived from essentially M. tuberculosis-specific T cells, which are generally more sensitive than tuberculin tests for detecting both active and latent disease in HIV-negative subjects. They are also more specific in Bacillus Calmette–Guérin (BCG)-vaccinated individuals. Although there are few data regarding their performance in HIV-infected patients, especially at low blood CD4 cell counts, we believe that IGRAs may have value in detecting latent TB infection and we recommend the use of IGRAs rather than TSTs as a screening tool for latent TB. However, their precise role remains unclear and draft National Institute for Health and Clinical Excellence (NICE) guidance suggests using IGRA testing in those patients with a CD4 count >200 cells/μL, and both an IGRA and a tuberculin test in those with CD4 counts below this threshold. Although physicians can perform both tests in severely immunosuppressed patients, we believe that there are few data to support this strategy and doing this would add complexity, cost and difficulties in interpretation. The majority of the Committee believe that an IGRA test alone would be sufficient. New data would be welcome in guiding physicians in this difficult area. We recommend screening for latent infection in HIV-infected patients dependent on a risk assessment based on country of origin, blood CD4 cell count and length of time on antiretroviral therapy. In addition, all HIV-positive close contacts of people who have infectious TB should be followed up and offered chemo-preventative therapy according to NICE guidelines [1]. Active TB needs to be excluded before considering treatment of latent infection, which is usually with isoniazid monotherapy for 6 months or isoniazid/rifampicin for 3 months. Starting HAART reduces the risk of reactivation of latent TB infection and is effective at reducing the incidence of new TB. We recommend that all HIV-positive patients should be offered HAART in line with the British HIV Association (BHIVA) treatment guidelines [2]. We recommend daily TB treatment whenever possible. Treatment may be given 5 days per week, but should be intensively supervised. This option may be useful in hospital or other highly supervised settings. Three-times-per-week directly observed therapy (DOT) should only be given to patients who are stable and clinically well and where local logistics enable this to be undertaken successfully. We do not recommend twice-weekly DOT for treatment of HIV/TB coinfected patients, especially in those with CD4 counts <100 cells/μL, as it has been associated with unacceptably high rates of rifamycin resistance. In cases where multiple drug resistance is not suspected, treatment should be started with four drugs (typically rifampicin, isoniazid, pyrazinamide and ethambutol) until sensitivities are known. We recommend a 6-month treatment regimen for drug-sensitive TB outside of the central nervous system (CNS). This is usually four drugs for 2 months, followed by isoniazid and rifampicin for a further 4 months (at least 182 doses of isoniazid and rifampicin and 56 doses of pyrazinamide and ethambutol in total). In drug-sensitive TB affecting the CNS we recommend 9 months of treatment. This usually consists of four drugs for 2 months, followed by 7 months of isoniazid and rifampicin [3]. Drug-resistant disease should be treated only by specialists with experience in such cases, in line with NICE guidelines [1]. Careful attention should be paid to drug interactions between TB drugs, HAART and other therapy. Rifampicin is a powerful inducer of cytochrome 450 (CYP450) and has effects on several metabolic pathways and P-glycoprotein (PgP). Rifampicin interacts with protease inhibitors (PIs), NNRTIs, chemokine (C-C motif) receptor 5 (CCR5) antagonists, and antimicrobials such as fluconazole. Rifabutin is a less potent inducer of CYP450 and may be used as an alternative to overcome some of these difficulties (for up-to-date drug interaction data go to http://www.hiv-druginteractions.org). Toxicity profiles of antiretrovirals and anti-tuberculosis drugs overlap and make it difficult to determine the causative drug. For example, rashes occur with NNRTIs, rifampicin and isoniazid. Isoniazid and stavudine both cause peripheral neuropathy. All patients on isoniazid should take pyridoxine to try and prevent this complication. Patients with chronic liver disease have higher rates of toxicity and need more frequent monitoring of liver function tests. Drug absorption may be affected by advanced HIV disease. Rifamycin-based TB regimens should be used whenever possible. Coadministration guidance for first-line antiretrovirals is given below. There are few long-term clinical outcome data to support use of these TB/HIV drug combinations. There are no major interactions between rifampicin or rifabutin and lamivudine, emtricitabine, tenofovir, abacavir, zidovudine or didanosine. Stavudine should not be given because of the increased risk of peripheral neuropathy with concomitant TB therapy. The preferred regimen for patients who have no contraindication is: *Where combinations are not recommended, specialist HIV treatment advice should be sought. We recommend that therapeutic drug monitoring (TDM) of NNRTIs and PIs should be performed when drug regimens are complex. Drug levels of anti-tuberculosis drugs should be measured when there is clinical concern regarding absorption or response to TB therapy. Starting HAART during TB treatment is complicated by overlapping toxicities, drug interactions and immune reconstitution disease (IRD), and high pill burdens may reduce adherence. Delaying HAART may lead to prolonged or worsening immune suppression. Physicians have to balance these risks when deciding when to initiate HAART. Recent data suggest early treatment reduces morbidity and mortality. We recommend, where possible: CD4 consistently >350 cells/μL: at physician discretion; CD4 100–350 cells/μL: as soon as practicable, but can wait until after completion of 2 months of TB treatment, especially when there are difficulties with drug interactions, adherence and toxicities; CD4 <100 cells/μL: start HAART as soon as practicable after starting TB therapy. See BHIVA HIV treatment guidelines for details on starting HAART [2]. DOT is regarded as the gold standard for delivering TB treatment, but it may not be possible to deliver all elements of the DOT package. Witnessed supervision of treatment may be impracticable and it is important to remember that patient-centred management is the cornerstone of treatment success. We recommend that DOT be used in all cases of MDR-TB. Patients with TB, with or without HIV infection, who are failing treatment or who relapse despite therapy pose particular management problems and should be referred to clinical colleagues who have expertise in the management of relapse and treatment failure, especially if taking HAART concomitantly. Every hospital/trust should have a policy for the control and prevention of TB. Specific consideration should be given to prevention of transmission of TB to and from immunosuppressed patients. Further guidance is contained in [4]. Worldwide, it is estimated that 14.8% of all new TB cases in adults are attributable to HIV infection. This proportion is much greater in Africa, where 79% of all TB/HIV coinfections are found. In 2007, 456 000 people globally died of HIV-associated TB [5]. All patients with TB, regardless of their perceived risk of HIV infection, should be offered an HIV test. In the United Kingdom, an increasing number of patients with TB are coinfected with HIV. In 2003, 8.3% of adults with TB were HIV coinfected [6]. The proportion is higher in London, with coinfection rates of 17–25% [7]. In HIV coinfection the clinical and radiographic presentation of TB may be atypical. Compared with the immune-competent population, TB/HIV-infected patients with active pulmonary TB are more likely to have normal chest radiographs or to have sputum that is smear negative but culture positive [8–10]. The clinician caring for HIV-infected patients therefore needs to have a high index of suspicion for TB in symptomatic individuals, especially those born abroad. As the investigation and treatment of both TB and HIV infection require specialist knowledge, it is mandatory to involve specialists in HIV, respiratory and/or infectious diseases. These guidelines update the BHIVA guidelines from 2005 and are designed to provide a clinical framework applicable to adults in the UK coinfected with HIV and TB. These guidelines do not cover children. They do not provide advice on HIV testing in adults with newly diagnosed TB. They are based on the evidence available, but some recommendations have to rely on expert opinion until further data are published. These guidelines should be used in conjunction with: NICE: Tuberculosis: Clinical diagnosis and management of TB, and measures for its prevention and control, 2006 [1]. BHIVA guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008 [2]. Department of Health, The Interdepartmental Working Group on Tuberculosis: The Prevention and Control of Tuberculosis in the United Kingdom, 1998 [4]. NICE: Tuberculosis Clinical diagnosis and management of TB, and measures for its prevention and control, update 2010 [11]. Treatment of TB benefits the individual and also the community. The aim of treatment is: to cure the patient of TB; to minimize the transmission of M. tuberculosis to other individuals; to eliminate M. tuberculosis infection. The quality of any investigation is related to the quality of the specimen and the clinical detail provided within the request. There must therefore be close liaison with the mycobacterial laboratory. Microscopic smears of body fluids remain an essential part of TB diagnosis. Results should be available within 1 working day. Identification of mycobacteria is performed at reference centres, and is based on morphology, growth and biochemical characteristics. M. tuberculosis needs to be distinguished from other mycobacteria, for which treatment may be different and there are no infection-control concerns. Cultures are central to the confirmation and identification of the mycobacterium, and for drug susceptibility testing. More rapid results are obtained from liquid media, which usually grow M. tuberculosis in 7–28 days. Drug susceptibility tests are usually available within 10–21 days of the laboratory receipt of isolates and are performed using standard assays. When it is important to differentiate rapidly, gene probes are increasingly used in some laboratories, but are less sensitive than culture and are used mainly on respiratory specimens. Most nucleic acid amplification methods to detect M. tuberculosis are complex, labour-intensive, and technically challenging. The sensitivity and specificity estimates of commercial nucleic acid amplification tests (NAATs) are highly variable, compared with culture [12,13]. All specimens, even those negative for M. tuberculosis on polymerase chain reaction (PCR), still require culture because a negative PCR does not exclude TB and a positive PCR does not indicate the drug susceptibility profile [14,15]. However, recently a fully automated molecular test for TB identification and drug resistance testing has been evaluated on sputum samples from adult patients with TB or MDR-TB [16]. The Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA), an automated molecular test for M. tuberculosis identification and resistance to rifampin, uses a hemi-nested real-time PCR assay. This assay identifies >97% of all patients with culture-confirmed TB, including >90% of patients with smear-negative disease. The result can be available in hours. The assay has been developed as a laboratory-based and point-of-care test for developing countries, but may be useful in rapid diagnosis of TB in the United Kingdom. Currently there are no data derived from children or using nonrespiratory specimens in HIV-infected persons. Molecular tests for rifampicin resistance are useful especially when MDR-TB is suspected, as about 95% of isolates that are rifampicin resistant will also be isoniazid resistant. As MDR-TB is defined as TB resistant to at least rifampicin and isoniazid, patients with positive molecular-based rifampicin resistance should be treated as having MDR-TB until the full resistance profile from cultures is available. Tuberculin testing can identify patients with latent infection but there are high false-negative rates in HIV-positive patients, especially in those with low CD4 cell counts [17–23]. In patients with AIDS or CD4 counts <200 cells/μL, the sensitivity of the test is only 0–20%. False positives occur after BCG immunization. Some data suggest that combining IGRAs and tuberculin testing improves sensitivity [1,24]. We do not recommend the routine use of TSTs. [CII] HIV-infected individuals with latent TB infection are much more likely to progress to active TB than HIV-uninfected people [25]. Detection and treatment of latent TB infection are therefore important. Blood tests are available that measure interferon-γ release from T cells after stimulation with antigens largely specific to M. tuberculosis [such as early secreted antigen target (ESAT-6) and culture filtrate protein (CFP-10)] [26]. The current commercially available tests are T-Spot.TB (Oxford Immunotec, Abingdon, Oxfordshire, UK) [which uses enzyme-linked immunosorbent spot (ELISPOT) technology to detect the antigen-specific T cells] and QuantiFERON® Gold In-Tube (Cellestis International Pty Ltd., Chadstone, Victoria, Australia) (an enzyme-linked immunosorbent assay). Both tests are approved for the diagnosis of latent TB infection in HIV-negative individuals. There are some differences between the two tests, although in general they are unaffected by previous BCG and/or infection with most other mycobacteria (an important exception in the United Kingdom being Mycobacterium kansasii). They are not licensed for the diagnosis of active TB, though the tests may be positive here too (as they detect the host immune response to mycobacterial infection). Limited data exist regarding their performance in HIV infection, but studies suggest that interferon-γ assays are more specific than TSTs, especially in BCG-vaccinated subjects [27–31]. This is an area of ongoing research. They also appear to retain sensitivity more reliably at lower CD4 cell counts, although the lower threshold has not yet been defined [32,33]. Their advantages also include being a single blood test with no need for patient recall to ‘read’ the result and no requirement for cold-chain storage. However, the blood samples need processing within a limited time, and ‘indeterminate’ (i.e. uninterpretable) IGRA results are more common in HIV-infected subjects. They are also more costly than tuberculin tests, although this may be offset by the savings in, for instance, healthcare worker time [34]. The T-spot TB test may have an advantage over the QuantiFERON® Gold In-Tube test as the number of lymphocytes used in the test is standardized. This is a rapidly developing area but, based on current data, we suggest that IGRAs rather than TSTs are used when screening HIV-positive individuals for latent TB infection. [BIII] Where a patient is considered to have active TB, IGRA tests should not be used as the means by which the diagnosis is confirmed or refuted. If a test is performed, the result must be interpreted in light of the clinical picture, microbiological data and an understanding of the assay's limitations in this population. Most adults with previously untreated TB are given a regimen in two phases: [AII] Initial phase Two months of isoniazid, rifampicin, pyrazinamide and ethambutol. These four drugs are necessary because of the relatively high rate of isoniazid resistance in the United Kingdom, which is 7.7% overall (HPA 2007), and higher in non-White ethnic groups and those with previous treatment. If drug sensitivity testing shows M. tuberculosis sensitive to first-line agents, ethambutol can be omitted. Continuation phase Four months of isoniazid and rifampicin in most patients with drug-sensitive TB, prolonged to 7 months in some circumstances (see ‘Longer continuation phase’ [AII]). All patients taking isoniazid should be prescribed pyridoxine (vitamin B6) 10–25 mg daily. TB therapy can be given five times per week with standard doses. Although there are no formal clinical trial data, considerable clinical experience suggests that five-times-weekly DOT is equivalent to seven-times-weekly treatment, and can thus be considered as ‘daily’. [AIII] In many cases the treatment conundrum is whether the patient has Mycobacterium avium complex or M. tuberculosis and often the physician will give the standard four-drug regimen until identification. In this situation, some physicians prefer to replace rifampicin with rifabutin and add azithromycin/clarithromycin. When nontuberculous mycobacteria are identified the regimen can be modified appropriately. The continuation phase should be extended to 7 months in: patients with drug-sensitive TB whose initial phase did not include pyrazinamide; patients with cavitating pulmonary disease and who remain sputum culture positive after 2 months of treatment [35]. The total treatment duration would thus be 9 months. The continuation phase should be extended to 7–10 months in cases of CNS involvement, for instance meningitis or tuberculoma. The total treatment duration would thus be at least 9 months. It is recommended that patients receive daily therapy [36]. However, in some circumstances intermittent therapy can be given three times per week with dose modification [37,38] but must be by DOT, as one study showed a risk of acquired rifamycin resistance in patients given thrice-weekly regimens ([DII]). However, DOT was used for all doses during the intensive phase but only for one dose of three per week during the continuation phase [39]. Two strategies used in HIV-negative patients have been associated with unacceptably high relapse rates and acquired rifampicin resistance in HIV-infected patients and are not appropriate for use in this population [40–44]. [EII] These are: once-weekly isoniazid-rifapentine in the continuation phase; twice-weekly isoniazid-rifampicin or isoniazid-rifabutin in patients with CD4 counts <100 cells/μL. Rifabutin has been successfully used instead of rifampicin in treating TB in HIV-negative patients [46,47]. It can be regarded as an alternative in HIV-positive patients, especially to avoid drug interactions with rifampicin, for example with PIs (see ‘Drug–drug interactions’). Rifabutin showed similar efficacy to rifampicin in a single-blind randomized study of 50 HIV-positive patients in Uganda [48] and a cohort of 25 patients in the United States [49]. However, there is a paucity of long-term data for rifabutin in HIV-positive adults. Rifabutin is also expensive and toxicities include bone marrow suppression, uveitis and arthralgia. We therefore recommend that rifampicin remains the drug of choice whenever possible. In circumstances where rifampicin cannot be used (most commonly when boosted PIs are needed to treat HIV infection), rifabutin should be substituted. Rifapentine has a long serum half-life which theoretically allows once-weekly dosing. However if used in the initial phase of treatment of TB in HIV-negative patients, rifapentine has unacceptable 2-year microbiological relapse rates and is not recommended. Development of rifapentine resistance appears to be more frequent in TB/HIV coinfected patients [42] and at present rifapentine cannot be recommended and should not be used. [EII] There are few data regarding the interactions of rifapentine with HAART. The optimal length of TB treatment in patients coinfected with HIV is unknown. Some trials suggest that short-course therapy need not be prolonged in HIV-infected individuals [37,50,51]. A review of six studies of patients with HIV infection and three studies of patients without HIV infection given treatment for 6 months (or longer) demonstrated considerable variability in published study design, eligibility criteria, site of disease, frequency and method of dosing, and outcome definitions [52]. In the reported studies, HIV-infected patients had cure rates of 59–97%, successful treatment rates of 34–100% and relapse rates of 0–10%. In patients without HIV infection, cure rates were 62–88%, successful treatment occurred in 91–99% of patients and relapse rates were 0–3%. Although the relapse rates appeared to be higher in some studies of coinfected patients, other outcomes were comparable when 6-month regimens were used. A study from Brazil showed that TB recurrence rates were high in the HIV-infected population but that, if there was completion of initial TB therapy, use of antiretroviral therapy, and subsequent increases in CD4 cell counts, then recurrence rates were low [53]. A recent retrospective review from the United States suggested that, although there were no failures in the 6-month regimen, relapse rates were four-times higher in HIV-infected patients treated with standard rifampicin-based regimens for 6 months than in those treated for longer [36]. However, the data were generated from a relatively small subset of patients as only 17% of the HIV-positive patients and 37% of the HIV-uninfected/unknown group were given just 6 months of rifampicin-based therapy. DOT was given to 57% of patients. It may be the case that, where adherence is suboptimal, 6 months of therapy is insufficient. The other important fact is that in this study reinfection could not be distinguished from relapse. A recent meta analysis suggests that 8 months of a rifamycin-based treatment be given, but the studies examined included those in which only 2 months of rifamycin were given and in the few studies of treatment longer than 6 months the reinfection issue was not addressed [54]. Long-term randomized trials are needed to address optimal treatment duration. We recommend that, for drug-sensitive TB not involving the CNS, regimens of 6 months should be given [41,50,51,55,56]. These should include at least 182 doses of isoniazid and rifampicin, and 56 doses of pyrazinamide (see ‘Definition of completion of TB therapy’). [AII] See also ‘Intermittent therapy’ [AII] and ‘Use of rifabutin’ [BII]. In HIV-infected adults with pulmonary or pleural TB, corticosteroids do not improve survival or reduce TB recurrence [57,58] and are not generally recommended [59]. In the general population, NICE guidelines recommend steroids in cases of active meningeal or spinal cord TB [1]. At present there is insufficient evidence regarding their use in HIV-infected people. A randomized controlled trial in Vietnam showed no difference in mortality or a combined outcome of death and disability in HIV-infected people with a clinical diagnosis of TB meningitis, whether they were given dexamethasone or placebo with standard TB treatment [60]. However, there were few HIV-infected people in this study and the diagnosis of TB was confirmed microbiologically in fewer than 50% of cases. This study may therefore have missed a clinically important difference. Until more data are available we recommend that HIV-infected adults with meningeal or spinal cord TB should be given corticosteroids. [BII] NICE guidelines recommend steroids for active pericardial TB. There are limited data to support this in HIV coinfection. A small randomized controlled trial of HIV-infected adults with presumed tuberculous pericarditis treated with standard TB therapy found that prednisolone resulted in better outcomes than placebo [61]. Mortality was reduced with prednisolone compared with placebo, and improvement in raised venous pressure, hepatomegaly, ascites and physical activity occurred more rapidly. Interestingly there was no faster resolution of pericardial fluid on chest radiography or echocardiogram, and as only 38% had positive M. tuberculosis cultures, some of the subjects may not have had pericardial TB. These results should therefore be interpreted with caution. Until more data are available in HIV-positive patients, we recommend that adults with pericardial TB should be given corticosteroids. [AII] Other uses of steroids have included their use in preventing ureteric stenosis in renal TB or enlargement of, for example, a mediastinal lymph node causing collapse of a lung lobe and in management of TB-related IRIS (see ‘IRIS’). The optimal dose of adjunctive corticosteroids is not known. Rifampicin induces the liver metabolism of corticosteroids, thus increasing their plasma clearance [62]. The corticosteroid and dose used in most adult trials of TB meningitis are dexamethasone 12–16 mg/day given intravenously until the patient starts taking medicines orally; then tablets can be used. Prednisolone 60 mg/day for 3 weeks and tapered over the next 3 weeks is an alternative [63]. The British Infection Society guidelines on TB meningitis [3] suggest that adults (>14 years old) should start treatment with dexamethasone 0.4 mg/kg/24 h with a reducing course over 6–8 weeks. This works out to be a higher dose for most patients seen in the United Kingdom. Studies have shown that corticosteroids increase the risks of high blood pressure and raised blood glucose, and can cause fluid retention [57,58]. The risk of infectious complications does not seem to be increased [57,58,61], although the data for an increase in the occurrence of Kaposi's sarcoma was found in some studies but not others. Treatment for a defined number of days without accounting for the number of doses taken may result in under-treatment. Determination of whether or not treatment has been completed should therefore be based on total number of doses taken as well as duration of therapy. For example: a 6-month daily regimen (given 7 days/week) should consis

Background/setting Treatment for 3 months with rifampicin (R) and isoniazid (H) (3RH) for latent tuberculosis infection (LTBI), defined as an inappropriately positive tuberculin skin test with no clinical or x-ray evidence of disease, has been used locally since 1989. The efficacy of this regimen in children in the UK has only been studied indirectly. The long-term outcome of those children treated with 3RH, in the Chest Clinic of this high tuberculosis (TB) incidence district, has been studied to derive a more direct assessment of effectiveness.Methods All children treated with 3RH for LTBI from 1989 to 2004 inclusive were matched with the local patient administration system (PAS), GP registration and local TB notification databases. Only those persons still registered locally on PAS, or locally GP registered were then checked for subsequent TB notification.Results A total of 334 patients were identified, of whom 252 remained locally, with 82 lost to follow-up; 3 cases of clinical TB developed in the 252 (1.19%), with 3113 years observation (mean 12.35 years) giving 0.964/1000 person years (95% CI 0.199 to 2.816). Sensitivity analyses showed a 'best case' scenario of 0.727/1000 person years (95% CI 0.15 to 2.12), and if 10% of those lost to follow-up developed clinical TB of 2.66/1000 person years (95% CI 1.33 to 4.77).Conclusions Follow-up of those cases treated with 3RH, for a mean of 12.35 years, and over 3100 patient years observation, shows a rate of active TB of under 1/1000 patient years. This suggests that 3RH has very high efficacy when used to treat LTBI in children in the UK and compares favourably with the expected untreated TB rate.

BACKGROUND:Abdominal tuberculosis (ATB) is a great mimic and an important cause of morbidity. Its incidence is more common in certain groups. AIM:To review the cases of ATB in Blackburn from 1985 to 2004, with emphasis on presentation, investigation, diagnosis, treatment and follow-up. METHODS:A retrospective cases note analysis from a prospectively compiled database. RESULTS:Eighty-six cases of ATB were on a prospective database of all tuberculosis (TB) cases in Blackburn for 1985-2004 inclusive. Full case papers were available for 82 and partial data for the remaining four cases. Median age was 34.8 years, with an equal sex distribution. South Asians accounted for 91% of cases. The highest proportion of patients had peritoneal TB, and a considerable number (27%) had TB at multiple sites. CONCLUSION:The diagnosis can be difficult to make because of the varied presentation, the low percentage with positive microscopy for acid-fast bacilli and the time delay of up to several weeks for a positive TB culture. The thresholds for laparoscopy and/or laparotomy for the diagnosis were therefore very low. The diagnosis could be made rapidly by these methods, and early treatment instituted. Six months short-course chemotherapy is very effective in ATB. This should be changed, if appropriate, on the basis of drug susceptibility data.

We report 79 cases of bone and joint tuberculosis between 1988 and 2005, eight of which were in the Caucasian population and 71 in the non-white population.The diagnosis was made in the majority (73.4%) by positive bacteriology and/ or histology. The mean age at the time of diagnosis was higher in the Caucasian group at 51.5 years (28 to 66) than in the South Asian group at 36.85 years (12 to 93). Only one patient had previous BCG immunisation.The spine was the site most commonly affected (44.3%). Surgical stabilisation and/ or decompression was performed in 23% of these cases because of cord compression on imaging or the presence of neurological signs.A six-month course of chemotherapy comprising of an initial two months of rifampicin, isoniazide, pyrazinamide and sometimes ethambutol followed by four months treatment with rifampicin and isoniazide, was successful in all cases without proven drug resistance.

We report 79 cases of bone and joint tuberculosis between 1988 and 2005, eight of which were in the Caucasian population and 71 in the non-white population. The diagnosis was made in the majority (73.4%) by positive bacteriology and/or histology. The mean age at the time of diagnosis was higher in the Caucasian group at 51.5 years (28 to 66) than in the South Asian group at 36.85 years (12 to 93). Only one patient had previous BCG immunisation. The spine was the site most commonly affected (44.3%). Surgical stabilisation and/or decompression was performed in 23% of these cases because of cord compression on imaging or the presence of neurological signs. A six-month course of chemotherapy comprising of an initial two months of rifampicin, isoniazide, pyrazinamide and sometimes ethambutol followed by four months treatment with rifampicin and isoniazide, was successful in all cases without proven drug resistance.

SETTING:A local government area in North West England with a significant population of Indian subcontinent (ISC) ethnic origin and a high incidence of tuberculosis. OBJECTIVE:To assess whether return visits to the ISC are associated with an increased risk of developing clinical tuberculosis. METHODS:Analysis of data prospectively obtained from ISC patients diagnosed with TB in 1998-2002 (cases) and age and sex matched ISC patients in two local GP practices (controls). RESULTS:There is at best weak evidence of association between case status and whether individuals have had a repeat visit to the subcontinent within 3 years of notification in this cohort; odds ratio 1.26 (95% CI (0.95, 1.76)); Fishers exact test P=0.09.

Multidrug-resistant tuberculosis (MDR-TB) is an increasing global problem, with most cases arising from a mixture of physician error and patient non-compliance during treatment of susceptible TB. The extent and burden of MDR-TB varies significantly from country to country and region to region. As with TB itself, the overwhelming burden of MDR-TB is in high-burden resource-poor countries. The diagnosis depends on confirming the drug susceptibility pattern of isolated organisms, which is often only possible in resource-rich settings. There should be a strong suspicion of drug resistance, including MDR-TB, in persons with a history of prior treatment or in treatment failure cases. Treatment in developed countries is expensive and involves an individualized regimen based on drug susceptibility data and use of reserve drugs. In resource-poor settings a WHO retreatment regimen may be used, but increasingly the move is to a directly observed treatment based 'DOTS-plus' regimen in a supported national TB programme. However, even where such treatment is given, the outcome for patients is significantly worse than that for fully susceptible TB and has a much higher cost.

AL Pozniak, RF Miller, MCI Lipman, AR Freedman, LP Ormerod, MA Johnson, S Collins and SB Lucas, on behalf of the BHIVA Guidelines Writing Committee Chelsea and Westminster NHS Healthcare Trust, London, UK, Centre for Sexual Health and HIV Research, Department of Primary Care and Population Sciences, Royal Free and University College Medical School, University College London, London, UK, Royal Free Hospital, London, UK, Cardiff University School of Medicine, Cardiff, UK, Blackburn Royal Infirmary, Blackburn, Lancashire, UK, HIV i-Base, London, UK, Department of Histopathology, GKT School of Medicine, St Thomas’ Hospital, London, UK

New evidence-based guidance on anti-TNF-α treatment is being developed by the Joint Tuberculosis Committee of the BTS in conjunction with the British Societies of Rheumatology and Gastroenterology Anti-tumour necrosis factor (TNF) treatment for rheumatoid arthritis and Crohn’s disease has been introduced over the last few years. Infliximab (Remicade; Schering-Plough), a humanised monoclonal antibody, is licensed for the treatment of both rheumatoid arthritis1 and Crohn’s disease,2 while etanercept (Enbrel; Wyeth Laboratories), a fusion protein binding free TNF-α using the soluble portion of the TNFR-2 receptor,3 and adalimumab (Humira; Abbott Laboratories), a fully humanised monoclonal antibody,4 are licensed for treating rheumatoid arthritis. Post-marketing surveillance in the USA5 has identified cases of tuberculosis (TB) associated with infliximab use and a smaller number with etanercept. TB cases have also been reported in association with adalimumab (Humira prescribing information, Abbott Laboratories, 2002). The cases …