M Lipman

Adverse events and treatment interruption in tuberculosis patients with and without HIV co-infection

Background: Serious treatment associated adverse events are thought to occur more frequently in individuals with tuberculosis (TB) who are co-infected with HIV. A study was undertaken to assess the frequency of serious (grade III/IV) adverse events and interruption of anti-TB treatment in the era of effective antiretroviral therapy. Methods: The incidence of serious adverse events was retrospectively compared in 312 individuals treated for TB, 156 of whom were co-infected with HIV. Results: 111 HIV infected individuals (71%) received highly active antiretroviral therapy at the same time as anti-TB treatment. Serious adverse events were recorded in 40% HIV infected and 26% HIV uninfected individuals (pu200a=u200a0.008). Peripheral neuropathy and persistent vomiting were more common in co-infected patients (p<0.001; pu200a=u200a0.006), although all cause interruption of anti-TB treatment occurred with similar frequency in the two groups (13% in HIV infected patients and 15% in HIV uninfected patients; pu200a=u200a0.74). In 85% of HIV infected patients and 87% of HIV uninfected individuals this was due to hepatotoxicity, which typically presented within 2 months of starting treatment. The median delay in restarting treatment was 4 weeks, so most individuals required full TB re-treatment. Conclusion: Despite a greater rate of serious (grade III/IV) adverse events among HIV infected individuals, discontinuation of anti-TB treatment occurred with a similar frequency in HIV infected and HIV uninfected individuals.

Active case finding for pulmonary tuberculosis using mobile digital chest radiography: an observational study

BACKGROUNDnMobile digital chest radiography (CXR) is used routinely to screen for pulmonary tuberculosis (PTB) in London among homeless populations, persons accessing drug treatment services and prisoners.nnnOBJECTIVEn1) To establish the sensitivity and specificity of mobile digital CXR, and 2) to test the hypothesis that actively identified cases have reduced odds of sputum smear positivity vs. those presenting passively to health care services from the same populations.nnnMETHODSnSensitivity and specificity were calculated using a gold standard comparator of culture-confirmed cases of PTB reported to the national surveillance system within 90 days of screening. Logistic regression was used to determine whether actively detected cases had reduced odds of smear positivity compared to passively detected cases after adjustment for confounding.nnnRESULTSnThe intervention had a sensitivity of 81.8% (95%CI 64.5-93.0) and a specificity of 99.2% (95%CI 99.1-99.3). After adjusting for confounding, there was evidence that cases identified through screening were less likely to be smear-positive than passively identified cases (OR 0.34, 95%CI 0.14-0.85; likelihood ratio test P = 0.022).nnnCONCLUSIONnDigital CXR achieves a high level of sensitivity and specificity in an operational setting; targeted mobile radiographic screening can reduce the risk of onward transmission by identifying cases before they become infectious.

Isoniazid resistant tuberculosis: a cause for concern?

The drug isoniazid (INH) is a key component of global tuberculosis (TB) control programmes. It is estimated, however, that 16.1% of TB disease cases in the former Soviet Union countries and 7.5% of cases outside of these settings have non-multidrug-resistant (MDR) INH resistance. Resistance has been linked to poorer treatment outcomes, post-treatment relapse and death, at least for specific sites of disease. Multiple genetic loci are associated with phenotypic resistance; however, the relationship between genotype and phenotype is complex, and restricts the use of rapid sequencing techniques as part of the diagnostic process to determine the most appropriate treatment regimens for patients. The burden of resistance also influences the usefulness of INH preventive therapy. Despite seven decades of INH use, our knowledge in key areas such as the epidemiology of resistant strains, their clinical consequences, whether tailored treatment regimens are required and the role of INH resistance in fuelling the MDR-TB epidemic is limited. The importance of non-MDR INH resistance needs to be re-evaluated both globally and by national TB control programmes.

Treatment regimens for rifampicin-resistant tuberculosis: highlighting a research gap

Treatment guidance for non-multidrug-resistant (MDR) rifampicin-resistant (RMP-R) tuberculosis (TB) is variable. We aimed to undertake a systematic review and meta-analysis of the randomised controlled trial (RCT) data behind such guidelines to identify the most efficacious treatment regimens. Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Despite 12u2009604 records being retrieved, only three studies reported treatment outcomes by regimen for patients with non-MDR RMP-R disease, preventing meta-analysis. Our systematic review highlights a substantial gap in the literature regarding evidence-based treatment regimens for RMP-R TB.

S4 Evaluation of TB peer educators—essential partners in metropolitan TB control

Background One in six of all notified tuberculosis (TB) cases in London are among homeless people, problem drug and alcohol users and prisoners (hard-to-reach). These groups are at high risk of delayed diagnosis, infectious and drug resistant TB and poor treatment outcomes. The Berlin Declaration (2007) stated that affected communities are essential partners in TB control. While initiatives involving hard-to-reach communities in HIV control have proven effective, evidence to support their contribution to TB control activities is lacking. We aimed to improve service access and uptake of TB screening among hard-to-reach groups by harnessing the authentic voice and experience of former TB patients from these affected communities. Method Seven former TB patients with a history of homelessness and drug/alcohol dependence were recruited and trained as peer educators to work alongside TB clinics and a mobile x-ray screening service. Qualitative and quantitative methods were used to evaluate their impact on service access and screening uptake. Results Peers recruited 3200 hard-to-reach clients at 101 screening sessions resulting in 45 hospital referrals between May 2009 and February 2010. Following TB peer training of homeless shelter hostel workers, screening uptake increased from 44% to 75%. Subsequent structured interviews with service users highlighted the importance of peer educators in raising TB awareness and promoting service access. Conclusion Our evaluation demonstrated that trained peer educators can improve service access and TB screening uptake in the short and medium term in hard-to-reach groups. The success of this approach argues for greater peer educator involvement in strategies to control metropolitan TB.

P160 Treating TB patients with no entitlement to social support—welcome to the social jungle

Background In the UK, TB medication is free but access to additional resources necessary for treatment completion is conditional. Patients with no recourse to public funds (NRPF), including undocumented and some European Economic Area migrants, have no rights to benefits, public housing or social care. The International Union Against Tuberculosis and Lung Disease (IUATLD) recommends that undocumented migrants with tuberculosis (TB) should receive free treatment and not be deported until completion of treatment. We used case reviews to explore how this guidance translates into current practice in London. Methods We reviewed clinical, social circumstances and treatment outcomes for 32 NRPF patients with active TB referred from September 2007 to June 2010 to Find and Treat, a pan-London multi-disciplinary project developed to strengthen TB control in hard-to-reach groups. Results The case reviews demonstrated that, while TB medication is free, lack of access to public funds severely compromises treatment access, completion and cure. Patients are unable to pay for transport to attend clinic appointments, buy food or access accommodation. Many (7/32) in fact were sleeping rough. More than a third (10/32) had resistant forms of TB, including 3 to a single drug (Isoniazid) and 7 with Multi Drug resistance (MDR). Despite close working relationships with Border Control Agencies, threat of deportation is a reality. Nine patients (28%) were lost to follow-up care, of which almost half (4/9) have never been found. Consequences included unsupervised medication, street homelessness, hospital admission (including for malnutrition) and treatment interruption and default. Conclusion Though ensuring access to free treatment, current guidance does not address the wider determinants of health in tuberculosis. This results in severe inequity of care, and poor treatment outcomes with potentially serious public health implications. Political commitment to provide for basic social needs as well as free medication for all patients is required to effectively control TB.

The Challenge of Estimating tuberculosis mortality accurately in England and Wales

BACKGROUNDnAccurate estimates of tuberculosis (TB) mortality are required to monitor progress towards the World Health Organization End TB goal of reducing TB deaths by 95% by 2035. We compared TB death data for England and Wales from the national surveillance system (Enhanced Tuberculosis Surveillance System [ETS]) and the vital registration system from the Office for National Statistics (ONS).nnnMETHODSnTB cases notified in ETS were matched to deaths in ONS (dONS) with International Classification of Diseases, Tenth Revision (ICD-10) codes indicating that TB caused/contributed to the death (A15-A19). Deaths captured in one but not both systems were assessed to identify if ONS captured all TB deaths and if there was under-notification of TB in ETS. We stratified deaths into active TB, TB sequelae, incidental deaths and not TB.nnnRESULTSnBetween 2005 and 2015, there were fewer deaths in ETS (dETS) than dONS with ICD-10 codes A15-A19 (n = 4207 vs. n = 6560); 57% of dETS were recorded as dONS and 53% of dONS were notified to ETS. A total of 9289 deaths were identified from dETS and dONS: 64% were due to active TB, 23% were TB sequelae, 6% were incidental and 7% were not TB.nnnCONCLUSIONSnTB deaths in ETS and ONS differ substantially. Almost one third of TB deaths recorded by ONS are not due to active TB; this can be amended through coding changes.

S28 Changing diagnostic pattern of hiv and tuberculosis co-infection in england, wales and northern ireland, 2000–2014

Background HIV co-infection of tuberculosis (TB) patients is associated with TB disease progression, treatment complications, and higher mortality. Over the last decade, national guidelines have encouraged earlier diagnosis of HIV infection and greater use of anti-retroviral therapy (ART). We investigated the relationship between HIV and TB diagnoses at a national level. Methods TB patients aged ≥15 years notified to Public Health England from 2000–2014 were linked to national HIV surveillance data. Amongst co-infected patients, we examined the order of TB and HIV diagnoses. Diagnoses were classed as ‘simultaneous’ if TB and HIV were diagnosed within 91 days of each other. Results 106,829 TB cases aged ≥15 years were notified to PHE between 2000 and 2014, of which 5792 (5.4%) were co-infected with HIV. The absolute number of HIV-TB diagnoses rose between 2000–2004, and then decreased from 543 (8.0%) in 2004 to 205 (3.2%) in 2014. Overall, 2,787/5,792 (49%) were diagnosed with TB and HIV simultaneously, whilst 549 (9%) were diagnosed with TB before and 2456 (42%) after HIV diagnosis. The relationship between TB and HIV diagnosis changed over time (figure 1). The absolute number of TB cases in people with known HIV rose from 75/224 (33%) in 2000 to 210/454 (46%) in 2007, then fell to 117/205 (57%) by 2014, but increased as a proportion of all HIV-TB cases from 2000 to 2014. There were corresponding declines in the proportion diagnosed simultaneously with TB and HIV from 298/543 (55%) in 2004 to 79/205 (39%) in 2014 and those first diagnosed with TB (51/224 (23%) in 2000 to 9/205 (4%) in 2014). Conclusions Within an overall decline in HIV-TB co-infection there has been a change in the pattern of co-infection. A greater proportion of cases now occur in people with known HIV infection, and fewer HIV infections are diagnosed after TB diagnosis. This may be explained by more HIV testing, including in TB clinics, resulting in earlier HIV diagnosis. However, as the number of people with HIV in the UK increases, sustained success requires better management of latent TB infection to prevent the occurrence of TB disease in people diagnosed with HIV. Abstract S28 Figure 1 First diagnosis for TB-HIV co-infected patients, 2000–2014.

S29 A randomised controlled trial comparing smartphone enabled remote video observation with direct observation of treatment for tuberculosis

Background Directly observed treatment (DOT) has been the standard of care for tuberculosis since the early 1990s. In England DOT is targeted at those considered to be at high risk of poor adherence and clinically complex patients. We report the first randomised controlled trial of smartphone-enabled video observation of treatment (VOT) for active tuberculosis compared to DOT. Methods Tuberculosis patients eligible for selective DOT in England were randomised to an offer of asynchronous VOT (daily remote observation using a smartphone app) or DOT (3 or 5 times weekly observation in community or clinic settings). Results 58% of 226 randomised patients had a history of homelessness, drug use, imprisonment, alcohol or mental health problems. Of the 112 patients randomised to an offer of VOT, 70% had over 80% of scheduled observations completed over two months (the primary outcome measure) compared to 31% of 114 patients randomised to an offer of DOT (p<0.001). The effect was, in part, due to 51% of those randomised to DOT having less than one week of observation (compared to 10% of those randomised to VOT), and so not starting treatment with their allocated regimen. VOT patients sustained high observation levels throughout treatment, whereas this declined rapidly in DOT patients. We estimate that observation of a six month course of treatment with daily VOT cost £1645 per patient compared to £5700 for five times per week DOT. Conclusions VOT is a more effective and cheaper approach to observation of tuberculosis treatment than clinic or community based DOT.

P113 Frequent co-detection of non-tuberculous mycobacteria with other microbes in a UK clinic population: what are the implications for treatment?

Introduction Non-Tuberculous Mycobacteria (NTM) are often isolated from patient samples, though their clinical relevance can be unclear. Treatment is not always effective and management decisions are usually based on repeat isolates with compatible clinical features. The presence of other micro-organisms, as well as the specific NTM itself, may be important. Here we report NTM and other microbe isolation frequency and their relationship to management decisions. Methods All NTM samples isolated from liquid culture systems between 09/05/11 and 03/04/13 at our centre were identified using hospital pathology databases. Subject’s negative mycobacterial cultures plus all positive relevant bacteria and virological isolates, as well as clinical history and progress were reviewed. Results NTM were isolated on 257 occasions from 102 patients, who provided a total of 693 samples for mycobacterial culture. Adjusting for positive samples obtained within a month of each other, there were 170 isolates - 150 of which came from 90 patients’ pulmonary samples. Common associated clinical conditions were non cystic fibrosis bronchiectasis (28, 31.1%), COPD (11, 12.2%), and HIV infection (6, 6.7%). The most frequent lung isolate was Mycobacterium avium intracellulare Complex, MAC, (47.8%), followed by M. fortuitum(14.4%), M. gordonae (10%), and M. kansasii (8.9%). Seven (7.8%) patients had multiple NTM species identified. 40 (44.4%) of the pulmonary patients also had bacteria or fungi isolated from lung samples. Pseudomonas sp. were present in 12 (13.3%), Haemophilus influenzae in 10 (11.1%), and Staphylococcus aureus in 6 (6.7%) patients. To date, 68.9% have not received regular anti-microbial therapy. 19 (21.1%) are on long term anti-bacterials, and 7 (7.8%) are being treated with specific anti-NTM therapy (5 of these MAC). Over the two year period 483 pulmonary samples have been tested for mycobacteria; at a mean frequency of 5.4 samples per patient, with approximately one in three being NTM positive. Conclusion Different microbes are frequently isolated on serial lung sampling from patients with NTM. Clinicians often utilise a treatment strategy that focuses on organisms other than NTM to control symptoms. The value of this approach requires longer term assessment, but highlights the importance of systematic, microbial surveillance cultures in pulmonary NTM management.