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.

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 12 604 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.

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.

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.

Treatment interruptions and inconsistent supply of anti-tuberculosis drugs in the United Kingdom.

SETTING: National Health Service (NHS) centres treating tuberculosis (TB) in the United Kingdom. OBJECTIVES: To describe NHS TB treatment centres' experience of obtaining anti-tuberculosis drugs to treat drug-susceptible and drug-resistant TB between 2007 and 2009. In particular: 1) any difficulties experienced in obtaining different drugs; 2) resulting interruptions or alterations in the prescribed regimen; 3) availability of paediatric formulations; and 4) resources available to identify and manage drug shortages. DESIGN: Questionnaires were sent to pharmacists at 168 treatment centres. RESULTS: Of the 77 (46%) treatment centres that responded, 63% (48/77) reported difficulties in obtaining anti-tuberculosis drugs. Consequently, 27% had to interrupt the prescribed treatment regimen at least once, whilst 19% had to alter the regimen. Of 55 centres treating multidrug-resistant tuberculosis, 36% reported difficulties obtaining second-line drugs, 16% had to interrupt the prescribed treatment regimen at least once and 5% had to alter the regimen. A lack of licensed liquid formulations for children resulted in 26% of treatment centres using unlicensed, variable-strength liquids and locally prepared suspensions. CONCLUSIONS: Difficulties obtaining drugs to treat both drug-susceptible and drug-resistant disease are common in the UK. There are particular risks for children. Our data identify an urgent need for national strategic guidance to ensure a consistent and reliable supply of anti-tuberculosis drugs.

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.

Radiological cavitation, sputum mycobacterial load and treatment response in pulmonary tuberculosis.

SETTING: Royal Free Hospital, London. OBJECTIVE: To investigate the relationship between sputum mycobacterial load, assessed by time to positivity (TTP) in liquid culture, radiological cavitation and change in sputum bacterial load in response to anti-tuberculosis treatment. DESIGN: The study was conducted on 95 patients treated for sputum culture-positive pulmonary tuberculosis (TB), with pre-treatment TTP and baseline chest X-ray (CXR). Of these, 31 had chest computed tomography scans assessed for number and volume of cavities. The microbiological treatment response was measured in 56 patients with serial TTP, and related to baseline radiological cavitation. RESULTS: Cavitation was present in 48% of patients, and was associated with a shorter TTP at baseline (P < 0.001). Patients with more cavities and greater total cavitary volume had a shorter TTP (P < 0.001 for both). No difference was demonstrated in the rate of change in TTP on treatment (P = 0.36) between patients with and without cavities. CONCLUSION: This study confirms that cavitation is associated with higher baseline sputum mycobacterial load. The rate of decline in bacterial load in response to treatment is similar in patients with and without radiologically demonstrable cavities, suggesting that response to, and hence duration of, effective treatment may be predicted by the initial number of organisms present in the sputum.

Think TB! Is the diagnosis of pulmonary tuberculosis delayed by the use of antibiotics?

SETTING: Effective tuberculosis (TB) control requires prompt diagnosis of infectious cases through early suspicion of pulmonary TB in all subjects with suspected respiratory infection. OBJECTIVE: To test our hypothesis that prior antibiotic treatment for presumed bacterial infection leads to a delay in diagnosing TB in a European country with low TB incidence. DESIGN: Adults with culture-confirmed pulmonary TB at a single metropolitan centre were assessed for the impact of any previous antibiotic treatment on symptoms and the time to starting specific anti-tuberculosis treatment. RESULTS: Of 83 patients, 42 (51%) received antibiotics prior to TB diagnosis, with symptomatic improvement reported in 20 of the 42 (48%) patients. This was unrelated to specific drug class. Although the median time to diagnosis in subjects receiving antibiotics was prolonged (P=0.001), this was not predicted by treatment response. In 94% of cases, the initial chest radiograph was suggestive of TB infection. CONCLUSION: Patients receiving antibiotics prior to TB confirmation experience a process-related delay in starting treatment. To minimise the risk of ongoing TB transmission, we propose that clinicians should include TB in their differential diagnosis and initiate simple, TB-focused investigations early on in the diagnostic process.

How good are systemic symptoms and blood inflammatory markers at detecting individuals with tuberculosis?

SETTING: The diagnosis of tuberculosis (TB) may be rejected in the absence of symptoms such as fever, sweats or weight loss. OBJECTIVES: To determine how frequently these features and blood test evidence of inflammation were absent in individuals with TB. METHODS: Prospective cohort study of 175 unselected subjects diagnosed with TB at a UK TB service between 2003 and 2006. RESULTS: Eight (5%) subjects identified by screening and 24 (14%) without culture confirmation were excluded. Of the remaining 143, fever, sweats or weight loss were absent in respectively 37%, 39% and 38%. All three symptoms were absent in 25%. In 88 subjects with pulmonary disease, all three symptoms were absent in 20% (10% of smear-positive cases). Overall, C-reactive protein was normal in 15%, erythrocyte sedimentation rate in 21% and lactate dehydrogenase in 55%. In a multivariable model, factors associated with absent symptoms included drug-resistant TB (adjusted odds ratio [aOR] 3.58, P = 0.004) and female sex (aOR 3.15, P = 0.004). CONCLUSIONS: In our population, TB, including pulmonary disease, frequently presented without fever, sweats or weight loss and with normal blood inflammatory markers. This information is of as much relevance to policy makers seeking to improve active case detection as to clinicians and the general public.

Clinical application of a rapid lung-orientated immunoassay in individuals with possible tuberculosis.

BACKGROUND: Immunological ex vivo assays to diagnose tuberculosis (TB) have great potential but have largely been blood-based and poorly evaluated in active TB. Lung sampling enables combined microbiological and immunological testing and uses higher frequency antigen-specific responses than in blood. METHODS: A prospective evaluation was undertaken of a flow cytometric assay measuring the percentage of interferon-gamma synthetic CD4+ lymphocytes following stimulation with purified protein derivative of Mycobacterium tuberculosis (PPD) in bronchoalveolar lavage fluid from 250 sputum smear-negative individuals with possible TB. A positive assay was defined as >1.5%. RESULTS: Of those who underwent lavage and were diagnosed with active TB, 95% (106/111) had a positive immunoassay (95% CI 89% to 98%). In 139 individuals deemed not to have active TB, 105 (76%) were immunoassay negative (95% CI 68% to 82%). Of the remaining 24% (34 cases) with a positive immunoassay, a substantial proportion had evidence of untreated TB; in two of these active TB was subsequently diagnosed. Assay performance was unaffected by HIV status, disease site or BCG vaccination. In culture-positive pulmonary cases, response to PPD was more sensitive than nucleic acid amplification testing (94% vs 73%). The use of early secretory antigen target-6 (ESAT-6) responses in 71 subjects was no better than PPD, and 19% of those with culture-confirmed TB and a positive PPD immunoassay had no detectable response to ESAT-6. CONCLUSIONS: These findings suggest that lung-orientated immunological investigation is a potentially powerful tool in diagnosing individuals with sputum smear-negative active TB, regardless of HIV serostatus.

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 (p = 0.008). Peripheral neuropathy and persistent vomiting were more common in co-infected patients (p<0.001; p = 0.006), 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; p = 0.74). 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.

Virological response to highly active antiretroviral therapy is unaffected by antituberculosis therapy.

We compared 156 human immunodeficiency virus (HIV)-infected patients who had tuberculosis with control populations of similar size. Of 111 patients with HIV infection and tuberculosis who received highly active antiretroviral therapy (HAART) and therapy for tuberculosis concurrently, 92 (83%) achieved or maintained virus loads of <50 copies/mL, and 99 (89%) achieved or maintained a >or=2 log10 reduction in virus load after 6 months. Virological response and changes in CD4 cell count were equivalent to those in 111 matched HIV-infected subjects without tuberculosis starting HAART. Tuberculosis recurrence rates were similar to those found in an HIV-uninfected population of 156 subjects (3% and 1%, respectively). Treatment for HIV and tuberculosis does not compromise outcomes for either disease.