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.

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.

The interpretation of nucleic acid amplification tests for tuberculosis: do rapid tests change treatment decisions?

OBJECTIVES: To describe changes in treatment decisions after receipt of nucleic acid amplification (NAA) test for the diagnosis of M. tuberculosis. METHODS: Retrospective notes review of treatment decisions in patients receiving a NAA test for suspected pulmonary or non-pulmonary tuberculosis at the Royal Free Hospital in London between March 2001 and February 2002. Notes were sought on a 50% random sample of patients with both smear and NAA negative specimens and all patients with other specimen results. RESULTS: Two hundred and fifty patients were tested with NAA; clinical details were obtained on 138; 61 were ever treated. Seventeen (17/18) smear-negative patients were started on treatment after a positive NAA; none of six smear-negative patients treated prior to a negative NAA result had treatment stopped. Seventeen (17/21) smear-positive patients were treated prior to NAA result and all were NAA positive; treatment was delayed in four smear-positive patients until receipt of an NAA and one NAA-negative patient was not treated. CONCLUSIONS: In routine practice a positive test in an untreated smear-negative patient leads to decision to treat in almost all, but the proportion testing positive is low (8% or 17/219). In patients already on treatment negative tests did not lead to decisions to stop.

Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection.

BACKGROUND: It has been suggested that deterioration of tuberculosis (TB) during appropriate treatment, termed a paradoxical reaction (PR), is more common and severe in HIV positive individuals on highly active antiretroviral therapy (HAART). METHOD: A study was undertaken to determine the frequency of PR and its associated features in a population of HIV+TB+ patients and a similar sized group of HIV-TB+ individuals. RESULTS: PR occurred in 28% of 50 HIV+TB+ patients and 10% of 50 HIV-TB+ patients. Disseminated TB was present in eight of 13 HIV+TB+ patients and four of five HIV-TB+ patients with PR. In 28 HIV+TB+ patients starting HAART, PR was significantly associated with commencing HAART within 6 weeks of starting antituberculosis treatment (p = 0.03) and was more common in those with disseminated TB (p = 0.09). No association was found between development of PR and baseline CD4 count or CD4 response to HAART. CONCLUSIONS: PR is common in HIV infected and uninfected individuals with TB. Early introduction of HAART and the presence of disseminated TB appear to be important in co-infected patients.