Management of Latent Tuberculosis Infections in Australia and New Zealand: A Review of Current Practice

Aim: To survey practices in the diagnosis and management of latent tuberculosis infection (LTBI) in Australia and New Zealand. Methods: Infectious diseases and respiratory physicians and trainees were invited to complete an online questionnaire concerning various aspects of LTBI management. Results: The questionnaire was completed by 126 clinicians self-reporting regular management of LTBI. Respondents were experienced physicians, with 95/126 (75.4%) having managed LTBI for more than 5 years. Forty-seven (37.3%) reported seeing more than 5 patients per month for assessment of LTBI. Substantial variation among clinicians was reported in relation to a number of common clinical scenarios. For instance, while 52/126 (43.7%) informed patients that the incidence of severe hepatotoxicity related to isoniazid monotherapy was 0.1–0.5%, 21/126 (15.7%) thought it was >5%. 36/126 (28.6%) clinicians would proceed with TNF-αtherapy following an indeterminate screening: interferon-γassay, while 78/126 (61.9%) would perform further investigations and 12/126 (9.5%) would initiate isoniazid therapy. Follow-up intervals during therapy varied from 1–3 monthly, with liver function testing performed routinely by 89/126 (70.6%). Conclusion: This study demonstrated a large degree of variation in clinical practice of LTBI management in Australia and New Zealand. Strategies for increasing uniformity of practice are required, including improved guidelines and physician education

The use of anti-tuberculosis therapy for latent TB infection

Tuberculosis infection is of global public health significance, with millions of incident cases each year. Many cases, particularly in low-prevalence settings, result from the reactivation of latent tuberculosis infection (LTBI); potentially acquired years prior to active disease. Up to one-third of the world’s population has been infected with LTBI, and so may be at risk for future active TB disease. A variety of antituberculosis medications and treatment regimens have now been evaluated in the management of LTBI, with the aim of eradicating tuberculosis bacilli and reducing the likelihood of subsequent reactivation disease. This article reviews LTBI therapies and their use in clinical contexts, and considers future directions for individual and population-based strategies in LTBI management

Management of Latent Tuberculosis Infections in Australia and New Zealand: A Review of Current Practice

Aim: To survey practices in the diagnosis and management of latent tuberculosis infection (LTBI) in Australia and New Zealand. Methods: Infectious diseases and respiratory physicians and trainees were invited to complete an online questionnaire concerning various aspects of LTBI management. Results: The questionnaire was completed by 126 clinicians self-reporting regular management of LTBI. Respondents were experienced physicians, with 95/126 (75.4%) having managed LTBI for more than 5 years. Forty-seven (37.3%) reported seeing more than 5 patients per month for assessment of LTBI. Substantial variation among clinicians was reported in relation to a number of common clinical scenarios. For instance, while 52/126 (43.7%) informed patients that the incidence of severe hepatotoxicity related to isoniazid monotherapy was 0.1–0.5%, 21/126 (15.7%) thought it was >5%. 36/126 (28.6%) clinicians would proceed with TNF-αtherapy following an indeterminate screening: interferon-γassay, while 78/126 (61.9%) would perform further investigations and 12/126 (9.5%) would initiate isoniazid therapy. Follow-up intervals during therapy varied from 1–3 monthly, with liver function testing performed routinely by 89/126 (70.6%). Conclusion: This study demonstrated a large degree of variation in clinical practice of LTBI management in Australia and New Zealand. Strategies for increasing uniformity of practice are required, including improved guidelines and physician education

Clinical standards for the management of adverse effects during treatment for TB

BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.CONTEXTE : Les effets indésirables (AE) du traitement de la TB sont une cause de morbidité, de mortalité et d’interruption du traitement. L’objectif de ces normes cliniques est d’encourager une meilleure pratique en matière de diagnostic et de prise en charge des AE. MÉTHODES : Ont participé 65/81 experts invités à un processus Delphi utilisant une échelle de Likert en 5 points pour évaluer des ébauches de normes. RÉSULTATS : Nous avons identifié huit normes cliniques. Chaque personne commençant un traitement antituberculeux devrait : Norme 1, être informée des AE avant et pendant le traitement ; Norme 2, être évaluée afin de détecter tout facteur susceptible d’augmenter le risque d’AE et faire l’objet d’un examen régulier afin d’identifier et de prendre en charge ces facteurs de manière proactive ; Norme 3, en cas d’AE, être évaluée avec soin et tenir compte d’éventuelles réactions allergiques ou d’hypersensibilité ; Norme 4, recevoir des soins appropriés pour minimiser la morbidité et la mortalité associées aux AE ; Norme 5, reprendre les médicaments antituberculeux après un AE grave selon un protocole standardisé avec une surveillance active de l’innocuité des médicaments ; Norme 6, les agents de santé doivent être formés aux AE, y compris à la manière de conseiller les personnes qui suivent un traitement antituberculeux, ainsi qu’à la surveillance et à la prise en charge actives des AE ; Norme 7 : tous les nouveaux médicaments et schémas antituberculeux doivent faire l’objet d’une surveillance active des AE et d’une notification ; et Norme 8 : les lacunes en matière de connaissances identifiées grâce à la surveillance active des AE doivent être systématiquement comblées par la recherche clinique. CONCLUSION : Ces normes fournissent une approche centrée sur la personne et fondée sur le consensus afin de minimiser l’impact des AE pendant le traitement de la TB

Critical Consideration of Tuberculosis Management of Papua New Guinea Nationals and Cross-Border Health Issues in the Remote Torres Strait Islands, Australia

The international border between Australia and Papua New Guinea (PNG) serves as a gateway for the delivery of primary and tertiary healthcare for PNG patients presenting to Australian health facilities with presumptive tuberculosis (TB). An audit of all PNG nationals with presumptive TB who presented to clinics in the Torres Strait between 2016 and 2019 was conducted to evaluate outcomes for PNG patients and to consider the consistency and equity of decision-making regarding aeromedical evacuation. We also reviewed the current aeromedical retrieval policy and the outcomes of patients referred back to Daru General Hospital in PNG. During the study period, 213 PNG nationals presented with presumptive TB to primary health centres (PHC) in the Torres Strait. In total, 44 (21%) patients were medically evacuated to Australian hospitals; 26 met the evacuation criteria of whom 3 died, and 18 did not meet the criteria of whom 1 died. A further 22 patients who met the medical evacuation criteria into Australia were referred to Daru General Hospital of whom 2 died and 10 were lost to follow-up. The cross-border movement of people from PNG into Australia is associated with an emergent duty of care. Ongoing monitoring and evaluation of patient outcomes are necessary for transparency and justice

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Methods used in the spatial analysis of tuberculosis epidemiology: a systematic review

Background: Tuberculosis (TB) transmission often occurs within a household or community, leading to heterogeneous spatial patterns. However, apparent spatial clustering of TB could reflect ongoing transmission or co-location of risk factors and can vary considerably depending on the type of data available, the analysis methods employed and the dynamics of the underlying population. Thus, we aimed to review methodological approaches used in the spatial analysis of TB burden. Methods: We conducted a systematic literature search of spatial studies of TB published in English using Medline, Embase, PsycInfo, Scopus and Web of Science databases with no date restriction from inception to 15 February 2017. The protocol for this systematic review was prospectively registered with PROSPERO (CRD42016036655). Results: We identified 168 eligible studies with spatial methods used to describe the spatial distribution (n = 154), spatial clusters (n = 73), predictors of spatial patterns (n = 64), the role of congregate settings (n = 3) and the household (n = 2) on TB transmission. Molecular techniques combined with geospatial methods were used by 25 studies to compare the role of transmission to reactivation as a driver of TB spatial distribution, finding that geospatial hotspots are not necessarily areas of recent transmission. Almost all studies used notification data for spatial analysis (161 of 168), although none accounted for undetected cases. The most common data visualisation technique was notification rate mapping, and the use of smoothing techniques was uncommon. Spatial clusters were identified using a range of methods, with the most commonly employed being Kulldorff's spatial scan statistic followed by local Moran's I and Getis and Ord's local Gi(d) tests. In the 11 papers that compared two such methods using a single dataset, the clustering patterns identified were often inconsistent. Classical regression models that did not account for spatial dependence were commonly used to predict spatial TB risk. In all included studies, TB showed a heterogeneous spatial pattern at each geographic resolution level examined. Conclusions: A range of spatial analysis methodologies has been employed in divergent contexts, with all studies demonstrating significant heterogeneity in spatial TB distribution. Future studies are needed to define the optimal method for each context and should account for unreported cases when using notification data where possible. Future studies combining genotypic and geospatial techniques with epidemiologically linked cases have the potential to provide further insights and improve TB control

Structure guided prediction of Pyrazinamide resistance mutations in pncA

Abstract: Pyrazinamide plays an important role in tuberculosis treatment; however, its use is complicated by side-effects and challenges with reliable drug susceptibility testing. Resistance to pyrazinamide is largely driven by mutations in pyrazinamidase (pncA), responsible for drug activation, but genetic heterogeneity has hindered development of a molecular diagnostic test. We proposed to use information on how variants were likely to affect the 3D structure of pncA to identify variants likely to lead to pyrazinamide resistance. We curated 610 pncA mutations with high confidence experimental and clinical information on pyrazinamide susceptibility. The molecular consequences of each mutation on protein stability, conformation, and interactions were computationally assessed using our comprehensive suite of graph-based signature methods, mCSM. The molecular consequences of the variants were used to train a classifier with an accuracy of 80%. Our model was tested against internationally curated clinical datasets, achieving up to 85% accuracy. Screening of 600 Victorian clinical isolates identified a set of previously unreported variants, which our model had a 71% agreement with drug susceptibility testing. Here, we have shown the 3D structure of pncA can be used to accurately identify pyrazinamide resistance mutations. SUSPECT-PZA is freely available at: http://biosig.unimelb.edu.au/suspect_pza/

Modelling the effect of short-course multidrug-resistant tuberculosis treatment in Karakalpakstan, Uzbekistan

Background: Multidrug-resistant tuberculosis (MDR-TB) is a major threat to global TB control. MDR-TB treatment regimens typically have a high pill burden, last 20 months or more and often lead to unsatisfactory outcomes. A 9-11 month regimen with seven antibiotics has shown high success rates among selected MDR-TB patients in different settings and is conditionally recommended by the World Health Organization. Methods: We construct a transmission-dynamic model of TB to estimate the likely impact of a shorter MDR-TB regimen when applied in a low HIV prevalence region of Uzbekistan (Karakalpakstan) with high rates of drug resistance, good access to diagnostics and a well-established community-based MDR-TB treatment programme providing treatment to around 400 patients. The model incorporates acquisition of additional drug resistance and incorrect regimen assignment. It is calibrated to local epidemiology and used to compare the impact of shorter treatment against four alternative programmatic interventions. Results: Based on empirical outcomes among MDR-TB patients and assuming no improvement in treatment success rates, the shorter regimen reduced MDR-TB incidence from 15.2 to 9.7 cases per 100,000 population per year and MDR-TB mortality from 3.0 to 1.7 deaths per 100,000 per year, achieving comparable or greater gains than the alternative interventions. No significant increase in the burden of higher levels of resistance was predicted. Effects are probably conservative given that the regimen is likely to improve success rates. Conclusions: In addition to benefits to individual patients, we find that shorter MDR-TB treatment regimens also have the potential to reduce transmission of resistant strains. These findings are in the epidemiological setting of treatment availability being an important bottleneck due to high numbers of patients being eligible for treatment, and may differ in other contexts. The high proportion of MDR-TB with additional antibiotic resistance simulated was not exacerbated by programmatic responses and greater gains may be possible in contexts where the regimen is more widely applicable