A systematic review of potential biomarkers for bacterial burden and treatment efficacy assessment in TB platform-based clinical trials.

Adaptive platform trials can be more efficient than classic trials for developing new treatments. Moving from culture-based to simpler- or faster-to-measure biomarkers as efficacy surrogates may enhance this advantage. We performed a systematic review of treatment efficacy biomarkers in adults with tuberculosis. Platform trials can span different development phases. We grouped biomarkers as: α, bacterial load estimates used in phase 2a trials; ß, early and end-of treatment endpoints, phase 2b-c trials; γ, post-treatment or trial-level estimates, phase 2c-3 trials. We considered as analysis unit (biomarker entry) each combination of biomarker, predicted outcome, and their respective measurement times or intervals. Performance metrics included: sensitivity, specificity, area under the receiver-operator curve (AUC), and correlation measures, ,and classified as poor, promising, or good. Eighty-six studies included 22864 participants. From 1356 biomarker entries, 318 were reported with the performance metrics of interest, with 103 promising and 41 good predictors. Group results: α, mycobacterial RNA and Lipoarabinomannan in sputum, and host metabolites in urine; ß, mycobacterial RNA and host transcriptomic or cytokine signatures for early treatment response; γ, host transcriptomics for recurrence. A combination of biomarkers from different categories could help designing more efficient platform trials. Efforts to develop efficacy surrogates should be better coordinated.

A cost-effectiveness evaluation of latent tuberculosis infection screening of a migrant population in Malaysia.

To estimate the costs and benefits of screening for latent tuberculosis infection (LTBI) in a migrant population in Malaysia. An economic model was developed from a Malaysian healthcare perspective to compare QuantiFERON-TB Gold Plus (QuantiFERON) with the tuberculin skin test (TST). A decision tree was used to capture outcomes relating to LTBI screening followed by a Markov model that simulated the lifetime costs and benefits of the patient cohort. The Markov model did not capture the impact of secondary infections. The model included an R shiny interactive interface to allow adaptation to other scenarios and settings. QuantiFERON is both more effective and less costly than TST (dominant). Compared with QuantiFERON, the lifetime risk of developing active TB increases by approximately 40% for TST due to missed LTBI cases during screening (i.e. a higher number of false negative cases for TST). For a migrant population in Malaysia, QuantiFERON is cost-effective when compared with TST. Further research should consider targeted LTBI screening for migrants in Malaysia based on common risk factors.

A systematic review of cost-utility analyses of screening methods in latent tuberculosis infection in high-risk populations.

BACKGROUND: The World Health Organisation (WHO) recommends that testing and treatment for latent tuberculosis infection (LTBI) should be undertaken in high-risk groups using either interferon gamma release assays (IGRAs) or a tuberculin skin test (TST). As IGRAs are more expensive than TST, an assessment of the cost-effectiveness of IGRAs can guide decision makers on the most appropriate choice of test for different high-risk populations. This current review aimed to provide the most up to date evidence on the cost-effectiveness evidence on LTBI testing in high-risk groups-specifically evidence reporting the costs per QALY of different testing strategies. METHODS: A comprehensive search of databases including MEDLINE, EMBASE and NHS-EED was undertaken from 2011 up to March 2021. Studies were screened and extracted by two independent reviewers. The study quality was assessed using the Bias in Economic Evaluation Checklist (ECOBIAS). A narrative synthesis of the included studies was undertaken. RESULTS: Thirty-two studies reported in thirty-three documents were included in this review. Quality of included studies was generally high, although there was a weakness across all studies referencing sources correctly and/or justifying choices of parameter values chosen or assumptions where parameter values were not available. Inclusions of IGRAs in testing strategies was consistently found across studies to be cost-effective but this result was sensitive to underlying LTBI prevalence rates. CONCLUSION: While some concerns remain about uncertainty in parameter values used across included studies, the evidence base since 2010 has grown with modelling approaches addressing the weakness pointed out in previous reviews but still reaching the same conclusion that IGRAs are likely to be cost-effective in high-income countries for high-risk populations. Evidence is also required on the cost-effectiveness of different strategies in low to middle income countries and countries with high TB burden.

Accuracy of interferon gamma release assays for the COVID-19 immunity assessment.

Emerging evidence suggests that T-cells play a significant role in COVID-19 immunity both in the context of natural infection and vaccination. Easy to use IGRA assays including QFN SARS are considered attractive alternatives to more "traditional" but laborious methods for detection of SARS-CoV-2-specific T-cell responses. In our Letter we are proposing explanations to an apparently lower than expected T-cell responses (44 % reactive individuals) reported by Krüttgen et al in a small cohort of healthy double vaccinated individuals. These results could have been affected by reporting raw optical density values instead of calculated Interferon-É£ concentrations which is supported by unexpectedly low mitogen responses in healthy individuals. This study highlights an importance of adhering to good laboratory practice principles as well as overall importance of accurate T-cell immunity assessment using IGRA assays.

Equivalence of the GeneXpert System and GeneXpert Omni System for tuberculosis and rifampicin resistance detection.

A laboratory validation study was conducted to assess the equivalence of Xpert MTB/RIF Ultra testing on the GeneXpert System and the GeneXpert Omni System ('Omni') for tuberculosis and rifampicin resistance. High concordance of the two devices was demonstrated for well-characterized clinical samples as well as control materials, with controls tested on Omni at normal and challenging environmental conditions (i.e. 35°C, 90% relative humidity). Equivalence of the Cts for all probes was also shown. Equivalence was demonstrated for the Omni and GeneXpert devices for tuberculosis and rifampicin resistance detection for a diverse range of clinical specimens and environmental conditions.

Is deployement of diagnostic test alone enough? Comprehensive package of interventions to strengthen TB laboratory network: three years of experience in Burkina Faso.

BACKGROUNDS: The laboratory plays a critical role in tuberculosis (TB) control by providing testing for diagnosis, treatment monitoring, and surveillance at each level of the health care system. Weak accessibility to TB diagnosric services still represents a big concern in many limited resources' countries. Here we report the experience of Burkina Faso in implementing a comprehensive intervention packages to strengthen TB laboratory capacity and diagnostic accessibility. METHODS: The intervention lasted from October 2016 to December 2018 and focused on two main areas: i) development of strategic documents and policies; ii) implementation of TB diagnostic technology. National TB laboratory data were collected between 2016 and 2018 and evaluated according to five programmatic TB laboratory indicators: i) Percentage of notified new and relapse TB cases with bacteriological confirmation; ii) Percentage of notified new and relapse TB cases tested by Xpert MTB/RIF; iii) Percentage of notified, bacteriologically confirmed TB cases with a drug susceptibility testing (DST) result for rifampin; iv) Percentage of notified MDR-TB cases on the estimated number of MDR-TB cases; v) The ration between the number of smear microscopy and Xpert MTB/RIF tests. We compared these indicators between a 1 year (2016-2017) and 2 years (2016-2018) timeframe. RESULTS: From 2016 to 2018, the percentage of bacteriologically confirmed cases increased from 67 to 71%. The percentage of new and relapse TB cases notified tested by Xpert MTB/RIF increased from 18% in 2016 to 46% in 2018 and the percentage of bacteriologically confirmed cases with an available DST result for rifampicin increased from 27% in 2016 to 66% in 2018.. The percentage of notified MDR-TB cases on the estimated number of MDR-TB cases in 2018 increased from 43% in 2016 to 78% in 2018. In 2018, the ratio between the number of smear microscopy and Xpert MTB/RIF tests decreased from 53% in 2016 to 21% in 2018. CONCLUSION: We demonstrated that the implementation of a comprehensive package of laboratory strengthening interventions led to a significant improvement of all indicators. External technical assistance played a key role in speeding up the TB laboratory system improvement process.

Tuberculosis treatment outcomes in a rural area of Senegal: a decade of experience from 2010 to 2019 by StopTB Italia.

Background: Tuberculosis (TB) unevenly affects individuals across the globe, especially in rural areas of low-income countries. Aim of the study was to assess the impact of social protection to increase TB awareness on treatment outcomes among TB patients in a rural area of Senegal. Materials & methods: The study, conducted in Fimela district (Senegal) from 1 January 2010 to 31 December 2019 and the intervention started from 31 January 2013, includes activities to increase awareness, active case finding, active follow-up and social protection. Results: Overall, 435 subjects - mainly male and young - were included in the analysis. Among TB cases, 94% had pulmonary involvement, 87% had no previous TB history, and 6% resulted positive HIV. Improved outcome was observed once intervention began (from 71 to 91%, p < 0.001); whereas mortality decreased (from 15 to 5%; p < 0.001), especially for those HIV co-infected for whom TB mortality rate dropped from 70 to 29%. Conclusion: After beginning the cooperation program, TB treatment success increased as a result of the decline of mortality, especially in people living with HIV.

Applying a Standardized Approach to Strengthen Performances of GeneXpert Networks programme: lessons learned from Burkina Faso, 2019.

GeneXpert scale-up is a historic step in the process of tuberculosis (TB) elimination. However, the global roll-out of the test has highlighted gaps that have limited its impact on the TB care cascade. Here we report the description of an innovative GeneXpert network strengthening tool called Applying a Standardized Approach to Strengthen Performances of GeneXpert Networks (ASAP-GxNet) and highlight results and challenges during implementation of the pilot in Burkina Faso. ASAP-GxNet is a 6-month competency-based programme involving an innovative GeneXpert assessment tool as well as a series of short courses and projects designed to qualitatively improve the network while strengthening the capacity of the national GeneXpert focal point to oversee the network. Progress of the GeneXpert network is measured before and at the end of the programme and is rated using a star system (0 to 4 stars). In Burkina Faso, implementation of the ASAP-GxNet programme resulted in improved management of the national GeneXpert network with a 21% increase in points from the start to the end of the programme. To our knowledge, ASAP-GxNet is the first programme to give an overall picture of the quality of GeneXpert networks and to investigate performance in terms of management behaviour. ASAP-GxNet has been developed to help national TB programmes coordinate efforts and needs and highlights the expected achievements of the GeneXpert network.

Advantages and Challenges of Tailored Regimens for Drug-Resistant Tuberculosis: A StopTB Italia Look into the Future.

The emerge of drug-resistant tuberculosis (TB) strain in recent decades is hampering the efforts of the international community to eliminate the disease worldwide. The World Health Organization (WHO) has drafted many strategies to achieve this ambitious goal. In the very beginning, the aim was to standardize inadequate regimens used in many countries and, thereafter, evolved to tackle the social determinants which hinder TB elimination. However, following the path of narrowing the clinical vision to deal with TB, there is an increased need to personalize the treatment considering both patients and pathogen unique characteristics. In our narrative review, we report the advantages and the backwards in developing a method to implement the concept of precision medicine to the treatment of TB. In this dissertation, we highlight the importance to address different aspects of the diseases encompassing the host and pathogen features, as well as the needs to further implement an adequate follow-up based on the available resources. Nevertheless, many things may hamper the vision of precision medicine in TB, such as the complexity and the costs to develop novel compounds and the costs related to global-scale implementation of patient-centered follow-up. To achieve the ambitious goal of TB elimination, a radical change in TB treatment is needed in order to give a more comprehensive approach based both on patients' peculiarities and driven by drug susceptibility tests and whole-genome sequencing.

The neglected role of Faith-based Organizations in prevention and control of COVID-19 in Africa.

The COVID-19 pandemic has exposed health system weaknesses of economically wealthy countries with advanced technologies. COVID-19 is now moving fast across Africa where small outbreaks have been reported so far. There is a concern that with the winter transmission will grow rapidly. Despite efforts of African Governments to promptly establish mitigating measures, rural areas, especially in sub-Saharan Africa, risk being neglected. In those settings, faith-based and other non-governmental organizations, if properly equipped and supported, can play a crucial role in slowing the spread of COVID-19. We describe our experience in two rural health facilities in eSwatini and Ethiopia highlighting the struggle towards preparedness and the urgency of international support to help prevent a major public health disaster.

From the past, a long way to future challenges for a greater control of tuberculosis.

Tuberculosis (TB) and humans have coexisted for more than 40,000 years; however TB remains a global threat to human kind. The international community has developed new tools for early detection, but TB strains evolved acquiring resistance to first-line therapeutic drugs with increasing treatment challenges. Furthermore, TB has formed also an alliance with human immunodeficiency virus; in this way the poorest populations are most affected. The current vaccine planning activity includes 14 new vaccines against TB (11 of those in the phaseII/III) developed with different techniques. Now, more than ever, new anti-TB drugs and new anti-TB regimens are urgently required as well as universal health care and social protection in order to tackle down both hard to treat TB and the social determinants of TB. Coordinated actions and sharing of information are needed to aspire everywhere to the best clinical practices and improve quality of life of patients and their families.

MDR/XDR-TB management of patients and contacts: Challenges facing the new decade. The 2020 clinical update by the Global Tuberculosis Network.

The continuous flow of new research articles on MDR-TB diagnosis, treatment, prevention and rehabilitation requires frequent update of existing guidelines. This review is aimed at providing clinicians and public health staff with an updated and easy-to-consult document arising from consensus of Global Tuberculosis Network (GTN) experts. The core published documents and guidelines have been reviewed, including the recently published MDR-TB WHO rapid advice and ATS/CDC/ERS/IDSA guidelines. After a rapid review of epidemiology and risk factors, the clinical priorities on MDR-TB diagnosis (including whole genome sequencing and drug-susceptibility testing interpretations) and treatment (treatment design and management, TB in children) are discussed. Furthermore, the review comprehensively describes the latest information on contact tracing and LTBI management in MDR-TB contacts, while providing guidance on post-treatment functional evaluation and rehabilitation of TB sequelae, infection control and other public health priorities.

Towards tailored regimens in the treatment of drug-resistant tuberculosis: a retrospective study in two Italian reference Centres.

BACKGROUND: The increased incidence of drug-resistant TB is a major challenge for effective TB control. Limited therapeutic options and poor treatment outcomes of DR-TB may increase drug-resistance rates. The objective of the study is to retrospectively compare MDR-TB and pre-XDR-TB treatment regimens and outcomes in two large TB reference centres in Italy from January 2000 to January 2015. METHODS: A retrospective, multicentre study was conducted at the Regional TB Reference Centre Villa Marelli Institute (Milan) and at the Reference Center for MDR-TB and HIV-TB, Eugenio Morelli Hospital (Sondalo). The supra-national Reference Laboratory in Milan performed DST. Inclusion criteria were: age ≥ 18 and culture-confirmed diagnosis of MDR- or pre-XDR TB. Chi-square or Fisher exact test was used to detect differences in the comparison between treatment outcomes, therapeutic regimens, and drug-resistances. Computations were performed with STATA 15. RESULTS: A total of 134 patients were selected. Median (IQR) age at admission was 33 (26-41) years and 90 patients (67.2%) were male. Pulmonary TB was diagnosed in 124 (92.5%) patients. MDR- and pre-XDR-TB cases were 91 (67.9%) and 43 (32.1%), respectively. The WHO shorter MDR-TB regimen could have been prescribed in 16/84 (19.1%) patients. Treatment success was not statistically different between MDR- and pre-XDR-TB (81.3% VS. 81.4%; P = 0.99). Mortality in MDR-TB and pre-XDR-TB groups was 4.4 and 9.3%, respectively (P = 0.2). Median duration of treatment was 18 months and a total of 110 different regimens were administered. Exposure to linezolid, meropenem, and amikacin was associated with a better outcome in both groups (P = 0.001, P < 0.001, and P = 0.004, respectively). CONCLUSIONS: Tailored treatment regimens based on DST results can achieve successful outcomes in patients with pre-XDR-TB.

ASAP-GxNet project in Burkina Faso: fulfil country capacity gaps to ensure efficient utilisation of GeneXpert instruments in tuberculosis care and cascade.

Improving availability, accessibility and quality of national GeneXpert networks through ASAP-GxNet http://ow.ly/umaZ30mGRpE.

Implementing TB control in a rural, resource-limited setting: the stop-TB Italia project in Senegal.

BACKGROUND: Since 2013 StopTB Italia Onlus supports the Senegalese National Tuberculosis Programme by improving diagnostic capability with technological interventions, ameliorating educational programs for health care personnel, rising awareness among civil society and providing economical support for patients during treatment. The purpose of our study was to assess the preliminary results of an interventional cooperation project in a peripheral health care facility in Senegal. METHODS: An observational, retrospective, pre-post study was conducted to compare Tuberculosis (TB) retention in care and outcome between a one-year period before and a four-year period after. RESULTS: Overall, 239 patients with active TB were included, 196 (82%) of whom after the starting of the collaboration project. At diagnosis 35/43(81.4%) vs 151/196 (77%) patients were smear sputum positive before and after the beginning of the project, respectively.At 2 months follow up 23/35 (65.7%) patients in 2012 vs. 139/151 (92%) patients in 2013-2016 had negative control AFB stain (p = 0.249), 4/35 (11.4%) vs 12/151 (8%) patients remained AFB stain positive (p = 0.17), 7/35 (20%) vs 0/151 died before the 2 months follow up (p <  0.0001). TB treatment outcome was more frequently favourable after the beginning of cooperation 29/43 (67.4%) vs. 176/196 (89.8%) patients, (p <  0.0001). Patients' mortality during treatment decreased from 8/43 (18.6%) in 2012 to 11/196 (5.6%) patients in the following years (p = 0.009). CONCLUSION: The implementation of diagnostic procedures, if integrated in a socio-economical intervention, impacts favourably on TB retention in care and treatment outcomes.

Multidrug-Resistant Tuberculosis in Côte d'Ivoire from 1995 to 2016: Results of National Surveys.

SETTING: Tuberculosis (TB) drug resistance survey was conducted in 2016-2017 to estimate the burden of drug-resistant TB in Côte d'Ivoire. DESIGN: A cross-sectional cluster-based survey was conducted. All eligible smear positive patients were interviewed using a structured questionnaire to collect clinical and sociodemographic information and tested by the Xpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) assay. If resistant to rifampicin, solid and liquid cultures were performed. Phenotypic drug susceptibility testing (DST) was conducted in liquid medium for rifampicin, isoniazid, ethambutol, streptomycin, ofloxacin, and amikacin. RESULTS: Of the 1105 sputum smear positive patients enrolled, 995 new and 100 previously treated patients were positive for Mycobacterium tuberculosis complex by Xpert. Proportion of patients with rifampicin resistance was 4.6% (95% CI: 2.4-6.7) and 22% (95% CI: 13.7-30.3), respectively, for new and previously treated patients. Second-line DST results were available for most rifampicin-resistant patients. None were resistant to amikacin, only two were ofloxacin-resistant. Apart from the antecedent of previously treatment for TB, no other risk factors for rifampicin resistance were detected. CONCLUSION: Prevalence of rifampicin resistance among TB patients in Côte d'Ivoire is higher than that in other countries in the region. Surveillance of drug resistance, through an expanded GeneXpert network, and programmatic management of drug-resistant TB (PMDT) must be strengthened in Côte d'Ivoire.