Impact of COVID-19 on diagnosis of tuberculosis, multidrug-resistant tuberculosis, and on mortality in 11 countries in Europe, Northern America, and Australia. A Global Tuberculosis Network study.

OBJECTIVES: Although evidence is growing on the overall impact of the COVID-19 pandemic on tuberculosis (TB) services, global studies based on national data are needed to better quantify the extent of the impact and the countries' preparedness to tackle the two diseases. The aim of this study was to compare the number of people with new diagnoses or recurrence of TB disease, the number of drug-resistant (DR)-TB, and the number of TB deaths in 2020 vs 2019 in 11 countries in Europe, Northern America, and Australia. METHODS: TB managers or directors of national reference centers of the selected countries provided the agreed-upon variables through a validated questionnaire on a monthly basis. A descriptive analysis compared the incidence of TB and DR-TB and mortality of the pre-COVID-19 year (2019) vs the first year of the COVID-19 pandemic (2020). RESULTS: Comparing 2020 vs 2019, lower number of TB cases (new diagnosis or recurrence) was notified in all countries (except USA-Virginia and Australia), and fewer DR-TB notifications (apart from France, Portugal, and Spain). The deaths among TB cases were higher in 2020 compared to 2019 in most countries with three countries (France, The Netherlands, USA-Virginia) reporting minimal TB-related mortality. CONCLUSIONS: A comprehensive evaluation of medium-term impact of COVID-19 on TB services would benefit from similar studies in multiple settings and from global availability of treatment outcome data from TB/COVID-19 co-infected patients.

Progress on diagnosis and treatment of drug-resistant tuberculosis in line with World Health Organization recommendations in six priority countries in the Western Pacific Region.

Background: Diagnosis and treatment of drug-resistant tuberculosis (DR-TB) have radically changed in accordance with recommendations from the World Health Organization (WHO) in the past decade, allowing rapid and simple diagnosis and shorter treatment duration with new and repurposed drugs. Methods: A descriptive analysis of the status and progress of DR-TB diagnosis and treatment in six priority countries in the Western Pacific Region was conducted using information from interviews with countries and the WHO TB database. Results: Over the past decade, the use of Xpert MTB/RIF has increased in the six priority countries, in parallel with implementation of national policies and algorithms to use Xpert MTB/RIF as an initial diagnostic test for TB and detection of rifampicin resistance. This has resulted in increases in the number of people diagnosed with multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB). Shorter treatment regimens with new and repurposed drugs have also been adopted for MDR/RR-TB cases, alongside a decentralized model of care, leading to improved treatment outcomes. Discussion: The Western Pacific Region has achieved considerable progress in the diagnosis and treatment of DR-TB, in line with the evolving WHO recommendations in the past decade. The continued commitment of Member States is needed to address remaining challenges, such as the impact of the coronavirus disease pandemic, suboptimal management and health system issues.

Drug resistant tuberculosis: Implications for transmission, diagnosis, and disease management.

Drug resistant tuberculosis contributes significantly to the global burden of antimicrobial resistance, often consuming a large proportion of the healthcare budget and associated resources in many endemic countries. The rapid emergence of resistance to newer tuberculosis therapies signals the need to ensure appropriate antibiotic stewardship, together with a concerted drive to develop new regimens that are active against currently circulating drug resistant strains. Herein, we highlight that the current burden of drug resistant tuberculosis is driven by a combination of ongoing transmission and the intra-patient evolution of resistance through several mechanisms. Global control of tuberculosis will require interventions that effectively address these and related aspects. Interrupting tuberculosis transmission is dependent on the availability of novel rapid diagnostics which provide accurate results, as near-patient as is possible, together with appropriate linkage to care. Contact tracing, longitudinal follow-up for symptoms and active mapping of social contacts are essential elements to curb further community-wide spread of drug resistant strains. Appropriate prophylaxis for contacts of drug resistant index cases is imperative to limit disease progression and subsequent transmission. Preventing the evolution of drug resistant strains will require the development of shorter regimens that rapidly eliminate all populations of mycobacteria, whilst concurrently limiting bacterial metabolic processes that drive drug tolerance, mutagenesis and the ultimate emergence of resistance. Drug discovery programs that specifically target bacterial genetic determinants associated with these processes will be paramount to tuberculosis eradication. In addition, the development of appropriate clinical endpoints that quantify drug tolerant organisms in sputum, such as differentially culturable/detectable tubercle bacteria is necessary to accurately assess the potential of new therapies to effectively shorten treatment duration. When combined, this holistic approach to addressing the critical problems associated with drug resistance will support delivery of quality care to patients suffering from tuberculosis and bolster efforts to eradicate this disease.

Tuberculosis Phenotypic and Genotypic Drug Susceptibility Testing and Immunodiagnostics: A Review.

Tuberculosis (TB), considered an ancient disease, is still killing one person every 21 seconds. Diagnosis of Mycobacterium tuberculosis (M.tb) still has many challenges, especially in low and middle-income countries with high burden disease rates. Over the last two decades, the amount of drug-resistant (DR)-TB cases has been increasing, from mono-resistant (mainly for isoniazid or rifampicin resistance) to extremely drug resistant TB. DR-TB is problematic to diagnose and treat, and thus, needs more resources to manage it. Together with+ TB clinical symptoms, phenotypic and genotypic diagnosis of TB includes a series of tests that can be used on different specimens to determine if a person has TB, as well as if the M.tb strain+ causing the disease is drug susceptible or resistant. Here, we review and discuss advantages and disadvantages of phenotypic vs. genotypic drug susceptibility testing for DR-TB, advances in TB immunodiagnostics, and propose a call to improve deployable and low-cost TB diagnostic tests to control the DR-TB burden, especially in light of the increase of the global burden of bacterial antimicrobial resistance, and the potentially long term impact of the coronavirus disease 2019 (COVID-19) disruption on TB programs.

TB-PRACTECAL: study protocol for a randomised, controlled, open-label, phase II-III trial to evaluate the safety and efficacy of regimens containing bedaquiline and pretomanid for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis.

BACKGROUND: Globally rifampicin-resistant tuberculosis disease affects around 460,000 people each year. Currently recommended regimens are 9-24 months duration, have poor efficacy and carry significant toxicity. A shorter, less toxic and more efficacious regimen would improve outcomes for people with rifampicin-resistant tuberculosis. METHODS: TB-PRACTECAL is an open-label, randomised, controlled, phase II/III non-inferiority trial evaluating the safety and efficacy of 24-week regimens containing bedaquiline and pretomanid to treat rifampicin-resistant tuberculosis. Conducted in Uzbekistan, South Africa and Belarus, patients aged 15 and above with rifampicin-resistant pulmonary tuberculosis and requiring a new course of therapy were eligible for inclusion irrespective of HIV status. In the first stage, equivalent to a phase IIB trial, patients were randomly assigned one of four regimens, stratified by site. Investigational regimens include oral bedaquiline, pretomanid and linezolid. Additionally, two of the regimens also included moxifloxacin (arm 1) and clofazimine (arm 2) respectively. Treatment was administered under direct observation for 24 weeks in investigational arms and 36 to 96 weeks in the standard of care arm. The second stage of the study was equivalent to a phase III trial, investigating the safety and efficacy of the most promising regimen/s. The primary outcome was the percentage of unfavourable outcomes at 72 weeks post-randomisation. This was a composite of early treatment discontinuation, treatment failure, recurrence, lost-to-follow-up and death. The study is being conducted in accordance with ICH-GCP and full ethical approval was obtained from Médecins sans Frontières ethical review board, London School of Hygiene and Tropical Medicine ethical review board as well as ERBs and regulatory authorities at each site. DISCUSSION: TB-PRACTECAL is an ambitious trial using adaptive design to accelerate regimen assessment and bring novel treatments that are effective and safe to patients quicker. The trial took a patient-centred approach, adapting to best practice guidelines throughout recruitment. The implementation faced significant challenges from the COVID-19 pandemic. The trial was terminated early for efficacy on the advice of the DSMB and will report on data collected up to the end of recruitment and, additionally, the planned final analysis at 72 weeks after the end of recruitment. TRIAL REGISTRATION: Clinicaltrials.gov NCT02589782. Registered on 28 October 2015.

How to Effectively Identify Patients With Rifampin-Resistant Tuberculosis in China: Perspectives of Stakeholders Among Service Providers.

To evaluate China's current rifampin-resistant tuberculosis (RR-TB) screening strategy from stakeholders' perspectives, the perceptions, attitudes, and interests of 245 stakeholders from three eastern, central, and western China provinces on RR-TB screening strategies, were investigated through stakeholder survey and interview. The attitudes toward three RR-TB screening strategies were statistically different: inclination to choose who to screen (Z = 98.477; P < 0.001), funding for rapid diagnostic technology screening either by reimbursed health insurance or directly subsidized financial assistance (Z = 4.142, P < 0.001), and respondents' attitude during RR-TB screening implementation levels (Z = 2.380, P = 0.017). In conclusion, RR-TB screening scope could be expanded by applying rapid diagnostic technologies. Provinces with different economic status could adjust their screening policies accordingly.

Drug-resistant tuberculosis: advances in diagnosis and management.

PURPOSE OF REVIEW: Diagnosis and treatment of drug-resistant tuberculosis (DR-TB) is undergoing substantial changes, owing availability of new diagnostic tools and drugs, coupled with global underdiagnosis and undertreatment. Recent developments are reviewed. RECENT FINDINGS: Molecular diagnostics, for Mycobacterium tuberculosis complex detection and prediction of drug resistance, implemented in the last decade, accelerated TB diagnosis with improved case detection. Nevertheless, access and coverage of drug-resistance testing remain insufficient. Genome sequencing-technologies, based on targeted next-generation sequencing show early potential to mitigate some of the challenges in the future. The recommendation to use an all oral, bedaquiline based regimen for treatment of multidrug-resistant/rifampicin-resistant TB is major advancement in DR-TB care. TB regimen using new and repurposed TB drugs demonstrate in recent clinical trials like, NIX-TB, ZeNIX and TB PRACTECAL considerable treatment success, shorten treatment duration and reduce toxicity. Their optimal use is threatened by the rapid occurrence and spread of strains, resistant to new drugs. Children benefit only very slowly from the progress. SUMMARY: There is notable progress in improved diagnosis and treatment of drug-resistant TB, but complicated by the COVID-19 pandemic the majority of TB patients worldwide don't have (yet) access to the advances.

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.

Accelerating development of new shorter TB treatment regimens in anticipation of a resurgence of multi-drug resistant TB due to the COVID-19 pandemic.

The WHO 2020 global TB Report estimates that in 2019 there were an estimated 500,000 cases of multi-drug resistant TB (MDR-TB) of which only 186,772 MDR-TB cases were diagnosed, and positive treatment outcomes were achieved in 57% of them. These data highlight the need for accelerating and improving MDR-TB screening, diagnostic, treatment and patient follow-up services. The last decade has seen three new TB drugs being licensed; bedaquiline, delamanid and pretomanid, and combinations these new, existing and repurposed drugs are leading to improved cure rates. The all oral six month WHO regimen for MDR-TB is more tolerable, has higher treatment success rates and lower mortality. However, the unprecedented ongoing COVID-19 pandemic is having major direct and indirect negative impacts on health services overall, including national TB programs and TB services. This adds further to longstanding challenges for tackling MDR-TB such as cost, rollout of diagnostics and drugs, and implementation of latest WHO guidelines for MDR-TB. In light of COVID-19 disruption of TB services, it is anticipated the numbers of MDR-TB cases will rise in 2021 and 2022 and will affect treatment outcomes further. Investing more in development of new TB drugs and shorter MDR-TB treatment regimens is required in anticipation of emerging drug resistance to new TB drug regimens. There is an urgent need for protecting current investments in TB services, sustaining gains being made in TB control and accelerating roll out of TB diagnostic and treatment services.

Recent updates in diagnosis and management of drug-resistant tuberculosis in India: A paradigm shift and the way ahead during the COVID-19 crisis.

The recent guidelines on the Programmatic Management of Drug-Resistant Tuberculosis (DR-TB) in India (PMDT) have been released in March 2021 on World TB Day. The new guidelines have considered emerging diagnostic trends including TrueNat, Xpert Mtb/XDR, Next generation sequencing and evaluation for resistance to newer drugs including Bedaquiline (Bdq) and Delamanid. The emerging therapeutic trends include focus on oral shorter Bdq based regimen with phasing out injectables use. The replacement sequence of drugs for DR-TB have also been updated. Updated definitions for pre-XDR, XDR, culture conversion and default have also been added. These guidelines are a paradigm shift which will make treating DR-TB easier and more efficient especially during the ongoing COVID-19 pandemic crisis.