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1.
Nat Rev Dis Primers ; 10(1): 22, 2024 Mar 24.
Article in English | MEDLINE | ID: mdl-38523140

ABSTRACT

Tuberculosis (TB) remains the foremost cause of death by an infectious disease globally. Multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB; resistance to rifampicin and isoniazid, or rifampicin alone) is a burgeoning public health challenge in several parts of the world, and especially Eastern Europe, Russia, Asia and sub-Saharan Africa. Pre-extensively drug-resistant TB (pre-XDR-TB) refers to MDR/RR-TB that is also resistant to a fluoroquinolone, and extensively drug-resistant TB (XDR-TB) isolates are additionally resistant to other key drugs such as bedaquiline and/or linezolid. Collectively, these subgroups are referred to as drug-resistant TB (DR-TB). All forms of DR-TB can be as transmissible as rifampicin-susceptible TB; however, it is more difficult to diagnose, is associated with higher mortality and morbidity, and higher rates of post-TB lung damage. The various forms of DR-TB often consume >50% of national TB budgets despite comprising <5-10% of the total TB case-load. The past decade has seen a dramatic change in the DR-TB treatment landscape with the introduction of new diagnostics and therapeutic agents. However, there is limited guidance on understanding and managing various aspects of this complex entity, including the pathogenesis, transmission, diagnosis, management and prevention of MDR-TB and XDR-TB, especially at the primary care physician level.


Subject(s)
Extensively Drug-Resistant Tuberculosis , Tuberculosis, Multidrug-Resistant , Humans , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Extensively Drug-Resistant Tuberculosis/diagnosis , Extensively Drug-Resistant Tuberculosis/drug therapy , Extensively Drug-Resistant Tuberculosis/epidemiology , Rifampin/therapeutic use , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/epidemiology , Tuberculosis, Multidrug-Resistant/diagnosis , Isoniazid/therapeutic use
3.
Lancet Respir Med ; 10(6): 603-622, 2022 06.
Article in English | MEDLINE | ID: mdl-35338841

ABSTRACT

The global tuberculosis burden remains substantial, with more than 10 million people newly ill per year. Nevertheless, tuberculosis incidence has slowly declined over the past decade, and mortality has decreased by almost a third in tandem. This positive trend was abruptly reversed by the COVID-19 pandemic, which in many parts of the world has resulted in a substantial reduction in tuberculosis testing and case notifications, with an associated increase in mortality, taking global tuberculosis control back by roughly 10 years. Here, we consider points of intersection between the tuberculosis and COVID-19 pandemics, identifying wide-ranging approaches that could be taken to reverse the devastating effects of COVID-19 on tuberculosis control. We review the impact of COVID-19 at the population level on tuberculosis case detection, morbidity and mortality, and the patient-level impact, including susceptibility to disease, clinical presentation, diagnosis, management, and prognosis. We propose strategies to reverse or mitigate the deleterious effects of COVID-19 and restore tuberculosis services. Finally, we highlight research priorities and major challenges and controversies that need to be addressed to restore and advance the global response to tuberculosis.


Subject(s)
COVID-19 , Tuberculosis , COVID-19/epidemiology , Humans , Incidence , Pandemics , Tuberculosis/diagnosis , Tuberculosis/epidemiology , Tuberculosis/therapy
5.
J Thorac Dis ; 12(11): 7076-7080, 2020 Nov.
Article in English | MEDLINE | ID: mdl-33282414
8.
Contemp Clin Trials ; 90: 105938, 2020 03.
Article in English | MEDLINE | ID: mdl-31981713

ABSTRACT

INTRODUCTION: Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen. METHODS/DESIGN: S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority. DISCUSSION: This phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels. TRIAL REGISTRATION: NCT02410772. Registered 8 April 2015,https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1.


Subject(s)
Antitubercular Agents/therapeutic use , HIV Infections/epidemiology , Moxifloxacin/therapeutic use , Rifampin/analogs & derivatives , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/epidemiology , Adolescent , Adult , Antitubercular Agents/administration & dosage , Directly Observed Therapy , Drug Administration Schedule , Drug Therapy, Combination , Equivalence Trials as Topic , Ethambutol/therapeutic use , Female , Humans , Male , Middle Aged , Moxifloxacin/administration & dosage , Rifampin/administration & dosage , Rifampin/therapeutic use , Young Adult
10.
J Clin Microbiol ; 57(8)2019 08.
Article in English | MEDLINE | ID: mdl-31189582

ABSTRACT

An in-house-developed pncA sequencing assay for analysis of pyrazinamide (PZA) resistance was evaluated using 162 archived Mycobacterium tuberculosis complex (MTBC) isolates with phenotypic PZA susceptibility profiles that were well defined by analysis of Bactec MGIT 960 PZA kit and PZase activity data. Preliminary results showed 100% concordance between pncA sequencing and phenotypic PZA drug susceptibility test (DST) results among archived isolates. Also, 637 respiratory specimens were prospectively collected, and 158 were reported as MTBC positive by the Abbott Realtime MTB assay (96.3% sensitivity [95% confidence interval {CI}: 92.2% to 98.7%]; 100% specificity [95% CI: 99.2% to 100.0%]). Genotypic and phenotypic PZA resistance profiles of these 158 MTBC-positive specimens were analyzed by pncA sequencing and Bactec MGIT 960 PZA kit, respectively. For analysis of PZA resistance, pncA sequencing detected pncA mutations in 5/5 (100%) phenotypic PZA-resistant respiratory specimens within 4 working days. No pncA mutations were detected among PZA-susceptible specimens. Combining archived isolates with prospective specimens, 27 were identified as phenotypic PZA resistant with pncA mutation. Among these 27 samples, 6/27 (22.2%) phenotypic PZA-resistant strains carried novel pncA mutations without rpsA and panD mutations. These included 5 with mutations (a deletion [Del] at 383T [Del383T], Del 380 to 390, insertion of A [A Ins] at position 127, A Ins at position 407, and G Ins at position 508) in pncA structural genes and 1 with a mutation (T-12C) at the pncA promoter region. All six of these strains had no or reduced PZase activities, indicating that the novel mutations might confer PZA resistance. Additionally, 25/27 phenotypic PZA-resistant strains were confirmed multidrug-resistant tuberculosis (MDR-TB) strains. As PZA is commonly used in MDR-TB treatment regimens, direct pncA sequencing will rapidly detect PZA resistance and facilitate judicious use of PZA in treating PZA-susceptible MDR-TB.


Subject(s)
Amidohydrolases/genetics , Antitubercular Agents/pharmacology , Drug Resistance, Multiple, Bacterial/genetics , Mycobacterium tuberculosis/drug effects , Pyrazinamide/pharmacology , Algorithms , Biological Specimen Banks , Genotype , Humans , Microbial Sensitivity Tests , Mutation , Polymerase Chain Reaction , Reproducibility of Results , Sensitivity and Specificity , Sequence Analysis, DNA , Tuberculosis/microbiology
12.
Tuberculosis (Edinb) ; 115: 76-80, 2019 03.
Article in English | MEDLINE | ID: mdl-30948180

ABSTRACT

To complement the development of new or repurposed drugs for improving the treatment outcomes of drug-susceptible and drug-resistant tuberculosis, current insight also focuses on the use of host-directed therapy. Metformin, a drug often used in the management of type 2 diabetes mellitus, has attracted attention by virtue of its favourable activity as an adjunctive agent against tuberculosis, discovered through laboratory and clinical studies. To definitively establish its role as a host-directed therapeutic in tuberculosis, more preclinical and clinical research is still required to better delineate its mechanism(s) of action and optimal clinical use.


Subject(s)
Antitubercular Agents/therapeutic use , Metformin/therapeutic use , Tuberculosis/drug therapy , Animals , Antitubercular Agents/pharmacology , Autophagy/drug effects , Drug Interactions , Drug Therapy, Combination , Forecasting , Host-Pathogen Interactions/drug effects , Humans , Immunity, Cellular/drug effects , Latent Tuberculosis/drug therapy , Macrophages/drug effects , Macrophages/microbiology , Metformin/pharmacology , Mice , Mycobacterium tuberculosis , Oxidative Stress/drug effects , Tuberculosis/immunology
14.
Infect Genet Evol ; 68: 98-104, 2019 03.
Article in English | MEDLINE | ID: mdl-30553063

ABSTRACT

Several genome-wide association studies (GWAS) identified new single nucleotide polymorphisms (SNPs) with susceptibility to Tuberculosis (TB). However, many of them were not replicated across ethnic groups. The cause of this phenomenon of genetic heterogeneity is uncertain. Here, we attempted to replicate and evaluate the mechanism that causes genetic heterogeneity in several putative TB predisposition loci found by previous GWAS, including chromosome 18q, ASAP1, DUSP14, and HLA-DQA1. A Chinese cohort of 1200 TB patients and 1280 population controls were genotyped. The results showed that genetic predisposition to TB might operate in an age-specific manner. While no significant association was found in the whole samples, a SNP of HLA-DQA1, rs9272785, showed suggestive association within the young-onset TB subgroup (onset at 20-40 years of age, N = 396). The results provide support for the hypothesis that there are different pathogenesis mechanisms causing clinical TB disease in different age groups, and that genetics probably play a substantial role only in young-onset TB.


Subject(s)
Genetic Predisposition to Disease , HLA-DQ alpha-Chains/genetics , Tuberculosis/epidemiology , Tuberculosis/genetics , Age of Onset , Alleles , Chromosomes, Human, Pair 18 , Genetic Heterogeneity , Genetic Linkage , Genetic Loci , Genome-Wide Association Study , Genotype , Hong Kong/epidemiology , Humans , Linkage Disequilibrium , Odds Ratio , Polymorphism, Single Nucleotide , Public Health Surveillance , Tuberculosis/microbiology
19.
Lancet ; 392(10150): 821-834, 2018 09 08.
Article in English | MEDLINE | ID: mdl-30215381

ABSTRACT

BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.


Subject(s)
Antitubercular Agents/therapeutic use , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/mortality , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/mortality , Amikacin/therapeutic use , Antitubercular Agents/administration & dosage , Capreomycin/therapeutic use , Carbapenems/therapeutic use , Clofazimine/therapeutic use , Diarylquinolines/therapeutic use , Drug Therapy, Combination , Fluoroquinolones/therapeutic use , Humans , Kanamycin/therapeutic use , Levofloxacin/therapeutic use , Linezolid/therapeutic use , Moxifloxacin , Recurrence , Treatment Failure
20.
Respirology ; 23(11): 978-990, 2018 11.
Article in English | MEDLINE | ID: mdl-29917287

ABSTRACT

Since standardized rifampin-based first-line regimens and fluoroquinolone-based second-line regimens were used to treat tuberculosis (TB), unfortunately without timely modification according to the drug resistance profile, TB and drug-resistant disease are still important public health threats worldwide. Although the last decade has witnessed advances in rapid diagnostic tools and use of repurposed and novel drugs for better managing drug-resistant TB, we need an appropriate TB control strategy and a well-functioning health infrastructure to ensure optimal operational use of rapid tests, judicious use of effective treatment regimens that can be rapidly tailored according to the drug resistance profile and timely management of risk factors and co-morbidities that promote infection and its progression to disease. We searched the published literature to discuss (i) standardized versus individualized therapies, including the choice between a single one-size-fit-all regimen versus different options with different key drugs determined mainly by rapid drug susceptibility testing, (ii) alternative regimens for managing drug-susceptible TB, (iii) evidence for using the World Health Organization (WHO) longer and shorter regimens for multidrug-resistant TB and (iv) evidence for using repurposed and novel drugs. We hope an easily applicable combination of biomarkers that accurately predict individual treatment outcome will soon be available to ultimately guide individualized therapy.


Subject(s)
Antitubercular Agents , Clinical Protocols/standards , Mycobacterium tuberculosis/drug effects , Patient Care Management , Tuberculosis, Multidrug-Resistant , Antitubercular Agents/classification , Antitubercular Agents/pharmacology , Global Health , Humans , Patient Care Management/methods , Patient Care Management/organization & administration , Patient Care Management/trends , Tuberculosis, Multidrug-Resistant/diagnosis , Tuberculosis, Multidrug-Resistant/drug therapy
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