Kogieleum Naidoo, Rubeshan Perumal
Affiliations
Centre for the AIDS Programme of Research in South Africa, Medical Research Council-CAPRISA HIV-Tuberculosis Pathogenesis and Treatment Research Unit, University of KwaZulu-Natal, Durban 4001, South Africa
Tuberculosis, the leading cause of death from a curable infectious disease, is a major threat to human health globally. WHO estimated that 10·6 million new cases of tuberculosis and 1·6 million tuberculosis-associated deaths occurred in 2021. The COVID-19 pandemic disrupted health systems and exposed prevailing deficiencies in tuberculosis-control programs globally, reversing the hard-won reduction of global tuberculosis incidence observed until 2020. Nevertheless, the past decade has celebrated several major scientific breakthroughs that could advance the achievement of a tuberculosis-free world.
Mathematical models suggest that to achieve a substantial reduction in tuberculosis incidence and mortality, widescale implementation of multiple strategies is required. These strategies include effective tuberculosis prevention to reduce latent infection; augmented case-finding and improved linkage to tuberculosis care to shorten the period of infectiousness; and context-specific infection control measures that consider population mobility, trust in health-care providers and health institutions, the force of tuberculosis transmission, and prevalence of HIV.
The period between the onset of tuberculosis disease and a tuberculosis diagnosis is characterised by increased infectiousness and risk of tuberculosis transmission, with greater transmission generated by index cases that are smear positive. Although the excess risk of tuberculosis transmission within households has been well characterised, tuberculosis transmission in high tuberculosis-burden or HIV-burden settings is also likely to occur in other congregate settings, including health-care facilities, recreational hubs, and transportation nodal points where individuals might cluster in space and over time. Current and planned research seeks to evaluate tuberculosis -transmission risk through breath aerosols for the detection of infectiousness among clinical and subclinical patients with tuberculosis and through geospatial mapping to identify tuberculosis hot- spots, which might offer opportunities for targeted interventions to halt transmission.1
Achieving tuberculosis eradication requires sensitive sputum-based and non-sputum-based diagnostic tools capable of diagnosing latent tuberculosis, predicting the risk of progression to active disease, and identifying Mycobacterium tuberculosis in individuals who are infectious. The widescale implementation of highly sensitive next-generation molecular tools for M tuberculosis detection, such as the Xpert MTB/ RIF Ultra, provides the potential to identify subclinical and clinical tuberculosis, making it suitable for both active and passive case finding.2,3 However, improved case detection without linkage to care limits the effects of passive tuberculosis case finding on tuberculosis morbidity and mortality.4 Preventive tuberculosis therapy shows incontrovertible individual-level benefits, but epidemiological and context-specific health system factors substantially moderate its effect at the population level.5 Any future tuberculosis prevention and treatment strategies should use the contemporary, although still incomplete, understanding of tuberculosis pathogenesis that has focused away from the dichotomy of latent and active disease to a more detailed perspective of the dynamic, multistate, bidirectional spectrum of latent, incipient, subclinical, and clinically active tuberculosis.6
After two decades of reliance on a multidrug, 6-month, drug-sensitive tuberculosis regimen, compelling evidence of a new regimen for tuberculosis treatment shortening has emerged.7 However, despite a WHO recommendation, restricted and inequitable access to component drugs, unknown safety and efficacy during antiretroviral therapy coadministration, and the lack of a safety and tolerability advantage over previous regimens have delayed the implementation and scale-up of this novel 4-month regimen for drug-sensitive tuberculosis. Diagnostic and treatment gaps are even larger for drug-resistant tuberculosis, despite increasing incidence rates globally. Rapid resistance profiling and access to safe, effective, and shortened treatment regimens are key to reducing drug-resistant tuberculosis incidence rates, prevalence rates, morbidity, and mortality. Rapid molecular diagnostics suitable for implementation in low-resource settings with high tuberculosis burden or HIV burdens are emerging and could produce treatment-informing results within 90 min.8 WHO-endorsed, all-oral, shorter, highly effective drug-resistant tuberculosis regimens represent substantial progress in the treatment of drug-resistant tuberculosis, in which previous pharmacotherapy was prohibitively long, toxic, and of suboptimal efficacy.9 However, the introduction of novel treatment regimens incorporating drugs with incompletely characterized genotypic–phenotypic concordance might be a threat to the durability of these regimens. For newer drugs, such as bedaquiline and pretomanid, the absence of high genotypic–phenotypic concordance limits the development of molecular assays for drug susceptibility testing. The availability of rapid phenotypic drug-susceptibility profiling to support the roll-out of new drugs would substantially change the future of drug-resistant tuberculosis care.
Panel
Examples of ongoing studies that aim to address outstanding research questions
Tuberculosis transmission
Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (PHOENIx MDR-TB; NCT03568383)
Tuberculosis diagnostics
Mycobacterium tuberculosis detection
Validating the Use of Blood Transcriptomic Signatures for the Diagnosis of Active Pulmonary Tuberculosis (ISIT-TB; NCT04995406). Early Risk Assessment in Household Contacts (≥10 Years) of TB Patients by New Diagnostic Tests in 3 African Countries (ERASE-TB; NCT04781257)
Xpert Active Case-finding Trial 3 (XACT-3; NCT04303104)
Resistance profiling
Triage Test for All Oral DR-TB Regimen (TRiAD Study; NCT05175794)
Treatment of tuberculosis or drug-resistant tuberculosis
Clofazimine- and Rifapentine-Containing Treatment Shortening Regimens in Drug-Susceptible Tuberculosis: The CLO-FAST Study (NCT04311502)
Safety and Efficacy Evaluation of 4-month Regimen of OPC-167832, Delamanid, and Bedaquiline in Participants With Drug-Susceptible Pulmonary TB (NCT05221502)
Vaccines
Clinical Trial to Investigate Therapeutic Vaccine (RUTI) Against Tuberculosis (TB; NCT04919239)
Study to Check the Efficacy and Safety of Recombinant BCG Vaccine in Prevention of TB Recurrence (NCT03152903)
Efficacy, Safety, and Immunogenicity Evaluation of MTBVAC in Newborns in Sub-Saharan Africa (MTBVACN3; NCT04975178)
BCG Revaccination in Children and Adolescents (BRiC; NCT05330884)
Safety and Immune Responses After Vaccination With Two Investigational RNA-based Vaccines Against Tuberculosis in Healthy Volunteers (NCT05537038)
M72/AS01E vaccine candidates are planned for phase 3 clinical trials ID93/GLA-SE vaccine candidates are planned for 2b/3 clinical trials
Despite several issues, BCG, which was first introduced in the 1920s, remains the only licensed tuberculosis vaccine. However, the past decade has seen substantial advances in tuberculosis vaccine development. Currently, ten vaccine candidates are undergoing clinical trial evaluation, including live-attenuated, viral-vector, protein subunit, and whole-cell inactivated vaccines.10 These vaccine candidates seek to prevent tuberculosis infection and progression to tuberculosis disease, as well as to be an adjunct to drug therapy for accelerating cure, shortening treatment, and preventing relapse. Furthermore, clinical trials of mRNA- based tuberculosis vaccine candidates are currently in development. A persistent challenge impeding tuberculosis vaccine development has been the lack of clearly defined immune correlates of protection as a surrogate for vaccine efficacy. Although cross-reactive, immunogenic tuberculosis antigens have been identified, characterising cell-mediated and humoral immunity signaling protection against tuberculosis infection and progression to tuberculosis disease remains elusive. Efficacy signals for preventing tuberculosis infection, progression to tuberculosis disease, and preventing relapse have been detected in early-phase vaccine studies, with confirmation underway in larger trials.
There is optimism around several major advances in the scientific understanding of tuberculosis transmission and pathogenesis, improved diagnostic assays for M tuberculosis detection and resistance profiling, and the implementation of shorter, safer, and more effective regimens for the treatment of tuberculosis. To achieve a tuberculosis- free world, however, more progress is needed in developing an effective tuberculosis vaccine, implementing coordinated tuberculosis control interventions with multiple aspects, mitigating the socioeconomic drivers of tuberculosis, and sustaining high levels of political support to bring new scientific advances to the field.
KN receives grants paid to her organisation from the US National Institutes of Health (1R01AI151173, R01AI152142, and 1R01AI138646), the European and Developing Countries Clinical Trials Partnership (RIA2019IR-2888), and the Bill and Melinda Gates Medical Research Institute (MRI-TBV01-201 and MRI TBV02-202). She is Chair of the SteerCo Centre for Biomedical Tuberculosis Research, an investigator for the Tuberculosis Transformative Science Group, and a member of the South African National Tuberculosis Think Tank. RP declares no competing interests.
References
1. Churchyard G Kim P Shah NS et al. What we know about tuberculosis transmission: an overview. J Infect Dis. 2017; 216: S629-S635
2. Dorman SE Schumacher SG Alland D et al. Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective multicentre diagnostic accuracy study. Lancet Infect Dis. 2018; 18: 76-84
3. Calligaro GL Zijenah LS Peter JG et al. Effect of new tuberculosis diagnostic technologies on community-based intensified case finding: a multicentre randomized controlled trial. Lancet Infect Dis. 2017; 17: 441-450
4. Churchyard GJ Stevens WS Mametja LD et al. Xpert MTB/ RIF versus sputum microscopy as the initial diagnostic test for tuberculosis: a cluster-randomized trial embedded in South African roll-out of Xpert MTB/RIF. Lancet Glob Health. 2015; 3: e450-e457
5. Swindells S Ramchandani R Gupta A et al. One month of rifapentine plus isoniazid to prevent HIV-related tuberculosis. N Engl J Med. 2019; 380: 1001-1011
6. Drain PK Bajema KL Dowdy D et al. Incipient and subclinical tuberculosis: a clinical review of early stages and progression of infection. Clin Microbiol Rev. 2018; 31: e00021-e00118
7. Dorman SE Nahid P Kurbatova EV et al. Four-month rifapentine regimens with or without moxifloxacin for tuberculosis. N Engl J Med. 2021; 384: 1705-1718
8. Penn-Nicholson A Georghiou SB Ciobanu N et al. Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by the Xpert MTB/ XDR assay: a cross-sectional multicentre diagnostic accuracy study. Lancet Infect Dis. 2022; 22: 242-249
9. Nyang’wa BT Berry C Kazounis E et al. A 24-week, all-oral regimen for rifampin-resistant tuberculosis. N Engl J Med. 2022; 387: 2331-2343
10. Miner MD Hatherill M Mave V et al. Developing tuberculosis vaccines for people with HIV: consensus statements from an international expert panel. Lancet HIV. 2022; 9: e791-e800
Credits: Naidoo, Kogieleum et al. Advances in tuberculosis control during the past decade. The Lancet Respiratory Medicine, Volume 11, Issue 4, 311 – 313