Tuberculosis remains the world’s leading infectious disease killer, and global targets to reduce tuberculosis incidence and mortality remain off-track despite recent advances in treatment and prevention, according to an invited review published in Respirology.
The review summarized recent clinical trials, epidemiologic studies, and World Health Organization guidance on tuberculosis screening, diagnostics, prevention, treatment, drug resistance, vaccine development, and long-term pulmonary complications.
The researchers emphasized that tuberculosis is increasingly understood as a disease spectrum rather than a binary distinction between latent and active disease. Based on prevalence surveys, about 50% of microbiologically confirmed tuberculosis cases were subclinical. Aerosol studies also suggested that patients with incipient or undiagnosed disease may transmit Mycobacterium tuberculosis, including in the absence of prominent cough. The review noted that current symptom-based screening strategies focused primarily on cough may therefore miss infectious patients because much aerosolization appears to occur during tidal breathing rather than coughing alone.
The researchers also highlighted increasing use of nucleic acid amplification tests, including Xpert MTB/RIF Ultra and Truenat MTB, for detection of M tuberculosis and rifampicin resistance. However, these tests do not distinguish live from dead organisms and may miss disease caused by nontuberculous mycobacteria. The review additionally identified broader access to rapid drug susceptibility testing for newer tuberculosis drugs as an ongoing priority.
In prevention, the researchers identified the M72/AS01E vaccine candidate as a leading development. In a phase 2b study, the vaccine demonstrated approximately 50% efficacy in preventing progression to tuberculosis disease among HIV-negative, interferon-gamma release assay–positive adults. A larger phase 3 multinational trial is ongoing and expected to be completed in 2028.
The review also described shorter tuberculosis preventive therapy options, including 1-month and 3-month rifapentine-based regimens with isoniazid. For contacts of patients with rifampicin-resistant or multidrug-resistant tuberculosis, 6 months of levofloxacin reduced tuberculosis incidence in recent trials. However, individual trial results were not statistically significant, event rates were low, musculoskeletal adverse events were more common, and the number needed to treat may be high, particularly among adults.
For drug-susceptible tuberculosis, the researchers highlighted the WHO-endorsed 4-month regimen of rifapentine, isoniazid, pyrazinamide, and moxifloxacin for patients aged 12 years or older. They noted that the regimen still requires adherence support and resistance testing for both rifampicin and moxifloxacin, and that access to rifapentine remains limited.
The researchers also cited the TRUNCATE trial as evidence that shorter treatment may be possible with risk-stratified approaches. In that trial, carefully selected and monitored patients with mild rifampicin-susceptible tuberculosis and no risk factors for failure or recurrence received an 8-week regimen that was noninferior to standard therapy. The findings should not be generalized to all patients, the review suggested, but may help inform future individualized treatment strategies.
For pulmonary multidrug-resistant or rifampicin-resistant tuberculosis, the review described the 6-month all-oral bedaquiline, pretomanid, linezolid, and moxifloxacin regimen as a major advance for eligible patients aged 14 years or older without prior exposure to bedaquiline or pretomanid and without more than 1 month of prior linezolid exposure. The researchers noted that patients who are ineligible for shorter regimens, including those with certain resistance patterns or prolonged prior drug exposure, may still require longer individualized treatment.
Patients with central nervous system tuberculosis, severe HIV-associated tuberculosis, tuberculosis pericarditis, bone and joint tuberculosis, and extensive drug resistance remain underrepresented in trials and often require prolonged or individualized therapy. Central nervous system tuberculosis is associated with high mortality, especially among patients with HIV, and most guidelines still recommend 9 to 12 months of treatment for drug-susceptible disease.
The review also discussed paradoxical inflammatory reactions during tuberculosis treatment. HIV-associated paradoxical tuberculosis immune reconstitution inflammatory syndrome can be managed with prednisolone at 1.5 mg/kg/day for 2 weeks followed by 0.75 mg/kg/day for 2 weeks. Preventive prednisolone may also reduce risk when antiretroviral therapy is initiated in patients with CD4 counts below 100 cells per microliter.
Bedaquiline resistance was identified as a major threat to recent progress. The researchers noted that bedaquiline now anchors both current standard regimens for rifampicin-resistant tuberculosis and nearly all investigational shorter regimens in development. Rising resistance therefore threatens not only current treatment strategies but also much of the near-term tuberculosis drug pipeline, underscoring the need for rapid drug susceptibility testing and continued development of compounds without cross-resistance.
Posttuberculosis lung disease was another major concern. The review stated that up to 60% of tuberculosis survivors have measurable respiratory impairment. Tuberculosis survivors also experience approximately threefold higher all-cause mortality compared with age-matched peers, and nearly half of tuberculosis-associated disability-adjusted life years may occur following treatment completion. Current management remains limited by a lack of evidence-based preventive and therapeutic strategies.
“Continued investments are needed to fill these gaps and make a world free of TB a more realistic scenario,” wrote lead study author Saskia Janssen, of TASK and Radboud University Medical Center, and colleagues.
Disclosures: Janssen reported support through a Horizon Europe Marie Sklodowska-Curie Actions Personal Fellowship. The researchers declared no conflicts of interest.
Source: Respirology
