New guidelines for the management of TB

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Reference: April 2025 | Issue 4 | Vol 11 | Page 20

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In January of this year, on foot of new clinical trial data, the European Respiratory Society (ERS), American Thoracic Society (ATS), US Centres for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) issued updated clinical practice guidelines for the treatment of tuberculosis (TB) in children and adults.¹ The recommendations are intended to serve as a targeted update to the treatment of TB and specifically as an adaptation of the WHO 2022 guidelines.

The guidelines include four new recommendations. New drug-susceptible (DS) TB recommendations include the
use of a novel four-month regimen for people with pulmonary TB and a shortened four-month regimen for children with non-severe TB. For drug-resistant (DR) TB, the guidelines recommend the use of novel regimens containing bedaquiline, pretomanid, and linezolid with or without moxifloxacin.

DS TB

Standard treatment for culture-positive DS TB has traditionally required at least six months of antibiotic treatment. Shorter, effective regimens would enable patients to be cured faster and could potentially reduce treatment costs, improve patient quality of life, and increase treatment adherence.

Results from the randomised, open-label, phase 3 Study 31/A5349 trial showed non-inferiority of a four-month rifapentine-based regimen containing moxifloxacin compared to the standard six-month regimen.² The cure rate with 84.6 per cent with the four-month regimen versus 85.4 per cent with the six-month therapy.

No significant differences in outcomes were identified between the regimens on the basis of smear grade, cavitation, radiologic extent, age, diabetes, body weight, or HIV status. It should be noted that the number of participants living with HIV, diabetes, extreme weight or older age was small.

The ERS/ATS/CDC/IDSA guidelines group assessed that overall certainty of evidence for benefits of cure and retention in treatment was high, moderate for adverse events, and low for acquisition of drug resistance and for all-cause mortality, based on the low frequency of harmful events. Consequently, the guidelines contain a conditional recommendation for the use of the four-month regimen of isoniazid, rifapentine, moxifloxacin, and pyrazinamide in people aged 12 years or older with DS pulmonary TB.

No information was available regarding the use of rifapentine-moxifloxacin for extrapulmonary TB (EP TB), during pregnancy or in young children. Rifapentine with isoniazid was not associated with unfavourable pregnancy outcomes in trials including weekly therapy for latent TB infection treatment.³ Paediatric studies are currently examining the pharmacokinetics of the four-month regimen. At present, weekly rifapentine with isoniazid is recommended for latent TB infection for persons aged two years and older.⁴

SHINE trial

The Shorter Treatment for Minimal TB in Children (SHINE) trial was a multicentre, randomised, controlled, two-arm noninferiority trial comparing a four-month regimen of two months of standard-dose isoniazid, rifampin, pyrazinamide, and ethambutol followed by two months of isoniazid and rifampin (2HRZE/2HR), with the standard six-month DS TB regimen of two months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by four months of isoniazid and rifampin (2HRZE/4HR) for the treatment of non-severe TB in children younger than 16 years.⁵

Non-severe TB was defined as intrathoracic lymph node TB without airway obstruction, uncomplicated TB pleural effusion, or paucibacillary and noncavitary disease confined to one lobe of the lungs, or without a miliary pattern.

The trial demonstrated a success rate of 97.1 per cent for the four-month regimen compared with 96.9 per cent for the six-month regimen. Non-inferiority was consistent across the intention to treat, per-protocol, and key secondary analyses, including the analyses restricted to patients independently adjudicated to have TB disease. Adverse event incidence was similar between the groups (7.8% and 8.0%, respectively).

Consequently, the guidelines recommend the four month treatment regimen for children and adolescents aged between three months and 16 years with non-severe TB (without suspicion or evidence of multidrug or rifampicin resistance).

For children and adolescents who do not meet the criteria for non-severe TB, it is recommended that they receive the standard six-month regimen or other regimens for which they are eligible.

It is acknowledged that the SHINE trial enrolled children and adolescents with symptomatic TB while, in the real world, many children are diagnosed while asymptomatic. The guidelines recommend that, provided patients meet the demographic, radiographic, epidemiologic, and clinical criteria for non-severe TB, without suspicion of multidrug or rifampicin resistance, these patients should also be eligible for the four-month regimen.

The guidelines stress that monitoring for potential recurrence is a priority for shorter regimens, and programmes should have plans to monitor children after treatment.

DR TB

Multi-drug resistant (MDR) TB (resistant to at least isoniazid and rifampin), rifampin-resistant (RR) TB, and TB in people intolerant of rifampin (due to severity of adverse effects) are associated with significant morbidity and mortality. These conditions have required substantially different medications and extended treatment durations compared with DS TB. Before 2019, global treatment success rates for MDR TB ranged from 50 to 88 per cent, often accompanied by significant adverse events.

The Nix-TB study demonstrated a 90 per cent treatment success rate for treatment of extensively drug-resistant (XDR) or MDR TB using a regimen of bedaquiline, pretomanid, and linezolid (BPaL) over a six-month period. Adverse events associated with this regimen were primarily attributed to a daily dose of 1,200mg of linezolid.⁶

In the ZeNix trial, lower linezolid dosing and shorter treatment durations were evaluated. In the trial, 181 participants with MDR/RR or pre-XDR TB received 26 weeks of BPaL.⁷ They were randomised to receive 1,200mg or 600mg of linezolid daily for nine or 26 weeks. Treatment with the 600mg linezolid regimen for 26 weeks demonstrated similar favourable outcomes, with a reduced incidence of peripheral neuropathy compared with the regimen containing 1,200mg.

Comparing ZeNix data (linezolid 600mg for 26 weeks; n=43) with longer observational standard of care (SoC) regimens (n=850), BPaL had higher treatment success (100% vs 74%), with lower mortality (0% vs 11%) and loss to follow up (0% vs 12%). Grade 3 or higher adverse events were observed more frequently with BPaL (14% vs 5%).

In TB-PRACTECAL, people receiving BPaL (n=60) for 24 weeks, including linezolid initiated at 600mg for MDR/RR or pre-XDR TB, had a higher success rate than persons receiving SoC (n=66) regimens (77% vs 52%) and fewer grade 3 or higher adverse events (20% vs 51%).⁸

Although the minimum age for eligibility was 15 years in TB-PRACTECAL and 14 years in ZeNix, the opinion of the guideline’s panel was that BPaL could be used in individuals aged 14 years and older.

Consequently the guidelines recommend six months of BPaL for adult and adolescents aged 14 years and older with RR pulmonary TB who have resistance or intolerance to fluoroquinolones and either have had no previous exposure to bedaquiline and linezolid or have been exposed for less than one month.

BPaLM

In adults and adolescents aged 14 years and older with RR, fluoroquinolone-susceptible pulmonary TB, the guidelines recommend the use of a six-month regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM), rather than the 15-month or longer regimens in patients.

This recommendation is largely based on the findings of the open-label, multicentre, randomised noninferiority TB-PRACTECAL trial, which compared three all-oral 24-week investigative regimens, including BPaLM, to WHO SoC regimens for participants with MDR/RR or pre-XDR TB with or without fluoroquinolone resistance. The SoC regimens included 9-12 months of injectable-containing regimens; 18-24-month pre-2019 WHO regimens; a 9-12-month all-oral regimen; and an 18-20-month all-oral regimen.

Participants receiving the BPaLM regimen (n=62) experienced higher levels of treatment success (89% vs 52%), lower levels of failure and recurrence (8% vs 26%), lower levels of loss to follow up (3% vs 20%), and lower levels of grade 3 or higher adverse events (21% vs 51%), compared with those treated with SoC regimens (n=66).

Limitations

It should be noted that  these recommendations are based on single or small studies and may not be applicable to the general population. Also, the clinical trials participants were younger than would generally be encountered in clinical practice. These studies also excluded children with severe TB or DR TB, pregnant individuals, and patients with severe forms of EP TB.