Nail in the Coffin for Injectable Therapy in Drug-Resistant TB?

Oral treatment containing bedaquiline was associated with better outcomes for patients with drug-resistant tuberculosis (TB) compared with an injectable treatment regimen, a retrospective cohort study showed.

In adjusted analyses, the rate of treatment success (defined as cure or treatment completion without evidence of recurrence) was 69.5% with the oral regimen versus 56.7% with the injectable regimen, reported Norbert Ndjeka, MMed, of the National Department of Health in Pretoria, South Africa, and colleagues.

Moreover, the bedaquiline group had a lower risk of mortality during treatment (17% vs 22.4%, respectively), and slightly higher disease-free survival rates (99% vs 97%), the authors wrote in Lancet Infectious Diseases.

They also noted that injectable agents used to treat this type of TB can result in ototoxicity and nephrotoxicity.

Bedaquiline is a diarylquinoline. It was initially made available in South Africa for patients with TB strains resistant to rifampicin, an injectable, and a fluoroquinolone. The program eventually expanded to all patients with longer rifampicin-resistant TB regimens who experienced hearing loss as a result of the injectable-based treatment.

The WHO previously recommended a shorter, injectable-containing regimen for this drug-resistant TB, but they changed their guidelines on Monday to recommend a 6-month oral regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin for patients without prior exposure to bedaquiline, pretomanid, and linezolid. For patients requiring a 9-month regimen, the all-oral regimen is the preferred treatment, they said.

In an accompanying editorial, Jennifer Furin, MD, PhD, of Harvard Medical School in Boston, and Petros Isaakidis, MD, PhD, of Médecins Sans Frontières in Cape Town, South Africa, went over the limited options for those with drug-resistant TB: either an 18- to 24-month regimen with bedaquiline or the shorter 9- to 12-month injectable regimen, which could lead to hearing loss.

However, both regimens in this study were 9- to 12-month regimens, they noted.

"The concept that a shorter regimen is better was accepted in the drug-resistant tuberculosis community, ignoring the long-term impact of hearing loss, because this was not a programmatic outcome captured or monitored in tuberculosis [program] registers," they wrote. "These long-term efficacy results from South Africa should finally stop the routine use of injectable therapy for drug-resistant tuberculosis."

Study Details

Ndjeka's group examined outcomes over 24 months among patients who received the oral regimen containing bedaquiline or the injectable regimen beginning in 2017. Both regimens were identical, except that bedaquiline replaced the injectable antibiotic, kanamycin, at the start of treatment, they explained.

Overall, 1,387 patients were included in this retrospective cohort analysis -- 688 in the bedaquiline group and 699 in the injectable group. Patients in the bedaquiline group were significantly older (median age 42 vs 34), and more likely to be men (61% vs 56%). About 68% to 72% of patients in both groups were living with HIV, and antiretroviral therapy (ART) use in both groups was over 90%.

A total of 361 patients died within 24 months of treatment, 162 in the bedaquiline group and 199 in the injectable group. Median time to death was longer in the bedaquiline group (4.9 months vs 2.5 months). However, there was no difference in the post-treatment rate of mortality between groups (7% vs 6%).

Ndjeka's team acknowledged several limitations to their study, including its observational nature and potential residual confounding. Different provinces had different rollouts of bedaquiline, they added, and post-treatment outcomes required a valid national ID, which could have led to selection bias. Safety results were not assessed, though the authors noted that prior research showed bedaquiline is "safer and associated with substantially lower rates of treatment discontinuation" compared with injectable therapy.

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