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Highlights from

The European Congress of Clinical Microbiology & Infectious Diseases

29th Annual Meeting

Amsterdam 13-16 April 2019

Bedaquiline-based regimens are effective and safe for MDR-TB but resistance is emerging

Take-home messages
  • Bedaquiline-based regimens are effective and safe for M/XDR-TB, but there is evidence of resistance
  • The efficacy of delamanid for M/XDR-TB has yet to be fully determined
  • The WHO published new MDR-TB guidelines in March 2019
“Bedaquiline is currently a super-drug and we do not see any treatment outcome difference between patients with MDR-TB and patients without MDR-TB because these bedaquiline-based regimens works so well.”

Dr Christoph Lange, Head of the Clinical Tuberculosis Centre, German Centre for Infection Research, Germany

Bedaquiline-based regimens are effective and safe for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB); however, resistance to the drug is emerging. The efficacy of delamanid has yet to be fully determined.

Dr Christoph Lange, Professor of Medicine at the University of Lübeck and Head of the Clinical Tuberculosis Centre, German Centre for Infection Research, Borstel, Germany, presented clinical evidence for these drugs and discussed new guidelines for M/XDR-TB at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2019, Amsterdam, the Netherlands.

Globally, TB incidence is decreasing by about 2% per year. However, between 2009 and 2018, the number of new cases of MDR-TB increased by about 20% per year. TB is one of the top-10 causes of death.

“The emergence of M and XDR-TB enormously complicates and jeopardises the goals of the WHO to eradicate TB,” said Dr Lange. “Treatment outcomes are very much dependent on the level of resistance of the causative bacterium,” he added.

In drug-susceptible patients, TB can be effectively treated in 84% of patients. 54% of patients with MDR-TB can be treated effectively, but only 34% of XDR-TB cases can be treated effectively. In the pre-antibiotic era, before 1947, only 20% of patients with TB survived.

Bedaquiline is a new class of drugs that inhibits ATP synthase. Most antibiotics for TB target cell wall assembly. The first study demonstrating bedaquiline's effectiveness was published in 2009. This 8-week bactericidal activity study included patients with MDR-TB on optimised backbone treatment; 21 patients received bedaquiline and 23 received placebo prospectively.

“The results were dramatic,” said Dr Lange. “More than 90% of those patients who received placebo did not achieve culture conversion within 8 weeks, but more than 50% in the bedaquiline group achieved culture conversion.”

Similar results were replicated in a phase IIb trial with a larger number of patients. This study also showed that there were no differences in adverse events between the bedaquiline and placebo groups. The effectiveness of bedaquiline was then demonstrated in a phase III trial and three post-marketing studies published in 2016 and 2017, which included a retrospective study of 428 patients.

“Bedaquiline is currently a super-drug and we do not see any treatment outcome difference between patients with MDR-TB and patients without MDR-TB because these bedaquiline-based regimens works so well,” Dr Lange told the audience.

However, bedaquiline resistance is a looming threat. Seven resistant strains have been collected from Germany and Austria in the last 2 years alone. “This is a worrisome number,” Dr Lange said.

Resistance to bedaquiline is acquired by the same mechanism as clofazimine and may be transferred. Researchers have seen that exposure to clofazimine induces resistance to bedaquiline.

“We need to be aware that this honeymoon phase of successful treatment may soon be over if bedaquiline and clofazimine are not used wisely for patients with MDR-TB,” he said.

Delamanid, in contrast to bedaquiline, inhibits mycolic acid assembly in the bacterial cell wall. An initial 8-week bactericidal activity study, similar in design to the bedaquiline study, showed that the addition of delamanid 100 mg or 200 mg twice daily to an optimised backbone regimen significantly increased the number of patients achieving culture conversion (p<0.05).

However, results from a multicentre, double-blind, placebo-controlled phase III trial of 511 patients published in January 2019 showed that there was no significant difference in effectiveness between delamanid- and placebo-based regimens (p=0.9). The results were partly explained by the unexpected effectiveness of the placebo arm, in which 77% of patients achieved cure.

“Delamanid may actually be better than it looks currently from this clinical trial but we need to see from other trials. The good news is that more data will come out in the near future,” Dr Lange explained.

In the week of World TB day (29 March) 2019, the WHO published new guidelines for the treatment of MDR-TB. The recommendations were based on a retrospective meta-analysis of 12,000 patients.

“This large retrospective analysis has revolutionised the WHO's recommendations on which drugs to use for the treatment of MDR-TB," said Dr Lange.

Dr Lange expressed some concern in relation to the evidence base for the new WHO guidelines.

“There’s one problem with the meta-analysis that the WHO guidelines are based - that it is based on the starting treatment the patient is given. About 90% of patients do not stay on their starting treatment but change their regimen during treatment. This has not gone into the analysis; so the patient may have a totally different treatment for the duration of the therapy,” he said.

“We do not really know which drug has been effective if 90% of the patients are changing their treatment at some point along their treatment course. We need to be cautious with this analysis and whether it really reflects the efficacy of the drugs,” he added.

Dr Lange concluded the talk by giving his own evidence-based recommendations for MDR-TB treatment, which were published in the International Journal of Tuberculosis and Lung Disease earlier this year.

Based on Lange C. New antimycobacterial drugs: a hope for drug-resistant tuberculosis (symposium S0488). Presented on Sunday 15 April 2019.

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The content and interpretation of these conference highlights are the views and comments of the speakers/ authors.

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