Long-term effectiveness of shortened DR-TB treatment regimen

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Results from an International Union Against Tuberculosis and Lung Disease (The Union)-led observational study show that a nine-month shortened treatment regimen for rifampicin-resistant tuberculosis (RR-TB) delivered to patients under programmatic conditions maintains a good level of effectiveness up to 24 months after completion. Until now there has been limited data on the long-term effectiveness of this treatment regimen after completion.

The study reports on the outcome during treatment and after completion of the injectable-containing shortened regimen using kanamycine and normal-dose moxifloxacin for 1006 people from nine francophone African countries. Sputum cultures were collected every six months up to 24 months following their treatment completion. The risk of any unfavourable outcome, of failure and relapse, and of death during and after treatment was analysed according to individual characteristics and initial drug susceptibility. 79.3 percent of people who underwent this treatment during the 2013-2015 inclusion period had a relapse-free successful outcome with 9.6 percent of people having a combined failure and relapse after 24 months. These programmatic results are very similar to those produced in the STREAM stage 1 randomised clinical trial.

“We believe that these results are of high public health relevance by showing the good long-term outcomes of this regimen in low-and middle-income settings”, said Valérie Schwoebel, lead author of the study and consultant for The Union. “We hope to see similar high-quality data on the long-term post-treatment success for other regimens, including all-oral shorter treatment regimens for drug-resistant TB.”

According to the latest data of the World Health Organisation (WHO), treatment outcomes for people with multidrug-resistant (MDR) and RR-TB show a global treatment success rate of 56%. The majority of these patients are expected to benefit through use of shorter treatment regimens. The regimen used in this study was included in the 2016 WHO guidelines as a recommended regimen. WHO’s 2018 revision to the guidelines maintained this recommendation with additional precautions and exclusion criteria.

The results support the WHO recommendation that all people with RR-TB be offered drug susceptibility testing for fluoroquinolones and reinforces the WHO 2018 recommended use of this regimen for patients with RR-TB likely to be susceptible to the newest generation of fluoroquinolones, but does not support exclusion criteria based on resistance to drugs other than fluoroquinolones.

Abstract
Background: Treatment outcomes of the shorter regimen for rifampicin-resistant tuberculosis are not completely established. We report on these outcomes two years after treatment completion among patients enrolled in an observational cohort study in nine African countries.
Methods: 1,006 patients treated with the nine-month regimen were followed every six months with sputum cultures up to 24 months after treatment completion. The risk of any unfavourable outcome, of failure and relapse, and of death during and after treatment was analysed according to patient’s characteristics and initial drug susceptibility by Cox proportional hazard models.

Findings: Respectively 67.8% and 57.2% patients had >=1 culture result six months and 12 months after treatment completion. Fourteen relapses were diagnosed. The probability of relapse-free success was 79.3% (95% confidence interval [CI] 76.6–82.0%) overall, 80.9% (95% CI 78.0–84.0%) among HIV-negative and 72.5% (95% CI 66.5–78.9%) among HIV-infected patients. Initial fluoroquinolone (adjusted hazard ratio [aHR] 6.7 [95% CI 3.4–13.1]) and isoniazid resistance (aHR 9.4 [95% CI 1.3–68.0]) were significantly associated with increased risk of failure/relapse and of any unfavourable outcome.
Interpretation: The close to 80% relapse-free success indicates the good outcome of the regimen in low-and middle-income settings. Results confirm the lesser effectiveness of the regimen in patients with initial resistance to fluoroquinolones and support the use of high-dose isoniazid, but do not support exclusion of patients for resistance to drugs other than fluoroquinolones.

Authors
Valérie Schwœbel, Arnaud Trébucq, Zacharie Kashongwe, Alimata S. Bakayoko, Christopher Kuaban, Juergen Noeske, Souleymane H Harouna, Mahamadou B Souleymane, Alberto Piubello, François Ciza, Valentin Fikouma, Michel Gasana, Martial Ouedraogo, Martin Gninafon, Armand Van Deun, Elisa Tagliani, Daniela M Cirillo, Kobto G Koura, Hans L Rieder

EClinical Medicine abstract

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