WCLH 2015: 9-Month Regimen Cures 82% of People with Multidrug-resistant TB in African Study


A 9-month standardized treatment regimen for multidrug-resistant tuberculosis (MDR-TB) cured 82% of people recruited to an observational study in Francophone Africa, according to a presentation at the 46th Union World Conference on Lung Health last week in Cape Town. The regimen showed similar effectiveness to the performance of 9-month MDR-TB treatment regimens in previous studies in Africa and Bangladesh, and with the exception of hearing loss, serious adverse events were rare.

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This finding gives further encouragement to the prospect of shortening MDR-TB treatment from 24 months to 9 months. A randomized study comparing 9-month and 24-month treatment for MDR-TB, the STREAM study, is due to report results in 2017. Further arms of the STREAM trial will test 2 additional MDR-TB treatment regimens: a 9-month all-oral regimen that does not require injections, and an even shorter 6-month regimen, both using the oral TB drug bedaquline.

This observational study was coordinated by the International Union Against Tuberculosis and Lung Disease and conducted in Benin, Burkina Faso, Burundi, Cameroon, Central African Republic, Côte d'Ivoire, Democratic Republic of Congo, Niger, and Rwanda. It recruited patients with confirmed rifampicin resistance, but excluded pregnant women and people who had received a previous second-line TB treatment regimen.

Participants received daily directly observed therapy using 4 months of kanamycin, moxifloxacin, prothionamide, isoniazid, clofazamine, ethambutol, and pyrazinamide (normally abbreviated as 4Km Mfx Pto H Cfz E Z), followed by 5 months of moxifloxacin, clofazamine, ethambutol, and pyrazinamide (5 Mfx Cfz E Z).

Drug susceptibility was established by molecular or phenotypic testing and checked by supranational laboratories, at baseline and on isolates obtained at month 6 of treatment or later. Outcomes of treatment were assessed by smear and culture testing and by clinical examination each month during treatment and every 6 months after the completion of treatment.

The study recruited 1029 participants over 29 months. Christopher Kuaban presented preliminary results for 408 participants who began treatment prior to July 2014. In this group 28% had experienced failure of standard first-line treatment with 2HREZ/4HR, 26% had failed the "category II" 8-month re-treatment regimen of 2HREZS/1HREZ/5HRE, 27% had relapsed after treatment, and 14% were new cases of drug-resistant infection (5% were unclassified). Just over half had major lung disease as a result of MDR TB (covering >50% of the lung area).

Smear and culture conversion was rapid for most participants. At 3 months 89% were culture negative and 77% were smear negative, and an overall intent-to-treat analysis showed that 82% were cured (defined as treatment termination without relapse and 3 consecutive negative cultures after a previous positive culture). The treatment failure rate was low (2.9%), but 6.6% were lost to follow-up and 7.8% died.

Overall, 22% of participants were HIV-positive and although treatment success rates did not differ by HIV status among those who survived, the death rate was higher among participants with HIV: 18% died, compared to 5% of HIV-negative participants.

High-level resistance to a fluoroquinilone was associated with a significantly lower cure rate (37.5% vs 83.7% for low-level resistance), while high-level resistance to isoniazid was associated with a modestly reduced likelihood of cure when compared to low-level resistance (76.1% vs 87.8%). Lack of susceptibility to fluoroquinolones was rare in this study population, affecting 8 participants, whereas high-level resistance to isoniazid was common, affecting just over a quarter of participants (n=109).

The most frequent severe and serious adverse event was hearing loss, affecting 8% of participants. Grade 1 liver enzyme elevations and gastrointestinal side effects were common, as was kidney toxicity, but these adverse events were rarely reported as severe. Hearing loss was significantly more common in people who already had some evidence of hearing loss at baseline (23% vs 4%) and in people living with HIV (17% vs 7%).

"These preliminary results from using a 9-month MDR-TB treatment regimen are excellent," said Arnaud Trebucq of the Union, a lead investigator of the study. "Implementing the shortened regimen is proving feasible and with improved outcomes compared with the standard MDR-TB treatment regimen."



C Kuaban, Z Kashongwe, A Bakayoko, et al. Preliminary results with a 9-month regimen for multidrug-resistant tuberculosis (MDR-TB) in francophone Africa. 46th World Conference on Lung Health. Cape Town, December 2-6, 2015. Late breaker abstract.