Disclosures: This study was supported by the TB Alliance (Global Alliance for TB Drug Development), the U.K. Department for International Development, the U.K. Department of Health, the Bill & Melinda Gates Foundation, the U.S. Agency for International Development, the Directorate General for International Cooperation of the Netherlands, Irish Aid, the Australia Department of Foreign Affairs and Trade, the Federal Ministry for Education and Research of Germany through KfW, a grant from the Medical Research Council and a grant from the National Research Foundation of South Africa. Nahid and Thwaites report no relevant financial disclosures.

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Triple-drug regimen yields favorable outcomes in drug-resistant TB

In a study conducted at three sites in South Africa, combination therapy with bedaquiline, pretomanid and linezolid led to favorable outcomes in most patients with highly drug-resistant tuberculosis.

The ongoing, open-label, single-group Nix-TB trial, which was published in The New England Journal of Medicine, assessed the safety and efficacy of the drug combination for 26 weeks in 109 patients with extensively drug-resistant TB and patients with multidrug-resistant TB that was not responsive to treatment or for which a second-line regimen had been discontinued due to adverse effects. The incidence of unfavorable outcome, defined as bacteriologic or clinical treatment failure or relapse during 6 months after the conclusion of treatment, served as the primary outcome. Favorable outcome at 6 months was defined as resolution of clinical disease or negative culture status if a patient’s outcome had not already been deemed unfavorable.

The median patient age was 35 years and median BMI was 19.7 kg/m2. The majority had cavities on chest radiographs and about half were men. Approximately half were also HIV positive, all of whom were treated with antiretroviral therapy during the trial. Of those enrolled, about 65% of patients had extensively drug-resistant TB, 17% had multidrug-resistant TB that did not respond to treatment and 17% had multidrug-resistant TB for which treatment was stopped due to adverse effects.

During the study, patients received oral bedaquiline (Sirturo, Janssen) 400 mg once daily for 2 weeks followed by 200 mg three times per week for 24 weeks in addition to pretomanid 200 mg daily for 26 weeks and linezolid 1,200 mg daily for up to 26 weeks. Linezolid dosing was adjusted depending on the toxic effects. The researchers also changed the dosing regimen of linezolid from 1,200 mg once daily to 600 mg twice daily during the study to assess whether the single daily dose would result in less clinical toxicity.

In a study conducted at three sites in South Africa, combination therapy with bedaquiline, pretomanid and linezolid led to favorable outcomes in most patients with highly drug-resistant tuberculosis.

Key findings

Results showed that 90% of patients had a favorable outcome at 6 months after the end of treatment. Unfavorable outcomes included seven deaths — six during treatment and one during follow-up — two relapses during follow-up and one loss to follow-up.

In subgroup analyses, a favorable outcome was observed in 89% of patients with extensively drug-resistant TB and 92% of patients with multidrug-resistant TB, findings that were consistent regardless of HIV status or linezolid dosing scheme, according to the researchers.

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All patients experienced at least one adverse event that occurred or worsened during treatment, with 17% of patients experiencing serious adverse events. Frequency of these events was similar regardless of HIV status. Peripheral neuropathy and myelosuppression, which are expected toxic side effects of linezolid, occurred in 81% and 48% of patients, respectively. The researchers noted, however, they were manageable with dose reductions or treatment interruptions.

All patients who survived completed 26 weeks of therapy, including two who extended to 39 weeks. Treatment interruption lasting longer than the allowed 35 consecutive days occurred in one patient and none permanently discontinued the regimen. Overall, about one-third of patients completed 26 weeks of linezolid treatment without any interruption, albeit with potential dose reduction, and 15% completed 26 weeks of linezolid treatment at a total daily dose of 1,200 mg without interruption or dose reduction.

More work necessary

In an accompanying editorial, Guy Thwaites, FRCP, from the Oxford University Clinical Research Unit in Ho Chi Minh City, Vietnam, and the Centre for Tropical Medicine and Global Health in Nuffield Department of Medicine at the University of Oxford in the United Kingdom, and Payam Nahid, MD, MPH, from the UCSF Center for Tuberculosis and division of pulmonary and critical care medicine at the University of California, San Francisco, wrote that the Nix-TB researchers “are to be congratulated. ... The study was rigorously conducted and laudably designed.” However, they also cautioned against relying on a small, single-group study conducted in one country, given the prevalence of TB.

“A rejuvenated program of innovative phase 3 and phase 3 clinical trials of new drugs and regimens, in conjunction with continued investment in tools for detecting and monitoring resistance, is required worldwide. It will take substantially greater investment and coordinated forms of collaboration among sponsors, industry, academic partners and policy decision-makers to develop and implement new evidence-based regimens that are fitting for a disease that has killed hundreds of millions of people,” Thwaites and Nahid wrote. “Until that happens, if the current inadequate investment path is held, history is bound to repeat itself — and for all the jubilation that comes with developing a new effective regimen, there will be more tragedy yet to come.” – by Melissa Foster

Disclosures: This study was supported by the TB Alliance (Global Alliance for TB Drug Development), the U.K. Department for International Development, the U.K. Department of Health, the Bill & Melinda Gates Foundation, the U.S. Agency for International Development, the Directorate General for International Cooperation of the Netherlands, Irish Aid, the Australia Department of Foreign Affairs and Trade, the Federal Ministry for Education and Research of Germany through KfW, a grant from the Medical Research Council and a grant from the National Research Foundation of South Africa. Nahid and Thwaites report no relevant financial disclosures.