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Delamanid expanded access novel treatment of drug resistant tuberculosis.

ABSTRACT: Tuberculosis (TB) remains a global emergency and is one of the most common infectious disease causes of death in developing countries. Current treatment regimens for multi-drug resistant TB are associated with low treatment success rates, are toxic, and require long duration of treatment. The need for shorter and more effective treatment regimens is urgent. Delamanid (Deltyba, or formerly known as OPC-67683) is a new dihydro-imidazooxazole anti-TB drug active against resistant forms of pulmonary TB. Delamanid kills Mycobacterium tuberculosis by inhibiting the synthesis of mycolic acids required for cell wall synthesis. Whilst delamanid has been included in the WHO Model List of Essential Medicine by the World Health Organization Expert Committee on Selection and Use of Essential Medicines and in international guidance for the treatment of multi-drug resistant TB since April 2014, its access in countries with the greatest need, has proven challenging. This review provides an update on currently available clinical safety and efficacy data on delamanid and offers a discussion on research priorities and recommendations for expedited, expanded access.

SUBMITTER: Rustomjee R

PROVIDER: S-EPMC4631416 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Delamanid expanded access novel treatment of drug resistant tuberculosis.

Rustomjee Roxana R Zumla Alimuddin A

Infection and drug resistance 20151029

Tuberculosis (TB) remains a global emergency and is one of the most common infectious disease causes of death in developing countries. Current treatment regimens for multi-drug resistant TB are associated with low treatment success rates, are toxic, and require long duration of treatment. The need for shorter and more effective treatment regimens is urgent. Delamanid (Deltyba, or formerly known as OPC-67683) is a new dihydro-imidazooxazole anti-TB drug active against resistant forms of pulmonary ...[more]

PMID: 26604805

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Project description:BackgroundPatients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.MethodsIn an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.ResultsA total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.ConclusionsThe combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).

Project description:BACKGROUND:Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis. METHODS:We enrolled 41 patients who had sputum-culture-positive extensively drug-resistant (XDR) tuberculosis and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring. RESULTS:By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P=0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed. CONCLUSIONS:Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.).

Project description:BackgroundIn 2013, approximately 480,000 people developed active multidrug-resistant tuberculosis (MDR-TB), while only 97,000 started MDR-TB treatment. We sought to estimate the impact of improving access to MDR-TB diagnosis and treatment, under multiple diagnostic algorithm and treatment regimen scenarios, on ten-year projections of MDR-TB incidence and mortality.MethodsWe constructed a dynamic transmission model of an MDR-TB epidemic in an illustrative East/Southeast Asian setting. Using approximate Bayesian computation, we investigated a wide array of potential epidemic trajectories consistent with current notification data and known TB epidemiology.ResultsDespite an overall projected decline in TB incidence, data-consistent simulations suggested that MDR-TB incidence is likely to rise between 2015 and 2025 under continued 2013 treatment practices, although with considerable uncertainty (median 17% increase, 95% Uncertainty Range [UR] -38% to +137%). But if, by 2017, all identified active TB patients with previously-treated TB could be tested for drug susceptibility, and 85% of those with MDR-TB could initiate MDR-appropriate treatment, then MDR-TB incidence in 2025 could be reduced by 26% (95% UR 4-52%) relative to projections under continued current practice. Also expanding this drug-susceptibility testing and appropriate MDR-TB treatment to treatment-naïve as well as previously-treated TB cases, by 2020, could reduce MDR-TB incidence in 2025 by 29% (95% UR 6-55%) compared to continued current practice. If this diagnosis and treatment of all MDR-TB in known active TB cases by 2020 could be implemented via a novel second-line regimen with similar effectiveness and tolerability as current first-line therapy, a 54% (95% UR 20-74%) reduction in MDR-TB incidence compared to current-practice projections could be achieved by 2025.ConclusionsExpansion of diagnosis and treatment of MDR-TB, even using current sub-optimal second-line regimens, is expected to significantly decrease MDR-TB incidence at the population level. Focusing MDR diagnostic efforts on previously-treated cases is an efficient first-step approach.

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Delamanid expanded access novel treatment of drug resistant tuberculosis.

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Delamanid expanded access novel treatment of drug resistant tuberculosis.

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