Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis

Dorman, Susan E.; Nahid, Payam; Kurbatova, Ekaterina V.; Phillips, Patrick P. J.; Bryant, Kia; Dooley, Kelly E.; Engle, Melissa; Goldberg, Stefan; Phan, Ha; Hakim, James; Johnson, John L.; Lourens, Madeleine; Martinson, Neil; Muzanyi, Grace; Narunsky, Kim; Nerette, Sandy; Nguyen, Nhung Viet; Pham, Thuong H.; Pierre, Samuel; Purfield, Anne; Samaneka, Wadzanai; Savic, Radojka M.; Sanne, Ian; Scott, Nigel; Shenje, Justin; Sizemore, Erin; Vernon, Andrew; Waja, Ziyaad; Weiner, Marc; Swindells, Susan; Chaisson, Richard E.

doi:10.1056/nejmoa2033400

Cited by 342 publications

(259 citation statements)

References 38 publications

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“…PC: Apr2020 Est. SC: Dec2020 US, Brazil, China, Haiti, Peru, India, Thailand, Vietnam, Kenya, Malawi, S.Africa, Uganda, Zimbabwe 2516 ≥ 12 Staged approach, CD4 ≥ 100 A 4-month rifapentine and moxifloxacin regimens Standard 6-month control 18 months Non-inferior [6.6%] Completed and published [ 31 ] Rifashort, NCT02581527 Reg: 21Oct2015 Est. PC: Jan2021 Est.…”

Section: Resultsmentioning

confidence: 99%

A systematic review of endpoint definitions in late phase pulmonary tuberculosis therapeutic trials

Hills¹,

Lyimo²,

Nahid

et al. 2021

Trials

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Background Safe, more efficacious treatments are needed to address the considerable morbidity and mortality associated with pulmonary tuberculosis (TB). However, the current practice in TB therapeutics trials is to use composite binary outcomes, which in the absence of standardization may inflate false positive and negative errors in evaluating regimens. The lack of standardization of outcomes is a barrier to the identification of highly efficacious regimens and the introduction of innovative methodologies Methods We conducted a systematic review of trials designed to advance new pulmonary TB drugs or regimens for regulatory approval and inform practice guidelines. Trials were primarily identified from the WHO International Clinical Trial Registry Platform (ICTRP). Only trials that collected post-treatment follow-up data and enrolled at least 100 patients were included. Protocols and Statistical Analysis Plans (SAP) for eligible trials from 1995 to the present were obtained from trial investigators. Details of outcome data, both explicit and implied, were abstracted and organized into three broad categories: favorable, unfavorable, and not assessable. Within these categories, individual trial definitions were recorded and collated, and areas of broad consensus and disagreement were identified and described. Results From 2205 trials in any way related to TB, 51 were selected for protocol and SAP review, from which 31 were both eligible and had accessible documentation. Within the three designated categories, we found broad consensus in the definitions of favorable and unfavorable outcomes, although specific details were not always provided, and when explicitly addressed, were heterogeneous. Favorable outcomes were handled the most consistently but were widely variable with respect to specification. In some cases, the same events were defined differently by different protocols, particularly in distinguishing unfavorable from not assessable events. Death was often interpreted as conditional on cause. Patients who did not complete the study because of withdrawal or loss to follow-up presented a particular challenge to consistent interpretation and analytic treatment of outcomes. Conclusions In a review of 31 clinical trials, we found that outcome definitions were heterogeneous, highlighting the need to establish clearer specification and a move towards universal standardization of outcomes across pulmonary TB trials. The ICH E9 (R1) addendum provides guidelines for undertaking and achieving this goal. PROSPERO registration PROSPERO CRD42020197993. Registration 11 August 2020.

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Section: Resultsmentioning

confidence: 99%

A systematic review of endpoint definitions in late phase pulmonary tuberculosis therapeutic trials

Hills¹,

Lyimo²,

Nahid

et al. 2021

Trials

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“…Interestingly, the influence of any of the parameters had a lesser impact when regimens were fortified, a feature that emerged in the recently published TBTC 31 study which showed that the combined arm of moxifloxacin with rifapentine proved non-inferior to conventional regimen among all subgroups analysed, irrespective of the baseline radiological abnormalities [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Predictors of unfavorable responses to therapy in rifampicin-sensitive pulmonary tuberculosis using an integrated approach of radiological presentation and sputum mycobacterial burden

et al. 2021

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Introduction Despite the exalted status of sputum mycobacterial load for gauging pulmonary tuberculosis treatment and progress, Chest X-rays supplement valuable information for taking instantaneous therapeutic decisions, especially during the COVID-19 pandemic. Even though literature on individual parameters is overwhelming, few studies have explored the interaction between radiographic parameters denoting severity with mycobacterial burden signifying infectivity. By using a sophisticated approach of integrating Chest X-ray parameters with sputum mycobacterial characteristics, evaluated at all the three crucial time points of TB treatment namely pre-treatment, end of intensive phase and completion of treatment, utilizing the interactive Cox Proportional Hazards model, we aimed to precisely deduce predictors of unfavorable response to TB treatment. Materials and method We extracted de-identified data from well characterized clinical trial cohorts that recruited rifampicin-sensitive Pulmonary TB patients without any comorbidities, taking their first spell of anti-tuberculosis therapy under supervision and meticulous follow up for 24 months post treatment completion, to accurately predict TB outcomes. Radiographic data independently obtained, interpreted by two experienced pulmonologists was collated with demographic details and, sputum smear and culture grades of participants by an independent statistician and analyzed using the Cox Proportional Hazards model, to not only adjust for confounding factors including treatment effect, but also explore the interaction between radiological and bacteriological parameters for better therapeutic application. Results Of 667 TB patients with data available, cavitation, extent of involvement, lower zone involvement, smear and culture grade at baseline were significant parameters predisposing to an unfavorable TB treatment outcome in the univariate analysis. Reduction in radiological lesions in Chest X-ray by at least 50% at 2 months and 75% at the end of treatment helped in averting unfavorable responses. Smear and Culture conversion at the end of 2 months was highly significant as a predictor (p<0.001). In the multivariate analysis, the adjusted hazards ratios (HR) for an unfavorable response to TB therapy for extent of involvement, baseline cavitation and persistence (post treatment) were 1.21 (95% CI: 1.01–1.44), 1.73 (95% CI: 1.05–2.84) and 2.68 (95% CI: 1.4–5.12) respectively. A 3+ smear had an HR of 1.94 (95% CI: 0.81–4.64). Further probing into the interaction, among patients with 3+ and 2+ smears, HRs for cavitation were 3.26 (95% CI: 1.33–8.00) and 1.92 (95% CI: 0.80–4.60) while for >2 zones, were 3.05 (95% CI: 1.12–8.23) and 1.92 (95% CI: 0.72–5.08) respectively. Patients without cavitation, zonal involvement <2, and a smear grade less than 2+ had a better prognosis and constituted minimal disease. Conclusion Baseline Cavitation, Opacities occupying >2 zones and 3+ smear grade individually and independently forecasted a poorer TB outcome. The interaction model revealed that Zonal involvement confined to 2 zones, without a cavity and smear grade up to 2+, constituting “minimal disease”, had a better prognosis. Radiological clearance >50% along with smear conversion at the end of intensive phase of treatment, observed to be a reasonable alternative to culture conversion in predicting a successful outcome. These parameters may potentially take up key positions as stratification factors for future trials contemplating on shorter TB regimens.

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“…This first-line recommendation has failed to adapt in the last thirty-five years despite increasing occurrence of drug resistance. Recently, a phase 3 trial provided evidence of a four-month treatment regimen with rifapentine and moxifloxacin [3]. Additionally, many efforts have been made to reduce the mycobacterial burden (reducing mortality and transmission), eradicating persistent mycobacterial populations, and to reduce drug-resistance through various incentives such as END-TB [4] and WHO End TB Strategy 2016 -2035 [5].…”

Section: Tuberculosis and Its Global Health Threatmentioning

confidence: 99%

Microfluidics as a Novel Technique for Tuberculosis: From Di-agnostics to Drug Discovery

Molloy¹,

Harrison²,

McGrath³

et al. 2021

Preprint

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Tuberculosis (TB) remains a global healthcare crisis with an estimated 10 million new cases and 1.4 million deaths per year TB is caused by infection with the major human pathogen Mycobacte-rium tuberculosis, which is difficult to rapidly diagnose and treat. There is an urgent need for new methods of diagnosis, sufficient in vitro models which capably mimic all physiological condi-tions of the infection, and high-throughput drug screening platforms. Microfluidic-based tech-niques provide single-cell analysis which reduces experimental time, the cost of reagents, and have been extremely useful for gaining insight into monitoring microorganisms. This review out-lines the field of microfluidics and discusses the use of this novel technique so far in M. tuberculo-sis diagnostics, research methods, and drug discovery platforms. The practices of microfluidics have promising future applications for diagnosing and treating TB.

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Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis

Cited by 342 publications

References 38 publications

A systematic review of endpoint definitions in late phase pulmonary tuberculosis therapeutic trials

A systematic review of endpoint definitions in late phase pulmonary tuberculosis therapeutic trials

Predictors of unfavorable responses to therapy in rifampicin-sensitive pulmonary tuberculosis using an integrated approach of radiological presentation and sputum mycobacterial burden

Microfluidics as a Novel Technique for Tuberculosis: From Di-agnostics to Drug Discovery

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