Tradeoffs in Introduction Policies for the Anti-Tuberculosis Drug Bedaquiline: A Model-Based Analysis

Kunkel, Amber; Cobelens, Frank; Cohen, Ted

doi:10.1371/journal.pmed.1002142

Cited by 9 publications

(6 citation statements)

References 34 publications

(25 reference statements)

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“…For example, even if probabilities of acquiring bedaquiline or pretomanid resistance turn out to be relatively high, initial increases in bedaquiline-resistant or pretomanid-resistant TB transmission could be counterbalanced by reduced RR-TB transmission; in addition, most acquired bedaquiline- and pretomanid resistance would occur in RS-TB strains for which other treatment options would still exist as long as the bedaquiline resistance were identified [29]. Our conclusions resemble those of a previous analysis which favored use of bedaquiline for all multidrug-resistant TB rather than only extensively-drug-resistant TB despite the increase in acquired bedaquiline resistance [30]. However, over several years and several cycles of transmission, compounding novel-drug resistance could pose a barrier to universal use of this novel regimen, with a moderately low barrier to resistance potentially resulting in novel-drug resistance in up to 5% of TB cases after 5 years and more than 10% of TB cases after 50 years under pessimistic assumptions and drug resistance transmission [31].…”

Section: Discussionsupporting

confidence: 74%

Estimating the impact of a novel drug regimen for treatment of tuberculosis: a modeling analysis of projected patient outcomes and epidemiological considerations

et al. 2019

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Background Regimens that could treat both rifampin-resistant (RR) and rifampin-susceptible tuberculosis (TB) while shortening the treatment duration have reached late-stage clinical trials. Decisions about whether and how to implement such regimens will require an understanding of their likely clinical impact and how this impact depends on local epidemiology and implementation strategy. Methods A Markov state-transition model of 100,000 representative South African adults with TB was used to simulate implementation of the regimen BPaMZ (bedaquiline, pretomanid, moxifloxacin, and pyrazinamide), either for RR-TB only or universally for all patients. Patient outcomes, including cure rates, time with active TB, and time on treatment, were compared to outcomes under current care. Sensitivity analyses varied the drug-resistance epidemiology, rifampin susceptibility testing practices, and regimen efficacy. Results Using BPaMZ exclusively for RR-TB increased the proportion of all RR-TB that was cured by initial treatment from 60 ± 1% to 67 ± 1%. Expanding use of BPaMZ to all patients increased cure of RR-TB to 89 ± 1% and cure of all TB from 87.3 ± 0.1% to 89.5 ± 0.1%, while shortening treatment by 1.9 months/person. In sensitivity analyses, reducing the coverage of rifampin susceptibility testing resulted in lower projected proportions of patients cured under all regimen scenarios (current care, RR-only BPaMZ, and universal BPaMZ), compared to the proportions projected using South Africa’s high coverage; however, this reduced coverage resulted in greater expected incremental benefits of universal BPaMZ implementation, both when compared to RR-only BPaMZ implementation and when compared to to current care under the same low rifampin susceptibility testing coverage. In settings with higher RR-TB prevalence, the benefits of BPaMZ were magnified both for RR-specific and universal BPaMZ implementation. Conclusions Novel regimens such as BPaMZ could improve RR-TB outcomes and shorten treatment for all patients, particularly with universal use. Decision-makers weighing early options for implementing such regimens at scale will want to consider the expected impact on patient outcomes and on the burden of treatment in their local context.

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Section: Discussionsupporting

confidence: 74%

Estimating the impact of a novel drug regimen for treatment of tuberculosis: a modeling analysis of projected patient outcomes and epidemiological considerations

et al. 2019

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“…The median frequencies of phenotypic and genotypic ABR amounted to 2.2% (IQR 1.1%–4.6%) and 4.4% (IQR 1.8%–5.8%), respectively. This is coherent with the results of a model estimation by Kunkel et al ., 41 who simulated a mean ABR frequency of 5.88% when using bedaquiline without tight restrictions for all patients with MDR-TB. However, for the latter study the method used for the determination of bedaquiline resistance was not specified.…”

Section: Discussionmentioning

confidence: 99%

“…Yet, should we be more prudent with the indication of bedaquiline, maybe restricting its use to patients with more advanced resistance patterns? Based on a meta-analysis of the effect of drugs (but not of regimens) Kunkel and colleagues 41 developed a mathematical decision model to estimate the impact of providing bedaquiline to different subcategories of DR-TB patients. They found that by limiting bedaquiline access solely to patients with more advanced resistance patterns, the risk of bedaquiline resistance might be reduced, but thus the risk of resistance to other drugs (e.g.…”

Section: Discussionmentioning

confidence: 99%

Acquired bedaquiline resistance during the treatment of drug-resistant tuberculosis: a systematic review

Mallick

Nair

Abbew

et al. 2022

JAC-Antimicrobial Resistance

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Background Drug-resistant tuberculosis (DR-TB) is considered to be a public health threat and is difficult to cure, requiring a lengthy treatment with potent, potentially toxic drugs. The novel antimicrobial agent bedaquiline has shown promising results for patients with DR-TB, improving the rate of culture conversion and reducing TB-related mortality. However, increasing numbers of cases with acquired bedaquiline resistance (ABR) have been reported in recent years. Methods This systematic review aimed to assess the frequency of ABR and characteristics of patients acquiring it. Studies showing data on sequential bedaquiline drug-susceptibility testing in patients treated with a bedaquiline-containing regimen were included. The databases CENTRAL, PubMed and Embase were manually searched, and 866 unique records identified, eventually leading to the inclusion of 13 studies. Phenotypic ABR was assessed based on predefined MIC thresholds and genotypic ABR based on the emergence of resistance-associated variants. Results The median (IQR) frequency of phenotypic ABR was 2.2% (1.1%–4.6%) and 4.4% (1.8%–5.8%) for genotypic ABR. Among the studies reporting individual data of patients with ABR, the median number of likely effective drugs in a treatment regimen was five, in accordance with WHO recommendations. In regard to the utilization of important companion drugs with high and early bactericidal activity, linezolid was included in the regimen of most ABR patients, whereas the usage of other group A (fluoroquinolones) and former group B drugs (second-line injectable drugs) was rare. Conclusions Our findings suggest a relevant frequency of ABR, urging for a better protection against it. Therefore, treatment regimens should include drugs with high resistance-preventing capacity through high and early bactericidal activity.

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“…However, in recent experience, such decisions have ignited ethical debates (152). Coupling mathematical modeling with field-based studies has proven useful for understanding the effectiveness of antimicrobial use policies, as highlighted in recent evaluations of the risk of resistance under population-wide access of the tuberculosis drug bedaquiline (153,154) and antimicrobial cycling to limit resistance selection in hospital settings (155,156).…”

Section: Antimicrobial Drugsmentioning

confidence: 99%

Emerging Challenges and Opportunities in Infectious Disease Epidemiology

Lewnard

Reingold

2019

American Journal of Epidemiology

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Much of the intellectual tradition of modern epidemiology stems from efforts to understand and combat chronic diseases persisting through the 20th century epidemiologic transition of countries such as the United States and United Kingdom. After decades of relative obscurity, infectious disease epidemiology has undergone an intellectual rebirth in recent years amid increasing recognition of the threat posed by both new and familiar pathogens. Here, we review the emerging coalescence of infectious disease epidemiology around a core set of study designs and statistical methods bearing little resemblance to the chronic disease epidemiology toolkit. We offer our outlook on challenges and opportunities facing the field, including the integration of novel molecular and digital information sources into disease surveillance, the assimilation of such data into models of pathogen spread, and the increasing contribution of models to public health practice. We next consider emerging paradigms in causal inference for infectious diseases, ranging from approaches to evaluating vaccines and antimicrobial therapies to the task of ascribing clinical syndromes to etiologic microorganisms, an age-old problem transformed by our increasing ability to characterize human-associated microbiota. These areas represent an increasingly important component of epidemiology training programs for future generations of researchers and practitioners.

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Tradeoffs in Introduction Policies for the Anti-Tuberculosis Drug Bedaquiline: A Model-Based Analysis

Cited by 9 publications

References 34 publications

Estimating the impact of a novel drug regimen for treatment of tuberculosis: a modeling analysis of projected patient outcomes and epidemiological considerations

Estimating the impact of a novel drug regimen for treatment of tuberculosis: a modeling analysis of projected patient outcomes and epidemiological considerations

Acquired bedaquiline resistance during the treatment of drug-resistant tuberculosis: a systematic review

Emerging Challenges and Opportunities in Infectious Disease Epidemiology

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