Assessing the impacts of short-course multidrug-resistant tuberculosis treatment in the Southeast Asia Region using a mathematical modeling approach

This study aimed to predict the impacts of shorter duration treatment regimens for multidrug-resistant tuberculosis (MDR-TB) on both MDR-TB percentage among new cases and overall MDR-TB cases in the WHO Southeast Asia Region. A deterministic compartmental model was constructed to describe both the transmission of TB and the MDR-TB situation in the Southeast Asia region. The population-level impacts of short-course treatment regimens were compared with the impacts of conventional regimens. Multi-way analysis was used to evaluate the impact by varying programmatic factors (eligibility for short-course MDR-TB treatment, treatment initiation, and drug susceptibility test (DST) coverage). The model predicted that overall TB incidence will be reduced from 246 (95% credible intervals (CrI), 221–275) per 100,000 population in 2020 to 239 (95% CrI, 215–267) per 100,000 population in 2035, with a modest reduction of 2.8% (95% CrI, 2.7%–2.9%). Despite the slight reduction in overall TB infections, the model predicted that the MDR-TB percentage among newly notified TB infections will remain steady, with 2.4% (95% CrI, 2.1–2.9) in 2020 and 2.5% (95% CrI, 2.3–3.1) in 2035, using conventional MDR-TB treatment. With the introduction of short-course regimens to treat MDR-TB, the development of resistance can be slowed by 38.6% (95% confidence intervals (CI), 35.9–41.3) reduction in MDR-TB case number, and 37.6% (95% CI, 34.9–40.3) reduction in MDR-TB percentage among new TB infections over the 30-year period compared with the baseline using the standard treatment regimen. The multi-way analysis showed eligibility for short-course treatment and treatment initiation greatly influenced the impacts of short-course treatment regimens on reductions in MDR-TB cases and percentage resistance among new infections. Policies which promote the expansion of short-course regimens and early MDR-TB treatment initiation should be considered along with other interventions to tackle antimicrobial resistance in the region.

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Multidisciplinary advisory teams to manage multidrug-resistant tuberculosis: the example of the French Consilium

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.18.0779 ◽

2019 ◽

Vol 23 (10) ◽

pp. 1050-1054

Author(s):

L. Guglielmetti ◽

J. Jaffré ◽

C. Bernard ◽

F. Brossier ◽

N. El Helali ◽

...

Keyword(s):

Multidrug Resistant ◽

New Drugs ◽

World Health ◽

Advisory Committees ◽

Treatment Regimens ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Health Organization

SETTING: The World Health Organization (WHO) recommends that multidrug-resistant tuberculosis (MDR-TB) treatment should be managed in collaboration with multidisciplinary advisory committees (consilia). A formal national Consilium has been established in France since 2005 to provide a centralised advisory service for clinicians managing MDR-TB and extensively drug-resistant (XDR-TB) cases.OBJECTIVE: Review the activity of the French TB Consilium since its establishment.DESIGN: Retrospective description and analysis of the activity of the French TB Consilium.RESULTS: Between 2005 and 2016, 786 TB cases or contacts of TB cases were presented at the French TB Consilium, including respectively 42% and 79% of all the MDR-TB and XDR-TB cases notified in France during this period. Treatment regimens including bedaquiline and/or delamanid were recommended for 42% of the cases presented at the French TB Consilium since 2009. Patients were more likely to be presented at the French TB Consilium if they were born in the WHO Europe Region, had XDR-TB, were diagnosed in the Paris region, or had resistance to additional drugs than those defining XDR-TB.CONCLUSION: The French TB Consilium helped supervise appropriate management of MDR/XDR-TB cases and facilitated implementation of new drugs for MDR/XDR-TB treatment.

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Active surveillance for adverse events in patients on longer treatment regimens for multidrug-resistant tuberculosis in Viet Nam

PLoS ONE ◽

10.1371/journal.pone.0255357 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0255357

Author(s):

Nguyen Bao Ngoc ◽

Hoa Vu Dinh ◽

Nguyen Thi Thuy ◽

Duong Van Quang ◽

Cao Thi Thu Huyen ◽

...

Keyword(s):

Risk Factors ◽

Adverse Events ◽

Bayesian Model Averaging ◽

Multidrug Resistant ◽

Treatment Regimens ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

Objective Management of multidrug-resistant tuberculosis (MDR-TB) is a significant challenge to the global healthcare system due to the complexity and long duration of the MDR-TB treatment. This study analyzed the safety of patients on longer injectable-based MDR-TB treatment regimens using active pharmacovigilance data. Method We conducted an observational, prospective study based on active pharmacovigilance within the national TB program. A total of 659 MDR-TB patients were enrolled and followed up at 9 TB- hospitals in 9 provinces of all 3 regions in Vietnam between 2014 and 2016. Patients received a treatment regimen (standardized or individualized) based on their drug susceptibility test result and their treatment history. Baseline and follow-up information was collected at the start and during treatment. Adverse events (AE) were defined and classified as serious adverse events (SAEs) or otherwise. Multivariate Cox regression following the Iterative Bayesian Model Averaging algorithm was performed to identify factors associated with AE occurrence. Results Out of 659 patients assessed, 71.3% experienced at least one AE, and 17.5% suffered at least one SAE. The most common AEs were gastrointestinal disorders (38.5%), arthralgia (34.7%), and psychiatric disorders (30.0%). The proportion of patients with nephrotoxicity and hearing loss or vestibular disorders were 7.4% and 15.2%, respectively. 13.1% of patients required modifications or interruption of one or more drugs. In 77.7% of patients, treatment was completed successfully, while 9.3% lost to follow-up, in 3.0% treatment failed, and 7.4% died. Some significant risk factors for nephrotoxicity included diabetes mellitus (HR = 8.46 [1.91–37.42]), renal dysfunction (HR = 8.46 [1.91–37.42]), alcoholism (HR = 13.28 [5.04–34.99]), and a higher average daily dose of injectable drugs (HR = 1.28 [1.14–1.43]). Conclusion While a majority of patients on the longer injectable-based regimens experienced non-serious AEs during MDR-TB treatment, one in six patients experienced at least an SAE. Active TB drug-safety monitoring is useful to understand the safety of MDR-TB treatment and explore the risk factors for toxicity. All-oral, shorter MDR-TB regimens might be able to reduce the inconvenience, discomfort, and toxicity of such regimens and increase adherence and likelihood of successful completion.

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Predicting the Outcomes of New Short-Course Regimens for Multidrug-Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modeling

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01487-18 ◽

2018 ◽

Vol 62 (12) ◽

Cited By ~ 2

Author(s):

Tan N. Doan ◽

Pengxing Cao ◽

Theophilus I. Emeto ◽

James M. McCaw ◽

Emma S. McBryde

Keyword(s):

Treatment Duration ◽

Treatment Success ◽

Empirical Evaluation ◽

Multidrug Resistant ◽

Pharmacodynamic Modeling ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Short Course ◽

Mdr Tb

ABSTRACT Short-course regimens for multidrug-resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug bedaquiline (BDQ) may have the potential to shorten MDR-TB treatment to less than 6 months when used in conjunction with standard anti-TB drugs. However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modeling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment. This model was then combined with a pharmacokinetic-pharmacodynamic model to simulate various short-course BDQ-containing regimens. Our modeling suggests that BDQ could reduce MDR-TB treatment duration to just 18 weeks (4 months) while still maintaining a very high treatment success rate (100% for daily BDQ for 2 weeks, or 95% for daily BDQ for 1 week during the intensive phase). The estimated time to bacterial clearance of these regimens ranges from 27 to 33 days. Our findings provide the justification for empirical evaluation of short-course BDQ-containing regimens. If short-course BDQ-containing regimens are found to improve outcomes, then we anticipate clear cost savings and a subsequent improvement in the efficiency of national TB programs.

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Time to Multidrug-Resistant Tuberculosis Treatment Initiation in Association with Treatment Outcomes in Shanghai, China

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02259-17 ◽

2018 ◽

Vol 62 (4) ◽

pp. e02259-17 ◽

Cited By ~ 6

Author(s):

Yong Chen ◽

Zhengan Yuan ◽

Xin Shen ◽

Jie Wu ◽

Zheyuan Wu ◽

...

Keyword(s):

Treatment Outcomes ◽

Treatment Initiation ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Treatment Delay ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Poor Outcomes

ABSTRACT In high tuberculosis (TB)-burden countries such as China, the diagnosis of multidrug-resistant tuberculosis (MDR-TB) using conventional drug susceptibility testing (DST) takes months, making treatment delay inevitable. Poor outcomes of MDR-TB might be associated with delayed, even inappropriate, treatment. The purposes of this study were to investigate the time to MDR-TB treatment initiation and to assess the association between early treatment and treatment outcomes. Between April 2011 and December 2014, this population-based retrospective cohort study collected the demographic and clinical characteristics and the drug susceptibility profiles of all registered MDR-TB patients in Shanghai, China. The dates of TB and MDR-TB diagnoses, DST performance, and treatment initiation were extracted to calculate the times to treatment. In total, 284 of 346 MDR-TB patients were eligible for analysis, and 68.3% (194/284) had favored outcomes. The median time to treatment initiation from TB diagnosis was 172 days among those with favored outcomes and 190 days among those with poor outcomes. Treatments initiated within 60 days after performing DST (odds ratio [OR], 2.56; 95% confidence interval [CI], 1.22 to 5.36) and empirical treatments (OR, 2.09; 95% CI, 1.01 to 4.32) were positively associated with favored outcomes. Substantial delays to MDR-TB treatment were observed when conventional DST was used. Early treatment predicted favored outcomes. Rapid diagnostic methods should be scaled up and improvements should be made in patient management and information linkage to reduce treatment delay.

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Deploying a novel tuberculosis molecular bacterial load assay to assess the elimination rate of Mycobacterium tuberculosis in patients with multidrug-resistant tuberculosis in Tanzania

10.1101/2020.09.02.280511 ◽

2020 ◽

Author(s):

Peter M. Mbelele ◽

Emmanuel A. Mpolya ◽

Elingarami Sauli ◽

Bariki Mtafya ◽

Nyanda E. Ntinginya ◽

...

Keyword(s):

Repeated Measures ◽

Bacterial Load ◽

Elimination Rate ◽

Multidrug Resistant ◽

Treatment Regimens ◽

Mixed Effects Modeling ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

AbstractBackgroundRifampin or multidrug-resistant-tuberculosis (RR/MDR-TB) treatment has transitioned to injectable-free regimens. We tested whether M. tuberculosis (Mtb) elimination rates measured by molecular bacterial load assay (TB-MBLA) in sputa correlate with composition of the RR/MDR-TB antibiotic regimen.MethodsSerial sputa were collected from patients with RR/MDR- and drug-sensitive TB at day 0, 3, 7, 14, and then monthly for 4 months of anti-TB treatment. TB-MBLA was used to quantify viable Mtb 16S rRNA in sputum for estimation of colony-forming-unit per mL (eCFU/mL). Mtb elimination rates were compared among regimens using nonlinear-mixed-effects modeling of repeated measures.ResultsAmong 37 patients with a total of 296 serial sputa; 7 patients received rifampin/isoniazid/pyrazinamide/ethambutol (RHZE), 8 an all-oral bedaquiline-based regimen, 9 an injectable and bedaquiline-containing regimen, and 13 an injectable-containing but bedaquiline-free regimen. The overall mean daily Mtb elimination was −0.24 [95% Confidence-Interval (CI); −0.39 to −0.08)] log10 eCFU/mL, and it varied with treatment-regimen (p < 0.001). Compared to the adjusted Mtb elimination of −0.17 (95% CI; −0.23 to −0.12) for the injectable-containing but bedaquiline-free reference regimen, the elimination rates were −0.62 (95% CI; −1.05 to −0.20) log10 eCFU/mL for the injectable and bedaquiline-containing regimen (p = 0.019), −0.35 (95% CI; −0.65 to −0.13) log10 eCFU/mL for the all-oral bedaquiline-based regimen (p = 0.054), and −0.29 (95% CI; −0.78 to +0.22) log10 eCFU/mL for RHZE (p = 0.332)ConclusionTB-MBLA distinguished Mtb elimination rates in sputa from patients receiving different treatment regimens, suggesting a reliable monitoring tool for RR/MDR-TB, that does not require mycobacterial culture.

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Improving access to contraception through integration of family planning services into a multidrug-resistant tuberculosis treatment programme

BMJ Sexual & Reproductive Health ◽

10.1136/bmjsrh-2019-200400 ◽

2019 ◽

Vol 46 (2) ◽

pp. 152-155

Author(s):

Emily F Cornish ◽

Jonathan Hudson ◽

Ross Sayers ◽

Marian Loveday

Keyword(s):

Contraceptive Use ◽

Multidrug Resistant ◽

Treatment Programme ◽

Post Intervention ◽

Female Patients ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Short Course ◽

Mdr Tb

ObjectivesMultidrug-resistant tuberculosis (MDR-TB) is a global public health priority. The advent of the World Health Organisation’s Short Course regimen for MDR-TB, which halves treatment duration, has transformed outcomes and treatment acceptability for affected patients. Bedaquiline, a cornerstone of the Short Course regimen, has unknown teratogenicity and the WHO therefore recommends reliable contraception for all female MDR-TB patients in order to secure eligibility for bedaquiline. We were concerned that low contraceptive uptake among female patients in our rural South African MDR-TB treatment programme could jeopardise their access to bedaquiline. We therefore conducted a service delivery improvement project that aimed to audit contraceptive use in female MDR-TB patients, integrate family planning services into MDR-TB care, and increase the proportion of female patients eligible for bedaquiline therapy.MethodsContraceptive use and pregnancy rates were audited in all female patients aged 13–50 years initiated on our MDR-TB treatment programme in 2016. We then implemented an intervention consisting of procurement of depot-medroxyprogesterone acetate (DMPA) for the MDR-TB unit and training of specialist MDR-TB nurses in administration of DMPA. The audit cycle was repeated for all female patients aged 13–50 years initiated on the programme in January–October 2017 (post-intervention).ResultsThe proportion of women on injectable contraceptives by the time of MDR-TB treatment initiation increased significantly in the post-intervention cohort (77.4% vs 23.9%, p<0.0001).ConclusionBy integrating contraceptive services into our MDR-TB programme we significantly increased contraceptive uptake, protecting women from the obstetric risks associated with pregnancy during MDR-TB treatment and maximising their eligibility for bedaquiline therapy.

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Drug exposure and susceptibility of second-line drugs correlate with treatment response in patients with multidrug resistant tuberculosis: a multi-centre prospective cohort study in China

European Respiratory Journal ◽

10.1183/13993003.01925-2021 ◽

2021 ◽

pp. 2101925

Author(s):

Xubin Zheng ◽

Lina Davies Forsman ◽

Ziwei Bao ◽

Yan Xie ◽

Zhu Ning ◽

...

Keyword(s):

Drug Exposure ◽

Multidrug Resistant ◽

Target Attainment ◽

Cart Analysis ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

The Impact ◽

Culture Conversion

BackgroundUnderstanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimize treatment. This study aimed to investigate the association between drug exposure, susceptibility and response to MDR-TB treatment.MethodsDrug exposure and susceptibility for second-line drugs were measured for patients with MDR-TB. Multivariate analysis was applied to investigate the impact of drug exposure and susceptibility on sputum culture conversion and treatment outcome. Probability of target attainment was evaluated. Random Forest and classification and regression tree (CART) analysis was used to identify key predictors and their clinical targets among patients on WHO-recommended regimens.ResultsDrug exposure and corresponding susceptibility were available for 197 patients with MDR-TB. Target attainment was highly variable ranging from 0% for ethambutol to 97% for linezolid, while patients with fluoroquinolones above targets had higher probability of two-month culture conversion (56.3% versus 28.6%, OR 2.91, 95% CI 1.42–5.94) and favourable outcome (88.8% versus 68.8%, OR 2.89, 95% CI 1.16–7.17). Higher exposure values of fluoroquinolones, linezolid and pyrazinamide were associated with earlier sputum culture conversion. CART analysis selected moxifloxacin AUC/MIC of 231 and linezolid AUC/MIC of 287 as best predictors for six-month culture conversion in patients receiving identical Group A-based regimen. These association were confirmed in multivariate analysis.ConclusionsOur findings indicated that target attainment of TB drugs is associated with response to treatment. The CART-derived thresholds may serve as targets for early dose adjustment in a future randomized controlled study to improve the MDR-TB treatment outcome.

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Genetic characterization of N-acetyltransferase 2 variants in acquired multidrug-resistant tuberculosis in Indonesia

Pharmacogenomics ◽

10.2217/pgs-2020-0163 ◽

2021 ◽

Author(s):

Rika Yuliwulandari ◽

Kinasih Prayuni ◽

Intan Razari ◽

Retno W Susilowati ◽

Yenni Zulhamidah ◽

...

Keyword(s):

Multidrug Resistant ◽

Resistance Rate ◽

Published Data ◽

Drug Induced ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Appropriate Treatment ◽

Acetylator Status ◽

Mdr Tb

Background: Owing to the high resistance rate of tuberculosis (TB) to isoniazid, which is metabolized by N-acetyltransferase 2 (NAT2), we investigated the associations between NAT2 variants and multidrug-resistant (MDR)-TB. Materials & methods: The acetylator status based on NAT2 haplotypes of 128 patients with MDR-TB in Indonesia were compared with our published data from patients with anti-TB drug-induced liver injury (AT-DILI), TB and the general population. Results: NAT2*4 was more frequent in the MDR-TB group than in the AT-DILI group, TB controls and general controls. NAT2*4/*4 was significantly more frequent in patients with MDR-TB than in those with AT-DILI. NAT2*5B/7B, *6A/6A and *7B/*7B were detected at lower frequencies in patients with AT-DILI. Rapid acetylators were significantly more frequent in patients with MDR-TB than in those with AT-DILI. Conclusion: These results provide an initial data for optimizing TB treatment in the Indonesian population, and suggest that NAT2 genotyping may help to select appropriate treatment by predicting TB-treatment effect.

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Prevalence and Molecular Characterization of Second-Line Drugs Resistance among Multidrug-ResistantMycobacterium tuberculosisIsolates in Southwest of China

BioMed Research International ◽

10.1155/2017/4563826 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Y. Hu ◽

L. Xu ◽

Y. L. He ◽

Y. Pang ◽

N. Lu ◽

...

Keyword(s):

Gene Mutations ◽

Multidrug Resistant ◽

Rapid Screening ◽

Second Line ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Improper Use ◽

Mdr Tb

This study aimed to investigate the prevalence of multidrug-resistant tuberculosis (MDR-TB) isolates resistant to the second-line antituberculosis drugs (SLDs) and its association with resistant-related gene mutations inMycobacterium tuberculosis(M.tb) isolates from Southwest of China. There were 81 isolates resistant to at least one of the SLDs among 156 MDR-TB isolates (81/156, 51.9%). The rates of general resistance to each of the drugs were as follows: OFX (66/156, 42.3%), KAN (26/156, 16.7%), CAP (13/156, 8.3%), PTO (11/156, 7.1%), PAS (22/156, 14.1%), and AMK (20/156, 12.8%). Therefore, the most predominant pattern was resistant to OFX compared with other SLDs (P<0.001). The results of sequencing showed that 80.2% OFX-resistant MDR-TB isolates containedgyrAmutation and 88.5% KAN-resistant isolates hadrrsmutations with the most frequent mutation being A1401G. These results suggest that improper use of SLDs especially OFX is a real threat to effective MDR-TB treatment not only in China but also in the whole world. Furthermore the tuberculosis control agencies should carry out SLDs susceptibility testing and rapid screening in a broader population of TB patients immediately and the SLDs should be strictly regulated by the administration in order to maintain their efficacy to treat MDR-TB.

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Multidrug-resistant tuberculosis (MDR-TB) and multidrug-resistant HIV (MDR-HIV) syndemic: challenges in resource limited setting

BMJ Case Reports ◽

10.1136/bcr-2019-230628 ◽

2019 ◽

Vol 12 (8) ◽

pp. e230628 ◽

Cited By ~ 1

Author(s):

Christian Francisco ◽

Mary Ann Lansang ◽

Edsel Maurice Salvana ◽

Katerina Leyritana

Keyword(s):

Psoas Abscess ◽

Multidrug Resistant ◽

Health Concern ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Resource Limited ◽

Persons Living With Hiv ◽

Mdr Tb ◽

Living With Hiv

Tuberculosis (TB) is common among persons living with HIV. This public health concern is aggravated by infection with multidrug-resistant organisms and adverse effects of polypharmacy. There are few published cases of multidrug-resistant tuberculosis (MDR-TB) in multidrug-resistant HIV (MDR-HIV) infected patients. We report a case of a 29-year-old Filipino man with HIV on zidovudine (AZT)-containing antiretroviral therapy (ART) but was eventually shifted to tenofovir due to anaemia. He presented with left flank tenderness, which was found to be due to an MDR-TB psoas abscess, and for which second-line anti-TB treatment was started. HIV genotyping showed MDR-HIV infection susceptible only to AZT, protease inhibitors and integrase inhibitors. Subsequently, he developed neck abscess that grew Mycobacterium avium complex and was treated with ethambutol and azithromycin. ART regimen was revised to AZT plus lamivudine and lopinavir/ritonavir. Erythropoietin was administered for recurrent AZT-induced anaemia. Both abscesses resolved and no recurrence of anaemia was noted.

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