Rifampicin-resistant Tuberculosis Research Articles

Rifampicin resistance conferring mutations among Mycobacterium tuberculosis strains in Rwanda.

The World Health Organization-endorsed phenotypic and genotypic drug-susceptibility testing (gDST/pDST) assays for the detection of rifampicin-resistant (RR) tuberculosis (TB), may miss some clinically relevant rpoB mutants, including borderline mutations and mutations outside the gDST-targeted hotspot region. Sequencing of the full rpoB gene is considered the reference standard for rifampicin DST but is rarely available in RR-TB endemic settings and when done indirectly on cultured isolates may not represent the full spectrum of mutations. Hence, in most such settings, the diversity and trends of rpoB mutations remain largely unknown. This retrospective study included rpoB sequence data from a longitudinal collection of RR-TB isolates in Rwanda across 30 years (1991-2021). Of 540 successfully sequenced isolates initially reported as RR-TB, 419 (77.6%) had a confirmed RR conferring mutation. The Ser450 Leu mutation was predominant throughout the study period. The Val170Phe mutation, not covered by rapid gDST assays, was observed in only four patients, three of whom were diagnosed by pDST. Along with the transition from pDST to rapid gDST, borderline RR-associated mutations, particularly Asp435Tyr, were detected more frequently. Borderline mutants were not associated with HIV status but presented lower odds of having rpoA-C compensatory mutations than other resistance-conferring mutations. Our analysis showed changes in the diversity of RR-TB conferring mutations throughout the study period that coincided with the switch of diagnostic tools to rapid gDST. The study highlights the importance of rapid molecular diagnostics reducing phenotypic bias in the detection of borderline rpoB mutations while vigilance for non-rifampicin resistance determinant region mutations is justified in any setting.

Role of GeneXpert in diagnosis of rifampicin resistant tuberculosis in patients with cervical lymphadenopathy

Tuberculosis is one of the most common causes for cervical lymphadenopathy apart from distant metastasis and lymphoma. Early diagnosis of this disease reduces the patient’s morbidity by initiating early course of Antitubercular treatment with complete resolution of disease. Hence, for diagnosis of this condition we are searching for a modality which can give results in shorter period of time, which is more sensitive, specific and most important easier to perform. Gene Xpert is one such modality which fits into these criteria. In our case series, we are aiming to study the role of Gene Xpert in diagnosis of rifampicin resistant tuberculosis in patients with cervical lymphadenopathy. In our study, excisional biopsy from cervical region was done in 30 cases and were sent for acid fast bacilli culture, Ziehl Neelsen staining and GeneXpert studies, histopathological examination and results were analyzed.

Navigating a Path to Rifampicin Resistance in Tuberculosis.

For model bacteria, genetic drug resistance usually arises from antibiotic-tolerant subpopulations, but whether this is true for the globally important pathogen Mycobacterium tuberculosis-the cause of tuberculosis-is not known. Here, we discuss a recent article by Sebastian et al. (J. Sebastian, A. Thomas, C. Levine, R. Shrestha, et al., mBio 14:e0279522, 2023, 10.1128/mbio.02795-22) which leverages a robotic transwell microtiter experimental system coupled with deep sequencing of a barcoded library of M. tuberculosis to answer this question for rifampicin resistance. The authors investigate two distinct forms of antibiotic-tolerant subpopulations-classical tolerance, characterized by prolonged minimum duration of killing, and "differentially detectable" (DD) bacilli that are viable but can be recovered only in liquid medium as opposed to plating. They demonstrate that, indeed, resistance arises preferentially from both rifampicin-tolerant subpopulations, though earlier in the DD population. Use of barcoded libraries and parallel culture systems shows promise in investigating phenotypes mediated by minority subpopulations of bacteria such as development of antibiotic resistance.

The mutation rate of rpoB gene showed an upward trend with the increase of MIRU10, MIRU39 and QUB4156 repetitive number

BackgroundMycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) is a frequently used typing method for identifying the Beijing genotype of Mycobacterium tuberculosis (Mtb), which is easily transformed into rifampicin (RIF) resistance. The RIF resistance of Mtb is considered to be highly related with the mutation of rpoB gene. Therefore, this study aimed to analyze the relationship between the repetitive number of MIRU loci and the mutation of rpoB gene.MethodsAn open-source whole-genome sequencing data of Mtb was used to detect the mutation of rpoB gene and the repetitive number of MIRU loci by bioinformatics methods. Cochran-Armitage analysis was performed to analyze the trend of the rpoB gene mutation rate and the repetitive number of MIRU loci.ResultsAmong 357 rifampicin-resistant tuberculosis (RR-TB), 304 strains with mutated rpoB genes were detected, and 6 of 67 rifampicin susceptible strains were detected mutations. The rpoB gene mutational rate showed an upward trend with the increase of MIRU10, MIRU39, QUB4156 and MIRU16 repetitive number, but only the repetitive number of MIRU10, MRIU39 and QUB4156 were risk factors for rpoB gene mutation. The Hunter-Gaston discriminatory index (HGDI) of MIRU10 (0.65) and QUB4156 (0.62) was high in the overall sample, while MIRU39 (0.39) and MIRU16 (0.43) showed a moderate discriminatory Power.ConclusionThe mutation rate of rpoB gene increases with the addition of repetitive numbers of MIRU10, QUB4156 and MIRU39 loci.

Rifampicin resistant Mycobacterium tuberculosis and associated factors among presumptive pulmonary tuberculosis patients in Mogadishu, Somalia.

Multi-drug resistant Mycobacterium tuberculosis is a growing public health problem in developing countries including Somalia. Although, the prevalence of multi-drug resistant tuberculosis among new and retreated cases is high, data on GeneXpert- Mycobacterium tuberculosis/rifampicin-resistant assay, which is a surrogate marker for multidrug resistance, is not well explored in Mogadishu. To determine the prevalence of rifampicin-resistant Mycobacterium tuberculosis and its associated factors among presumptive pulmonary tuberculosis patients visiting tuberculosis centers in Mogadishu, Somalia. A multicenter cross-sectional study was conducted in three tuberculosis treatment centers from March 12 to April 30, 2021. Laboratory professionals collected sputum sample consecutively from presumptive pulmonary tuberculosis participants and performed a GeneXpert assay to determine the rifampicin resistance. Socio-demographic and clinical data were collected using structured questionnaire. Logistic regression analyses were performed to assess factors associated with rifampicin resistance using an adjusted odds ratio at a 95% confidence interval. Statistical significance was considered at a p-value of less than 0.05. A total of 370 presumptive tuberculosis suspects were included; of whom 58.4% were females and the mean age of the participants was 44.3 ± 14 years. Mycobacterium tuberculosis was detected in 63 (17%) (95% confidence interval = 13.2-20.8) suspects. Of these the prevalence of rifampicin-resistant Mycobacterium tuberculosis was 35% (95% confidence interval = 30.2-39.8). Anti-tuberculosis treatment history (adjusted odds ratio = 4.1; 95% confidence interval = 1.91-6.75), monthly income less than $100 USD (adjusted odds ratio = 2.2; 95% confidence interval = 1.77-5.98) and being diagnosed with Asthma (adjusted odds ratio = 2.63; 95% confidence interval = 1.3-7.3) were significantly associated with rifampicin-resistant tuberculosis. A considerable proportion of rifampicin-resistant tuberculosis is reported in these study settings. The strong association between multidrug resistance tuberculosis and patients' retreatment history of tuberculosis, low income, and co-morbidity with asthma highlights the need for more efforts in tuberculosis treatment and monitoring programs to limit the emergence of multi-drug resistant strain in the study areas.

Tuberculosis and HIV coinfection and rifampicin-resistant tuberculosis among patients living with HIV in Northern part of West Bengal, India

Background: India is one of the top most country among the high tuberculosis (TB) burden countries and ranks the third highest human immunodeficiency virus (HIV) burden country in the world contributing to 23% of the total global load. Mycobacterium tuberculosis (MTB) and HIV are known to act synergistically and result in higher mortality rates. TB-HIV coinfection and emergence of drug resistant forms of MTB can impact positively on treatment outcomes. Aims and Objectives: The aim of this study was to determine of the prevalence of TB-HIV co-infection among MTB and to determine the prevalence of rifampicin (RIF) resistant TB among HIV seropositive patients. Materials and Methods: It was a retrospective and observational study carried out in the Department of Microbiology, Malda Medical College, Malda, West Bengal. Records of all patients that tested using CBNAAT during March 2016–December 2019 in the CBNAAT laboratory of Malda Medical College were assessed. Data generated during this period were collected and analyzed. The statistical analysis was done in tabulation form and different charts and tables were used for displaying data. Results: A total of 6503 samples were tested in CBNAAT laboratory during March 2016–December 2019. Out of 6503, 3098 samples were positive for CBNAAT (MTB detected).Of 3098 MTB, 8.91% (276/3098) were RIF resistant. Among 3098 MTB, 91.22% (2826/3098) were pulmonary TB (PTB) and 8.78% (272/3098) were extra PTB. Out of 6503 total samples, 664 were reported patients living with HIV. The prevalence of TB-HIV coinfection was 3.91% (121/3098) among MTB positive cases. Of all TB-HIV coinfected cases, most of the patients (67.77%) were in the age group of 20–39 years and males (77.69%) contributed to more than females. Of 121 TB-HIV coinfected, 88.43% (107/121) were sensitive to RIF and 11.57% (14/121) were resistant to RIF. Conclusion: The present study reported that the prevalence of TB-HIV coinfection was 3.91% and the prevalence of RIF resistant TB in HIV seropositive patients was higher than HIV seronegative patients. Thus, all TB patients should be screened for HIV and all HIV-positive individuals should be screened for TB along with drug resistance for better management.

A Scoring System Based on Laboratory Parameters and Clinical Features to Predict Unfavorable Treatment Outcomes in Multidrug- and Rifampicin-Resistant Tuberculosis Patients.

The growth of antibiotic resistance to Mycobacterium TB represents a major barrier to the goal of "Ending the global TB epidemics". This study aimed to develop and validate a simple clinical scoring system to predict the unfavorable treatment outcomes (UTO) in multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) patients. A total of 333 MDR/RR-TB patients were recruited retrospectively. The clinical, radiological and laboratory features were gathered and selected by lasso regression. These variables with area under the receiver operating characteristic curve (AUC)>0.6 were subsequently submitted to multivariate logistic analysis. The binomial logistic model was used for establishing a scoring system based on the nomogram at the training set (N = 241). Then, another independent set was used to validate the scoring system (N = 92). The new scoring system consists of age (8 points), education level (10 points), bronchiectasis (4 points), red blood cell distribution width-coefficient of variation (RDW-CV) (7 points), international normalized ratio (INR) (7 points), albumin to globulin ratio (AGR) (5 points), and C-reactive protein to prealbumin ratio (CPR) (6 points). The scoring system identifying UTO has a discriminatory power of 0.887 (95% CI=0.835-0.939) in the training set, and 0.805 (95% CI=0.714-0.896) in the validation set. In addition, the scoring system is used exclusively to predict the death of MDR/RR-TB and has shown excellent performance in both training and validation sets, with AUC of 0.930 (95% CI=0.872-0.989) and 0.872 (95% CI=0.778-0.967), respectively. This novel scoring system based on seven accessible predictors has exhibited good predictive performance in predicting UTO, especially in predicting death risk.

Clinical profile and outcome in patients with rifampicin-resistant tuberculosis taking shorter multidrug-resistant tuberculosis treatment regimen at a tertiary care hospital in South Gujarat

Background: India remains one of the six countries with an enormous multidrug-resistant tuberculosis (MDR TB) burden. Shorter MDR regimen is more economical/cheaper, shorter and having an improved adherence for Rifampicin resistant (RR)-TB. There were not many studies on this shorter MDR regimen (containing high-dose moxifloxacin) in India, we had carried out this study to find out outcomes and adverse drug reactions (ADRs) of this Shorter MDR regimen. Aims and Objectives: To study the clinical profile, interim and final outcome, and ADRs in RR-TB patients taking shorter MDR regimens. Materials and Methods: Prospective observational longitudinal study which was carried out in the Department of Respiratory Medicine Department, New Civil Hospital, Surat from January 2019 to June 2020. All patients who were diagnosed as RR-TB by cartridge-based nucleic acid amplification were enrolled in the study. Eligible Patients (n = 60) were started on shorter MDR regimen and were followed up. Results: Out of these 60 patients 35 (58.3%) were male and 25 (41.6%) were female. The age group mainly included was between 20 and 40 years. Out of 60 patients, 55 (91.6%) had pulmonary and 5 (8.3%) had extrapulmonary TB. Interim Outcome in the form of culture conversion at the end of 4th, 5th, and 6th month was seen in 21 (45.65%), 37 (80.43%), and 45 (97.83%), respectively. The final outcome among 60 patients were 33 (55%) cured, 12 (20%) treatment completed, 6 (10%) lost to follow-up, 5 (8.33%) regimen changed, 3 (5%) died, and failure in 1 (1.66%). These results were matching with most of the other studies. Conclusion: This study showed successful outcome (cured and treatment completed) in 45 patients (75%) and adverse outcome (died, lost to follow-up, and failure) in 10 patients (16.67%). A shorter MDR regimen is shorter, cheaper, effective in most of the RR-TB patients and is well tolerated with mild side effects.

Sugar and sugar-free liquid formulations of delamanid for patients with rifampicin-resistant TB.

BACKGROUND: Delamanid (DLM) tablets are recommended for the treatment of rifampicin-resistant TB. However, no liquid or dispersible tablet formulation of DLM is currently commercially available for patients with challenges ingesting these tablets. The aim of this study was to develop stable extemporaneous liquid formulations of DLM that can be stored at room temperature for several weeks.METHODS: DLM tablets were suspended in 1) simple syrup and 2) a specially formulated sugar-free vehicle. These suspensions containing DLM 5 mg/mL were stored in plastic prescription bottles at room temperature or 30°C for 30 days. These suspensions were evaluated for appearance, potency, pH, and microbial counts at Days 0, 15, and 30.RESULTS: The potency of DLM in each formulation remained at 98-104% of the theoretical concentration for 30 days. The appearance, pH, and microbial count did not change for the sugar-free formulation during the 30-day storage period. Microbial growth, however, was observed in the simple syrup formulation on Day 30 but not on Day 15.CONCLUSION: DLM can be formulated in sugar or sugar-free suspensions and stored at room temperature or 30°C for at least 15 and 30 days, respectively.

Trends in Rifampicin Resistance Among Children With Presumptive TB in the Pre-COVID and COVID-Era

Publications on COVID-19's impact on the global tuberculosis burden are from adult cohorts, pediatric data are lacking for inform decision. We compared the TB trends in southern Nigerian children in the pre-COVID-19 and COVID-19 era. This was a retrospective, cross-sectional study of early morning sputum/gastric washing or stool samples from children with presumptive TB evaluated using GeneXpert in a tertiary hospital from January 2016 to May 2022. Of the 20 589 persons screened for presumed TB in the pre-COVID-19 and the COVID-19 era, only 1104 (88.7%) of 1245 children had complete data for analysis. In the COVID era, a significantly higher number of children were presumed to have TB 755 (68.4%), P < .001. The overall incidence of MTB detected by Xpert MTB/RIF during the study period was 6.4% (71/1104). The incidence of MTB in the pre-COVID-19 era was 24/349 (6.9%), which was slightly higher than the COVID-19 era (47/755; 6.2%), P > .05). The annual trends of MTB detected peaked in 2019 [18/115; 15.7%] in the pre-COVID-19 era, then plummeted to 12/228 (5.3%) in 2020 in the COVID-19 era, and reached its all-time low of 6/160 (3.8%) in the first half of 2022, (P < .001). The overall incidence of Rifampicin-resistant TB (RR-TB) was 2.8% among the MTB detected cases and all occurred in the COVID-19 era. This study found a significant decline in MTB diagnosis and in the emergence of RR-TB in the COVID-19 era. This necessitates re-prioritizing worldwide efforts to manage childhood tuberculosis, including increased testing, if the aim of eliminating tuberculosis by 2035 is to be met.

Study the prevalence of rifampicin resistance among pulmonary tuberculosis patients by genexpert assay from a tertiary care hospital of North India.

Rifampicin (RIF) resistance (RR) tuberculosis (TB) has posed a great challenge to TB control programs globally. Evidence of RIF-RR can help as a surrogate marker to find out multidrug-resistance cases. The study aimed to determine the prevalence of RIF-RR in pulmonary TB (PTB) patients over the 4 years at Dr. RPGMC, Tanda, from the year 2018 to 2021. This was a retrospective study conducted at Dr. RPGMC, Tanda at Kangra, where we checked (from January 2018 to December 2021) clinically suspected PTB patients, whose samples were sent to the laboratory for GeneXpert assay to identify Mycobacterium TB/RIF (MTB/RIF) testing. Of the total 11,774 clinically suspected PTB specimens were collected, and identified by GeneXpert MTB/RIF assay, in which 2358 samples were MTB positive and 9416 were MTB negative. Among 2358 MTB-positive samples, 2240 (95%) samples were RIF sensitive, in which 1553 (65.9%) were males and 687 (29.1%) were females, 76 (3.2%) samples were RIF-RR, in which 51 (2.2%) were males and 25 (1%) were females, and 42 (1.8%) samples were RIF indeterminate, in which 25 (1%) were males and 17 (0.8%) were females. The rate of RIF-RR was found 3.2% of total samples which was more in males. The overall positivity rate was 20%, and the rate of positivity decreased from 32% to 14% over the 4 years in sputum samples. Hence, the GeneXpert assay was found to be very important tool to detect RIF-RR among suspected PTB patients.

The Role of Pyridoxine in the Prevention and Treatment of Neuropathy and Neurotoxicity Associated with Rifampicin-Resistant Tuberculosis Treatment Regimens: A Topic Review

The Role of Pyridoxine in the Prevention and Treatment of Neuropathy and Neurotoxicity Associated with Rifampicin-Resistant Tuberculosis Treatment Regimens: A Topic Review

Distribution of Rifampicin-Resistant Tuberculosis Patients based on Presumptive Drug-Resistant Tuberculosis Criteria at Dr. Hasan Sadikin Hospital 2016–2019

Background: Diagnosis of drug-resistant tuberculosis (DR-TB) begins with identifying presumptive DR-TB patients using Xpert MTB/RIF, as a diagnostic test to detect resistance to rifampicin. The study aimed to identify the distribution of rifampicin-resistant tuberculosis (RR-TB) patients based on presumptive DR-TB criteria at Dr. Hasan Sadikin General Hospital Bandung. Moreover, this study also explored the Xpert MTB/RIF Ct values.Methods: This was a descriptive-retrospective study from 570 medical records of DR-TB patients collected at the Multidrug-resistant tuberculosis (MDR-TB) clinic of Dr. Hasan Sadikin General Hospital from 2016 to 2019. The inclusion criteria were suspected patients with the Xpert MTB/RIF Ct values in the very low-low and medium-high categories. Data were analyzed using frequency distribution. Results: The most common presumptive DR-TB criteria among DR-TB patients were relapse cases (52.3%). Presumptive DR-TB criteria, with a high percentage result of medium-high Ct values, were category II treatment failure (80.9%).Conclusion: Relapse case and category II treatment failure are presumptive DR-TB criteria, which need more attention from clinicians.

РЕЗУЛЬТАТЫ ЛЕЧЕНИЯ РИФАМПИЦИН-УСТОЙЧИВОГО ТУБЕРКУЛЕЗА У ЖЕНЩИН С СИНДРОМОМ ЗАВИСИМОСТИ ОТ АЛКОГОЛЯ

Background. Tuberculosis is still one of the urgent medical and social problems and poses a threat to human health around the world. Purpose of work: To study the features of rifampicin-resistant tuberculosis in male and female patients with alcohol dependence syndrome. Material and methods. The subjects were 219 patients with active rifampicin-resistant pulmonary tuberculosis and a diagnosis of alcohol dependence syndrome. During the study, two groups of patients were formed: group I – the main group (n=33) – included females with rifampicin-resistant pulmonary tuberculosis and alcohol dependence syndrome, group II – the comparison group (n=186) – was composed of males with rifampicin-resistant pulmonary tuberculosis and alcohol dependence syndrome. Results. Termination of bacterial excretion, confirmed by the bacteriological method, was obtained in 60.6% of the patients in the main group and in 57.2% of the patients in the comparison group (p&gt;0.05). The analysis of radiological data (plain chest radiograph, linear tomogram) showed that closure of the decay cavities in the lungs was observed only in 6 (28.6%) and 50 (49.1%) cases (p&lt;0.05), respectively. Conclusions. The modern social picture of rifampicin-resistant tuberculosis is represented by working-age individuals suffering from alcohol dependence syndrome, those who are not employed, women of reproductive age.

High proportion of RR-TB and mutations conferring RR outside of the RRDR of the rpoB gene detected in GeneXpert MTB/RIF assay positive pulmonary tuberculosis cases, in Addis Ababa, Ethiopia.

Globally, TB is the leading cause of infectious disease morbidity and mortality with many diagnostic uncertainties. Access to affordable and rapid diagnostics remained a major challenge for many developing countries which bear the greatest burden of TB delaying the initiation time to treatment. This study aimed to assess the GeneXpert MTBRIF assay probe utility for the detection of pulmonary TB and Rifampicin-resistant TB cases in Addis Ababa, Ethiopia. A cross-sectional study was performed from October 2019 to July 2020 in Saint Peter TB Specialized Hospital in Addis Ababa metropolitan area, Ethiopia. This study enrolled 216 clinically suspected new presumptive pulmonary TB cases confirmed by GeneXpert MTB/RIF Assay. Sociodemographic and clinical characteristics were captured using a structured tool. Data were entered in Microsoft Excel 2019, checked for inconsistency, cleaned promptly, and exported to IBM SPSS Statistics for Windows, Version 26.0. Armonk, N.Y: IBM Corp, the USA for analysis. Descriptive analysis and binary and multivariate logistics regression were performed and all statistical significance was determined at a 95% confidence level. The majority of the study participants, 55.1% [119/216] were males aged 6-80 years. The prevalence of RR MTB was 11.11% [24/216]. A higher proportion of RR TB was found in female patients [54.2%, 13/24], in patients in the age group of 30-50 years [45.8%, 11/24], in married individuals [62.5%, 15/24], in persons whose residence is urban [79.2%, 19/24], in persons who had a previous history of TB symptoms [100%, 24/24], in persons who had a history of contact with active and LTBI [33.3%, 8/24], and in persons who had a history of HIV and IDUs [41.7%, 10/24]. Occupation (AOR 22.868, 95% CI 1.655-316.022, p = 0.019), history of previous PTB+ (AOR 4.222, 95% CI 1.020-17.47, p = 0.047), and history of HIV and IDUs (AOR 4.733, 95% CI 1.416-15.819, p = 0.012) were independent predictors associated with RR-TB emergence. The commonest mutation 62.5% [15/24] was found in probe E (codons 529-533) region. There was no mutation associated with probe A (codons 507-511), probe B (codons 511-518), and probe C (codons 518-523) regions, as well as no combination of missed probes, was revealed. However, 12.5% [3/24] of RR TB patients were found without unidentified missed probe types detected outside of the RRDR. The delta Ct max was >4.0 and the highest proportion of 35.6% [77/216] RR TB was detected in samples of medium DNA load. The proportion of RR-TB we observed in this study was high. Similarly, a higher proportion of RR TB was detected outside of the RRDR. Moreover, a significant number of the GeneXpert MTB/RIF Assay probes were identified as unhybridized and this critical observation would mean that most of the probes had no or minimal utility in this geographical region. This calls for further studies to uncover mutation in the rpoB gene conferring RR and reshape TB triage and definite diagnostic algorithm in Ethiopia.

More treatment options for rifampicin-resistant tuberculosis: the role of economic evaluation in informing uptake

There have been substantial advances in treatment options for multidrug-resistant and rifampicin-resistant tuberculosis. Just a few years ago, a typical patient faced months of painful injections, life-changing adverse effects, and a very small chance of cure. This year, WHO announced forthcoming updates to global guidelines including 6-month and 9-month all-oral regimens for treatment of multidrug-resistant and rifampicin-resistant tuberculosis.1 In the context of these rapidly changing options for treating multidrug-resistant and rifampicin-resistant tuberculosis and persisting high costs of newer drugs such as bedaquiline, countries are facing difficult decisions about when and how to incorporate new drug regimens into national guidelines, and the economic effects of new regimens will be a key consideration in their uptake.

Economic evaluation of shortened, bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis (STREAM stage 2): a within-trial analysis of a randomised controlled trial

The STREAM stage 2 trial assessed two bedaquiline-containing regimens for rifampicin-resistant tuberculosis: a 9-month all-oral regimen and a 6-month regimen containing an injectable drug for the first 2 months. We did a within-trial economic evaluation of these regimens. STREAM stage 2 was an international, phase 3, non-inferiority randomised trial in which participants with rifampicin-resistant tuberculosis were randomly assigned (1:2:2:2) to the 2011 WHO regimen (terminated early), a 9-month injectable-containing regimen (control regimen), a 9-month all-oral regimen with bedaquiline (oral regimen), or a 6-month regimen with bedaquiline and an injectable for the first 2 months (6-month regimen). We prospectively collected direct and indirect costs and health-related quality of life data from trial participants until week 76 of follow-up. Cost-effectiveness of the oral and 6-month regimens versus control was estimated in four countries (oral regimen) and two countries (6-month regimen), using health-related quality of life for cost-utility analysis and trial efficacy for cost-effectiveness analysis. This trial is registered with ISRCTN, ISRCTN18148631. 300 participants were included in the economic analyses (Ethiopia, 61; India, 142; Moldova, 51; Uganda, 46). In the cost-utility analysis, the oral regimen was not cost-effective in Ethiopia, India, Moldova, and Uganda from either a provider or societal perspective. In Moldova, the oral regimen was dominant from a societal perspective. In the cost-effectiveness analysis, the oral regimen was likely to be cost-effective from a provider perspective at willingness-to-pay thresholds per additional favourable outcome of more than US$4500 in Ethiopia, $1900 in India, $3950 in Moldova, and $7900 in Uganda, and from a societal perspective at thresholds of more than $15 900 in Ethiopia, $3150 in India, and $4350 in Uganda, while in Moldova the oral regimen was dominant. In Ethiopia and India, the 6-month regimen would cost tuberculosis programmes and participants less than the control regimen and was highly likely to be cost-effective in both cost-utility analysis and cost-effectiveness analysis. Reducing the bedaquiline price from $1·81 to $1·00 per tablet made the oral regimen cost-effective in the provider-perspective cost-utility analysis in India and Moldova and dominate over the control regimen in the provider-perspective cost-effectiveness analysis in India. At current costs, the oral bedaquiline-containing regimen for rifampicin-resistant tuberculosis is unlikely to be cost-effective in many low-income and middle-income countries. The 6-month regimen represents a cost-effective alternative if injectable use for 2 months is acceptable. USAID and Janssen Research & Development.

1433. Factors Associated with Unsuccessful Treatment Outcomes among Patients with Rifampicin Resistant Tuberculosis - Tajikistan, 2015-2020

Abstract Background Tajikistan has a high burden of multidrug resistant TB, including rifampicin-resistant TB (RR-TB). Treatment options are more limited and include standard treatment (T1), bedaquiline/delamanid contained individual treatment (T2), short treatment (T3), modified short treatment (T4), and bedaquiline/pretomanid/linezolid treatment (T5). To inform national treatment plans, we assessed trends in RR-TB and determined factors associated with unsuccessful treatment. Methods We conducted a retrospective cohort study in Dushanbe, Tajikistan, from 2015 to 2020 using patient records. Patients had successful treatment outcomes if they completed treatment or were cured, and unsuccessful if they had treatment failure, were lost-to-follow-up, or died. We report relative risk (RR) and 95% confidence interval from multivariable Poisson regression. Results From 2015 to 2020, there was a decrease in incidence of TB (68.6 to 47.2 per 100,000) and RR-TB (10.6 to 7.2) with a 33% drop 2019 to 2020. Proportion of unsuccessful outcomes also decreased (30% to 15% 2015-2020). Of 522 patients, 515 had RR-TB. Of these, 39% received T1, 43% T2, 15% T3, 2% T4, and 0.4% T5 (Table 1). Overall, 23% had unsuccessful treatment outcomes. Patients on T1 had higher unsuccessful outcome compared to those on T2 - T5 (31% vs 19%, 14%, 0% and 0%, respectively). Unsuccessful outcomes were associated with combined isoniazid, rifampin and streptomycin resistance, alcohol and drug use. For patients receiving T1, unsuccessful outcome was associated with unemployment (RR: 2.7; 1.1-6.8), HIV (RR: 2.3, 1.5-3.4), hepatitis C (RR: 2.2, 1.4-3.4), and concomitant disease (RR: 2.1, 1.4-3.1). For patients receiving T2, risk of unsuccessful outcome was lower for females (RR: 0.4, 0.2-0.7) (Table 2). Conclusion Decrease in incidence is promising. Results highlight the need to transition RR-TB patients to non-standard treatment. Closer follow-up of patients with combined resistance, alcohol or drug use, HIV, hepatitis C, and concomitant diseases may contribute to successful outcome. Disclosures All Authors: No reported disclosures.

Trends of Xpert MTB/RIF in the diagnosis of Mycobacterium tuberculosis and rifampicin resistance in Southwest Nigeria: A 4-year retrospective study

Objectives: In recent years, there has been an increased uptake of Xpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) for the diagnosis of tuberculosis (TB), with added benefits for detecting rifampicin-resistant TB (RR-TB). We set out to determine the trends in notification of MTB and RR-TB over 4 years in a tertiary hospital in Southwest Nigeria. Materials and Methods: This is a retrospective analysis of single early morning sputum/gastric washing sample for presumed TB in a tertiary health center between January 2016 and December 2019. Xpert MTB/RIF was used to detect (MTB) and RR-TB. Results: The mean age of the 4625 presumptive TB patients was 43.4 (18.8) years, with the majority aged 31–45 (30.6%). Males totaled 2247 (49.6%). Human immunodeficiency virus (HIV) coinfection was found in 756 (16.7%) of them. Using the Xpert MTB/RIF assay, the overall MTB notification was 12.9% (584/4526) and was associated with HIV status, P &lt; 0.001. MTB notification trends increased from 5.6% in 2016 to 23.8% in 2019, P &lt; 0.001. The overall yield of RR-TB was 7.5%. The proportion of RR-TB from TB cases declined from 28% in 2016 to 4.6% in 2019. Forty-two of the 44 cases of the RR-TB (42/572; 7.3%, [95% CI: 5.31, 9.75]) were new cases, with TB treatment failure and relapse cases accounting for 10.1% (2/11; 10.1%, [95% CI: 0.35, 42.5]) of all RR-TB cases (P &lt; 0.01). RR-TB was associated with being older than 45 years (adjusted odds ratio = 2.046, [95% CI: 1.046, 4.004]). HIV infection status and gender had no effect on RR-TB status. Conclusion: This study found an increase in MTB detection with Xpert MTB/RIF utilization. Ages &gt;45 years have 2–4-fold increased risk of developing RR-TB and should be targeted for drug resistance prevention.

Safety, effectiveness, and adherence of a short and all-oral treatment regimen for the treatment of rifampicin-resistant tuberculosis in Niger: a study protocol of a pragmatic randomised clinical trial with stratified block randomisation

BackgroundRifampicin-resistant tuberculosis (RR-TB) treatment requires combination treatment, which frequently causes serious adverse events and globally results in not much more than 60% treatment success. In Niger, a high cure rate was obtained with a RR-TB treatment strategy based on a second-line injectable drug (SLID)-containing Short Treatment Regimen (STR), with linezolid replacing the SLID in patients with ototoxicity. Given the availability of novel anti-tuberculosis drugs, WHO recommends all-oral RR-TB treatment. Considering the high level of success with the Niger treatment strategy, it would only be justified to replace it in case robust evidence shows that the WHO all-oral bedaquiline/linezolid (BDQ/LZD)-containing STR (experimental arm) performs better than the Niger RR-TB treatment strategy, (control arm) in terms of safety, effectiveness and adherence.MethodsA pragmatic randomised clinical trial (RCT) using stratified block randomisation, conducted between April 2021 and March 2024, prospectively enrols participants diagnosed with RR-TB in one of the four RR-TB units of the nation. Depending of the month in which patients are diagnosed with RR-TB, patients with FQ-susceptible RR-TB are enrolled in either the experimental arm or control arm.DiscussionTo increase the feasibility of conducting a RCT, embedded in routine activities of all Niger’s RR-TB Units, we used a creative trial design. We randomised by monthly blocks, whereby the regimen used changes every month, using the month of RR-TB diagnosis as stratifying variable. This approach was deemed feasible for Niger's national tuberculosis programme, as it simplifies the work of the clinicians running the RR-TB units. Our creative design may serve as an example for other national programs. Findings will inform national and international RR-TB treatment guidelines, and will also strengthen the evidence-base on how to develop robust RR-TB treatment regimens.Trial registrationPan African Clinical Trial Register PACTR202203645724919. Registered on 15 March 2022.