Effectiveness and safety of modified fully oral 9-month treatment regimens for rifampicin-resistant tuberculosis: a prospective cohort study.

BACKGROUND: In 2020, WHO guidelines prioritised the use of a standard fully oral short treatment regimen (STR) consisting of bedaquiline, levofloxacin or moxifloxacin, ethionamide, ethambutol, high-dose isoniazid, pyrazinamide, and clofazimine for the management of rifampicin-resistant tuberculosis. A high prevalence of resistance to constituent drugs precluded its widespread use by countries in the WHO European region. We evaluated three 9-month fully oral modified STRs (mSTRs) in which ethionamide, ethambutol, isoniazid, and pyrazinamide were replaced by linezolid, cycloserine, or delamanid (or a combination). METHODS: This multicountry, prospective, single-arm, cohort study examined the effectiveness and safety of mSTRs for fluoroquinolone-susceptible, rifampicin-resistant pulmonary tuberculosis in 13 countries in the WHO European region during 2020-23. We enrolled adults and children of all ages with bacteriologically confirmed rifampicin-resistant, fluoroquinolone-susceptible pulmonary tuberculosis, and children (aged 0-18 years) with clinically diagnosed disease and a confirmed contact with rifampicin-resistant, fluoroquinolone-susceptible tuberculosis. Participants aged 6 years or older received one of two regimens: bedaquiline, linezolid, levofloxacin, clofazimine, and cycloserine; or bedaquiline, linezolid, levofloxacin, clofazimine, and delamanid. Children younger than 6 years received delamanid, linezolid, levofloxacin, and clofazimine. Participants were followed up for 12 months after successful treatment completion to detect recurrence and death. The primary outcome was the cumulative probability of not having an unsuccessful study outcome (defined as treatment failure, on-treatment loss to follow-up, death, or recurrence) before 22 months of study follow-up. The primary safety outcome was the incidence of each adverse event of interest (peripheral neuropathy, optic neuritis, myelosuppression, hepatitis, prolonged QT interval, hypokalaemia, and acute kidney injury) of grade 3 or higher severity during the treatment course. FINDINGS: Between Aug 28, 2020 and May 26, 2021, 7272 patients were screened and 2636 were included in the treatment cohort. 1966 (74·6%) were male, 670 (25·4%) were female, and median age was 43 years (IQR 33-53). Treatment success was recorded for 2181 (82·7%) participants. The cumulative probability of not having an unsuccessful study outcome 22 months after treatment initiation was 79% (95% CI 78-81). Increasing age (adjusted hazard ratio 2·61 [95% CI 1·70-4·04] for people aged >64 years vs 35-44 years), HIV-positive status (1·53 [1·16-2·01]), presence of bilateral cavities (1·68 [1·29-2·19]), smoking history (1·34 [1·05-1·71]), baseline anaemia (1·46 [1·15-1·86]), unemployment (1·37 [1·04-1·80]), elevated baseline liver enzymes (1·40 [1·13-1·73]), and excessive alcohol use (1·47 [1·14-1·89]) were positively associated with unsuccessful study outcomes. In the safety cohort of 2813 participants who received at least one dose, 301 adverse events of interest were recorded in 252 (9·0%) participants with the most frequent being myelosuppression (139 [4·9%] participants, 157 [52·2%] events). INTERPRETATION: The high treatment success and good safety results indicate considerable potential for the use of mSTRs in programmatic conditions, especially for individuals not eligible for the current WHO-recommended 6-month regimen and in settings with a need for alternative options. FUNDING: The Global Fund to Fight AIDS, Tuberculosis and Malaria; United States Agency for International Development; Government of Germany; and WHO. TRANSLATION: For the Russian translation of the abstract see Supplementary Materials section.

Trends in the availability and prices of quality-assured tuberculosis drugs: a systematic analysis of Global Drug Facility Product Catalogs from 2001 to 2024.

BACKGROUND: The Global Drug Facility (GDF) of the Stop TB Partnership was launched in 2001 with the goal of increasing access to quality-assured tuberculosis (TB) drugs and products. We aimed to describe the TB drugs and prices available from the GDF over time and to assess trends. METHODS: We searched the internet, including an internet archive, for past and recent GDF Product Catalogs and extracted the listed TB drugs and prices. We calculated the lowest price for the most common drug formulations assuming drugs with similar active pharmaceutical ingredients (APIs) are substitutes for each other. We assessed time trends in the TB drugs and prices offered by the GDF in univariable regressions over the longest possible period. RESULTS: We identified 43 different GDF Product Catalogs published between November 2001 and May 2024. These product catalogs included 122 single medicines (31 APIs), 28 fixed-dose combinations (9 API combinations), and 8 patient kits (8 API regimens and other materials). The number of TB drugs listed in the GDF Product Catalog increased from 9 (8 APIs) to 55 (32 APIs). The price decreased for 17, increased for 19, and showed no trend for 12 APIs. The price of 15 (53.6%) of 28 APIs used against drug-resistant TB decreased, including the price of drugs used in new treatment regimens. The decreasing price trend was strongest for linezolid (-16.60 [95% CI: -26.35 to -6.85] percentage points [pp] per year), bedaquiline (-12.61 [95% CI: -18.00 to -7.22] pp per year), cycloserine (-11.20 [95% CI: -17.40 to -4.99] pp per year), pretomanid (-10.47 [95% CI: -15.06 to -5.89] pp per year), and rifapentine (-10.46 [95% CI: -12.86 to -8.06] pp per year). The prices of 16 (61.5%) of 23 APIs for standard drug-susceptible TB treatment increased, including rifampicin (23.70 [95% CI: 18.48 to 28.92] pp per year), isoniazid (20.95 [95% CI: 18.96 to 22.95] pp per year), ethambutol (9.85 [95% CI: 8.83 to 10.88] pp per year), and fixed-dose combinations thereof. CONCLUSIONS: The number of TB drugs available from the GDF has substantially increased during its first 23 years of operation. The prices of most APIs for new TB treatments decreased or remained stable. The prices of most APIs for standard drug-sensitive TB treatment increased.

Correction: The contribution of drug import to the cost of tuberculosis treatment: A cost analysis of longer, shorter, and short drug regimens for Karakalpakstan, Uzbekistan.

[This corrects the article DOI: 10.1371/journal.pgph.0000567.].

Comparative effectiveness of adding delamanid to a multidrug-resistant tuberculosis regimen comprised of three drugs likely to be effective.

Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study. We used pooled logistic regression to estimate the observational analogue of the intention-to-treat effect (aITT) adjusting for baseline confounders and to estimate the observational analogue of the per-protocol effect (aPP) using inverse probability of censoring weighting to control for time-varying confounding. At treatment initiation, 362 patients received three likely effective drugs (delamanid-free) or three likely effective drugs plus delamanid (delamanid-containing). Over 80% of patients received two to three Group A drugs (bedaquiline, linezolid, moxifloxacin/levofloxacin) in their regimen. We found no evidence the addition of delamanid to a three-drug regimen increased two-month (aITT relative risk: 0.90 (95% CI: 0.73-1.11), aPP relative risk: 0.89 (95% CI: 0.66-1.21)) or six-month culture conversion (aITT relative risk: 0.94 (95% CI: 0.84, 1.02), aPP relative risk: 0.93 (95% CI: 0.83, 1.04)). In regimens containing combinations of three likely effective, highly active anti-TB drugs the addition of delamanid had no discernible effect on culture conversion at two or six months. As the standard of care for MDR/RR-TB treatment becomes more potent, it may become increasingly difficult to detect the benefit of adding a single agent to standard of care MDR/RR-TB regimens. Novel approaches like those implemented may help account for background regimens and establish effectiveness of new chemical entities.

Detection of Mycobacterium tuberculosis Complex Using the Xpert MTB/RIF Ultra Assay on the Stool of Pediatric Patients in Dushanbe, Tajikistan.

We report the findings of a prospective laboratory diagnostic accuracy study to evaluate the sensitivity, specificity, and predictive values of the Xpert MTB/RIF Ultra assay for Mycobacterium tuberculosis detection in fresh stool specimens from children under 15 years of age with confirmed tuberculosis (TB) disease from Dushanbe, Tajikistan. Six hundred eighty-eight (688) participants were enrolled from April 2019 to October 2021. We identified 16 participants (2.3%) with confirmed TB disease, defined as ≥1 TB sign/symptom plus microbiologic confirmation. With the Xpert MTB/RIF Ultra assay for stool, we found a sensitivity of 68.8% (95% CI, 46.0 to 91.5) and a specificity of 98.7% (95% CI, 97.8 to 99.5) in confirmed TB disease. Our results are comparable to other published studies; however, our cohort was larger and our confirmed TB disease rate lower than most. We also demonstrated that this assay was feasible to implement in a centralized hospital laboratory in a low-middle-income Central Asian country. However, we encountered obstacles such as lack of staffing, material ruptures, outdated government protocols, and decreased case presentation due to COVID-19. We found eight patients whose only positive test was an Xpert Ultra stool assay. None needed treatment during the study; however, three were treated later, suggesting such cases require close observation. Our report is the first from Central Asia and one of a few from a low-middle-income country. We believe our study demonstrates the generalizability of the Xpert MTB/RIF Ultra assay on fresh stool specimens from children and provides further evidence supporting WHO's approval of this diagnostic strategy. IMPORTANCE The importance of this report is that it provides further support for WHO's recent recommendation that fresh stool is an acceptable sample for GeneXpert TB testing in children, especially small children who often cannot produce an adequate sputum sample. Diagnosing TB in this age group is difficult, and many cases are missed, leading to unacceptable rates of TB illness and death. In our large cohort of children from Dushanbe, Tajikistan, the GeneXpert stool test was positive in 69% of proven cases of TB, and there were very few false-positive tests. We also showed that this diagnostic strategy was feasible to implement in a low-middle-income country with an inefficient health care delivery system. We hope that many more programs will adopt this form of diagnosing TB in children.

Costs and import costs of past, present, and future TB drug regimens: a case study for Karakalpakstan, Uzbekistan.

BACKGROUND: Tuberculosis (TB) drugs and their import are costly. We assessed how shorter TB drug regimens, which were non-inferior or superior in recent TB trials, can affect the costs for purchasing and importing TB drugs. METHODS: We estimated the drug costs and import costs of 39 longer and shorter TB drug regimens using TB drug prices from the Global Drug Facility and import cost estimates for a TB program in Karakalpakstan, Uzbekistan. Drug regimens from recent TB trials were compared with TB drug regimens following present or past World Health Organization recommendations. RESULTS: We estimated an import cost of $4.19 and a drug cost of $43 per standard 6-month drug-sensitive (DS)-TB regimen. A new 17-week DS-TB regimen from the TBTC Study 31 currently requires more tablets and is more expensive to import ($6.08) and purchase ($233). The TB program can substantially decrease import costs ($2.26-14) and drug costs ($391-2308) per multidrug-resistant (MDR)-TB regimen when using new 6-month or shorter drug regimens from the Nix-TB, NExT, TB PRACTECAL, ZeNix, or BEAT TB trials instead of 9-20-month regimens with import costs of $9.96-507 and drug costs of $354-15 028. For a commonly used 20-month all-oral, bedaquiline-containing MDR-TB regimen, we estimated costs of $41 for drug import and $1773 for drug purchase. CONCLUSIONS: The implementation of a new and shorter DS-TB regimen may increase the costs for drug purchase and import. The implementation of new and shorter MDR-TB regimens may decrease the costs for drug purchase and/or drug import.

Global impact of COVID-19 on childhood tuberculosis: an analysis of notification data.

BACKGROUND: There is concern that the COVID-19 pandemic has damaged global childhood tuberculosis management. Quantifying changes in childhood tuberculosis notifications could support more targeted interventions to restore childhood tuberculosis services. We aimed to use time-series modelling to evaluate the impact of COVID-19 on child tuberculosis notifications. METHODS: Annual tuberculosis case notification data reported to WHO by 215 countries were used to calculate annual notification counts for the years 2014-20, stratified by age groups (0-4, 5-14, and ≥15 years) and sex. We used time-series modelling to predict notification counts for 2020, and calculated differences between these predictions and observed notifications in 2020 for each of the six WHO regions and at the country level for 30 countries with high tuberculosis burden. We assessed associations between these differences and the COVID-19 stringency index, a measure of COVID-19 social impact. FINDINGS: From 2014 to 2019, annual tuberculosis notification counts increased across all age groups and WHO regions. More males than females in the 0-4 years age group and ≥15 years age group had notifications in all years from 2014 to 2020 and in all WHO regions. In the 5-14 years age group, more females than males were notified globally in all years, although some WHO regions had higher notifications from males than females. In 2020, global notifications were 35·4% lower than predicted (95% prediction interval -30·3 to -39·9; 142 525 observed vs 220 794 predicted notifications [95% prediction interval 204 509 to 237 078]) for children aged 0-4 years, 27·7% lower (-23·4 to -31·5; 256 398 vs 354 578 [334 724 to 374 431]) in children aged 5-14 years, and 18·8% lower (-15·4 to -21·9; 5 391 753 vs 6 639 547 [6 375 086 to 6 904 007]) for people aged 15 years or older. Among those aged 5-14 years, the reduction in observed relative to predicted notifications for 2020 was greater in males (-30·9% [-24·8 to -36·1]) than females (-24·5% [-18·1 to -29·9]). Among 28 countries with high tuberculosis burden, no association was observed between the stringency of COVID-19 restrictions and the relative difference in observed versus predicted notifications. INTERPRETATION: Our findings suggest that COVID-19 has substantially affected childhood tuberculosis services, with the youngest children most affected. Although children have mostly had fewer severe health consequences from COVID-19 than have adults, they have been disproportionately affected by the effects of the pandemic on tuberculosis care. Observed sex differences suggest that targeted interventions might be required. As countries rebuild health systems following the COVID-19 pandemic, it is crucial that childhood tuberculosis services are placed centrally within national strategic plans. FUNDING: Medical Research Council.

Treatment of Rifampicin-Resistant Tuberculosis Disease and Infection in Children: Key Updates, Challenges and Opportunities.

Children affected by rifampicin-resistant tuberculosis (RR-TB; TB resistant to at least rifampicin) are a neglected group. Each year an estimated 25,000-30,000 children develop RR-TB disease globally. Improving case detection and treatment initiation is a priority since RR-TB disease is underdiagnosed and undertreated. Untreated paediatric TB has particularly high morbidity and mortality. However, children receiving TB treatment, including for RR-TB, respond well. RR-TB treatment remains a challenge for children, their caregivers and TB programmes, requiring treatment regimens of up to 18 months in duration, often associated with severe and long-term adverse effects. Shorter, safer, effective child-friendly regimens for RR-TB are needed. Preventing progression to disease following Mycobacterium tuberculosis infection is another key component of TB control. The last few years have seen exciting advances. In this article, we highlight key elements of paediatric RR-TB case detection and recent updates, ongoing challenges and forthcoming advances in the treatment of RR-TB disease and infection in children and adolescents. The global TB community must continue to advocate for more and faster research in children on novel and repurposed TB drugs and regimens and increase investments in scaling-up effective approaches, to ensure an equitable response that prioritises the needs of this vulnerable population.

Programme costs of longer and shorter tuberculosis drug regimens and drug import: a modelling study for Karakalpakstan, Uzbekistan.

Background: The introduction of new and often shorter tuberculosis (TB) drug regimens affects the cost of TB programmes. Methods: We modelled drug purchase and import costs for 20-month, 9-month and 4- to 6-month TB drug regimens based on 2016-2020 treatment numbers from a TB programme in Karakalpakstan, Uzbekistan, and 2021 Global Drug Facility prices. Results: On average, 2225±374 (±sd) people per year started TB treatment, 30±2.1% of whom were diagnosed with drug-resistant forms of TB. Transitioning from a 6-month to a 4-month drug-susceptible (DS)-TB drug regimen increased the TB programme's annual DS-TB drug cost from USD 65±10 K to USD 357±56 K (p<0.001) and its drug import cost from USD 6.4±1.0 K to USD 9.3±1.4 K (p=0.008). Transitioning from a 20-month all-oral multidrug-resistant (MDR)-TB drug regimen to a 9-month MDR-TB drug regimen with an injectable antibiotic decreased the TB programme's annual MDR-TB drug cost from USD 1336±265 K to USD 266±53 K (p<0.001) and had no significant effect on the drug import cost (USD 28±5.5 K versus USD 27±5.4 K; p=0.88). Purchasing (USD 577±114 K) and importing (USD 3.0±0.59 K) the 6-month all-oral MDR-TB drug regimen cost more than procuring the 9-month MDR-TB drug regimen but less than the 20-month all-oral MDR-TB drug regimen (both p<0.01). Conclusion: Introducing new and shorter TB drug regimens could increase the cost of TB programmes with low drug resistance rates and decrease the cost of TB programmes with high drug resistance rates.

The contribution of drug import to the cost of tuberculosis treatment: A cost analysis of longer, shorter, and short drug regimens for Karakalpakstan, Uzbekistan.

Tuberculosis (TB) programs depend on a continuous supply of large amounts of high-quality TB drugs. When TB programs procure TB drugs from international suppliers, such as the Global Drug Facility, they can incur import costs for international transport, customs clearance, and national transport. We assessed the drug costs and import costs of 18 longer (≥18 months), 10 shorter (9-12 months), and 8 short (≤6 months) drug regimens for drug-sensitive (DS) and multidrug-resistant (MDR)-TB treatment. Costs per regimen were estimated by multiplying recommended drug amounts with 2021 Global Drug Facility prices and drug import costs of a TB program in Karakalpakstan, Uzbekistan. The standard short-course treatment of DS-TB requires taking 730 fixed-dose combination tablets, which weigh 0.79 kg and cause an import cost of $4.19 (9.8% of the regimen's drug cost of $43). A new 4-month DS-TB regimen requires taking 1358 tablets, which weigh 1.1 kg and cause an import cost of $6.07 (2.6% of the regimen's drug cost of $233). MDR-TB regimens that last between 24 weeks and 20 months involve 546-9368 tablets and injections. The drugs for these MDR-TB regimens were estimated to weigh 0.42-96 kg and cause an import cost of $2.26-507 per drug regimen (0.29-11% of a regimen's drug cost of $360-15,028). In a multivariable regression analysis, an additional treatment month increased the import cost of a drug regimen by $5.45 (95% CI: 1.65 to 9.26). Use of an injectable antibiotic in a regimen increased the import cost by $133 (95% CI: 47 to 219). The variable and potentially sizable import costs of TB regimens can affect the financial needs of TB programs. Drug regimens that are shorter and all-oral tend to reduce import costs compared to longer regimens and regimens including an injectable drug.

Outcomes with a shorter multidrug-resistant tuberculosis regimen from Karakalpakstan, Uzbekistan.

BACKGROUND: In 2016, World Health Organization guidelines conditionally recommended standardised shorter 9-12-month regimens for multidrug-resistant (MDR) tuberculosis (TB) treatment. We conducted a prospective study of a shorter standardised MDR-TB regimen in Karakalpakstan, Uzbekistan. METHODS: Consecutive adults and children with confirmed rifampicin-resistant pulmonary TB were enrolled between September 1, 2013 and March 31, 2015; exclusions included prior treatment with second-line anti-TB drugs, and documented resistance to ofloxacin or to two second-line injectable agents. The primary outcome was recurrence-free cure at 1 year following treatment completion. RESULTS: Of 146 enrolled patients, 128 were included: 67 female (52.3%), median age 30.1 (interquartile range 23.8-44.4) years. At the end of treatment, 71.9% (92 out of 128) of patients achieved treatment success, with 68% (87 out of 128) achieving recurrence-free cure at 1 year following completion. Unsuccessful outcomes during treatment included 22 (17.2%) treatment failures with fluoroquinolone-resistance amplification in 8 patients (8 out of 22, 36.4%); 12 (9.4%) lost to follow-up; and 2 (1.5%) deaths. Recurrence occurred in one patient. Fourteen patients (10.9%) experienced serious adverse events. Baseline resistance to both pyrazinamide and ethambutol (adjusted OR 6.13, 95% CI 2.01; 18.63) and adherence <95% (adjusted OR 5.33, 95% CI 1.73; 16.36) were associated with unsuccessful outcome in multivariable logistic regression. CONCLUSIONS: Overall success with a standardised shorter MDR-TB regimen was moderate with considerable treatment failure and amplification of fluoroquinolone resistance. When introducing standardised shorter regimens, baseline drug susceptibility testing and minimising missed doses are critical. High rates globally of pyrazinamide, ethambutol and ethionamide resistance raise questions of continued inclusion of these drugs in shorter regimens in the absence of drug susceptibility testing-confirmed susceptibility.

Factors associated with time to sputum culture conversion of rifampicin-resistant tuberculosis patients in Klaipeda, Lithuania in 2016-2019: a cohort study.

The global proportion of successful treatment outcomes of Multidrug-Resistant/Rifampicin-Resistant Tuberculosis (MDR/RR-TB) remains unacceptably low. Time to culture conversion is important in making treatment-related decisions and is used as an interim predictor of pulmonary MDR/RR-TB treatment success. No previous studies have been conducted to assess determinants of time to culture conversion for MDR/RR-TB patients in Lithuania. Secondary analysis of data of culture-positive MDR/RR-TB patients, treated in Republican Klaipeda Hospital between 1st July 2016 and 1st July 2019 was performed. Culture conversion was defined as two consecutive negative cultures on solid media submitted at least 30 days apart. Factors associated with culture conversion were estimated by crude and multivariable Cox regression accounting for competing risks. In total, 115 consecutive patients starting treatment were included in the study. Of them, the majority was male (86/115; 74.8%) with a mean age of 48 (standard deviation (SD) ±12) years and Human Immunodeficiency Virus (HIV) negative (105/115; 91.3%). Nearly two-thirds (72/115; 62.6%) had XDR (extensive drug resistance) or MDR/RR-TB with additional resistance to second-line injectables or fluoroquinolones. Of 115 culture-positive patients at baseline, 103 (89.6%) patients achieved culture conversion during 12 months of treatment. The median time to culture conversion was 1.1 months (interquartile range: 0.9-1.8). Patients aged ≥60 years compared with <40 years [adjusted hazard ration (aHR): 0.40, 95% confidence interval (CI): 0.18-0.86], smokers (aHR: 0.39, 95% CI: 0.2-0.73), patients with positive sputum smear microscopy at baseline (aHR: 0.40, 95% CI: 0.25-0.63), cavities on initial chest X-ray (aHR: 0.56, 95% CI: 0.35-0.88) and resistance to at least one fluoroquinolone drug (aHR: 0.52, 95% CI: 0.32-0.84) were slower to culture convert. In conclusion, we recommend providing additional counseling, treatment adherence interventions and scale up the use of new and repurposed TB drugs to patient groups at risk of worse interim treatment outcome: patients aged 60 and above, with resistance to fluoroquinolones, smear-positive, smokers, or with signs of extensive disease evident on initial chest radiography.

Factors associated with culture conversion among adults treated for pulmonary extensively drug-resistant tuberculosis during 2018-2019 in the Russian Federation: an observational cohort study.

Treatment outcomes for Multidrug/Rifampicin-Resistant Tuberculosis (MDR/RR-TB) and Extensively Drug-Resistant Tuberculosis (XDR-TB) remain poor across the globe and in the Russian Federation. Treatment of XDR-TB is challenging for programmes and patients often resulting in low success rates and onward transmission of drug-resistant strains. Analysis of factors affecting culture conversion rate among XDR-TB patients may serve as a basis for optimization of treatment regimens. We conducted a retrospective cohort study using health records from 54 patients with pulmonary XDR-TB treated at a tertiary level facility in the Russian Federation. The study population included adult patients with culture-positive pulmonary XDR-TB who started treatment between 1 January 2018-30 June 2019. Culture conversion was defined as two consecutive negative cultures, collected at least 30 days apart. The date of sputum culture conversion was taken from the first of two consecutive negative sputum cultures fulfilling these criteria. We measured time to culture conversion using cumulative incidence functions accounting for competing risks and applied binary cause-specific Cox regressions to assess associated factors. Sputum culture conversion was recorded for 43 (79.6%) patients. Median time to culture conversion adjusted for competing risk of loss to follow up was 4 months [95% confidence interval (CI): 2-5]. The number of patients who had culture converted by treatment months 2, 4, and 6 were 12 (22%), 29 (54%) and 38 (70%) respectively. In unadjusted analysis, positive baseline sputum smear microscopy [hazard ratio (HR): 0.34, 95% CI: 0.18-0.66; p=0.001), hepatitis C (HR: 0.35, 95% CI: 0.14-0.89; p=0.023], and human immunodeficiency virus (HR: 0.30 95%, CI: 0.09-0.97; p=0.045), and receipt of fewer than 4 effective drugs in the treatment regimen (HR: 0.13, 95% CI: 0.03-0.60; p=0.009) were associated with delayed culture conversion. When compared to their combined use, patients receiving regimens with bedaquiline only (HR: 0.12, 95% CI: 0.03-0.49; p=0.003) or linezolid only (HR: 0.21, 95% CI: 0.06-0.69; p=0.010) were less likely to achieve timely culture conversion. Factors delaying sputum culture conversion should be considered in the management of patients with XDR-TB and considered by clinicians for regimen design and treatment strategies. Our study outlines the importance of simultaneous inclusion of bedaquiline and linezolid in treatment regimens for patients with XDR-TB to reduce time to sputum conversion and increase treatment success.

Accuracy of molecular drug susceptibility testing amongst tuberculosis patients in Karakalpakstan, Uzbekistan.

OBJECTIVES: In this retrospective study, we evaluated the diagnostic accuracy of molecular tests (MT) for the detection of DR-TB, compared to the gold standard liquid-based drug susceptibility testing (DST) in Karakalpakstan. METHODS: A total of 6670 specimens received in the Republican TB No 1 Hospital Laboratory of Karakalpakstan between January and July 2017 from new and retreatment patients were analysed. Samples were tested using Xpert MTB/RIF and line probe assays (LPA) for the detection of mutations associated with resistance. The sensitivity and specificity of MTs were calculated relative to results based on DST. RESULTS: The accuracy of MT for detection of rifampicin resistance was high, with sensitivity and specificity over 98%. However, we observed reduced sensitivity of LPA for detection of resistance; 86% for isoniazid (95% CI 82-90%), 86% for fluoroquinolones (95% CI 68-96%), 70% for capreomycin (95% CI 46-88%) and 23% for kanamycin (95% CI 13-35%). CONCLUSIONS: We show that MTs are a useful tool for rapid and safe diagnosis of DR-TB; however, clinicians should be aware of their limitations. Although detection of rifampicin resistance was highly accurate, our data suggest that resistance mutations circulating in the Republic of Karakalpakstan for other drugs were not detected by the methods used here. This merits further investigation.

Patient and health-care worker perspectives on the short-course regimen for treatment of drug-resistant tuberculosis in Karakalpakstan, Uzbekistan.

INTRODUCTION: Standard multidrug-resistant tuberculosis (MDR-TB) treatment is lengthy, toxic, and insufficiently effective. New drugs and a shorter treatment regimen (SCR) are now recommended. However, patient and health-care worker (HCW) perspectives regarding the SCR are unknown. We aimed to determine the views and experiences of patients with MDR-TB and HCW regarding the SCR in Karakalpakstan, Uzbekistan. METHODS: In a qualitative study, we conducted 48 in-depth interviews with 24 people with MDR-TB and 20 HCW, purposively recruited to include those with a range of treatment-taking experiences and employment positions. Data were analysed thematically using Nvivo 12, to identify emergent patterns, concepts, and categories. Principles of grounded theory were drawn upon to generate findings inductively from participants' accounts. RESULTS: All patients viewed the SCR favourably. The SCR was seen as enabling an expedited return to work, studies, and "normality". This reduced the burden of treatment and difficulties with treatment fatigue. The SCR appeared to improve mental health, ease difficulties with TB-related stigma, and foster improved adherence. While patients wanted shorter treatment, it was also important that treatment be tolerable and effective. However, HCW doubted the appropriateness and effectiveness of the SCR, which influenced their confidence in prescribing the regimen. CONCLUSION: The SCR was said to benefit treatment completion and patients' lives. HCW concerns about SCR appropriateness and effectiveness may influence who receives the regimen. These are important considerations for SCR implementation and MDR-TB treatment developments, and dissonance between patient and HCW perspectives must be addressed for successful implementation of shorter regimens in the future.

Person-centred care in practice: perspectives from a short course regimen for multi-drug resistant tuberculosis in Karakalpakstan, Uzbekistan.

INTRODUCTION: Person-centred care, an internationally recognised priority, describes the involvement of people in their care and treatment decisions, and the consideration of their needs and priorities within service delivery. Clarity is required regarding how it may be implemented in practice within different contexts. The standard multi-drug resistant tuberculosis (MDR-TB) treatment regimen is lengthy, toxic and insufficiently effective. 2019 World Health Organisation guidelines include a shorter (9-11-month) regimen and recommend that people with MDR-TB be involved in the choice of treatment option. We examine the perspectives and experiences of people with MDR-TB and health-care workers (HCW) regarding person-centred care in an MDR-TB programme in Karakalpakstan, Uzbekistan, run by Médecins Sans Frontières and the Ministry of Health. METHODS: A qualitative study comprising 48 interviews with 24 people with MDR-TB and 20 HCW was conducted in June-July 2019. Participants were recruited purposively to include a range of treatment-taking experiences and professional positions. Interview data were analysed thematically using coding to identify emerging patterns, concepts, and categories relating to person-centred care, with Nvivo12. RESULTS: People with MDR-TB were unfamiliar with shared decision-making and felt uncomfortable taking responsibility for their treatment choice. HCW were viewed as having greater knowledge and expertise, and patients trusted HCW to act in their best interests, deferring the choice of appropriate treatment course to them. HCW had concerns about involving people in treatment choices, preferring that doctors made decisions. People with MDR-TB wanted to be involved in discussions about their treatment, and have their preference sought, and were comfortable choosing whether treatment was ambulatory or hospital-based. Participants felt it important that people with MDR-TB had knowledge and understanding about their treatment and disease, to foster their sense of preparedness and ownership for treatment. Involving people in their care was said to motivate sustained treatment-taking, and it appeared important to have evidence of treatment need and effect. CONCLUSIONS: There is a preference for doctors choosing the treatment regimen, linked to shared decision-making unfamiliarity and practitioner-patient knowledge imbalance. Involving people in their care, through discussions, information, and preference-seeking could foster ownership and self-responsibility, supporting sustained engagement with treatment.

A case report of a child with probable drug resistant tuberculous pericarditis with a review of challenges involved in diagnosis, treatment and follow up of children with DR-TB pericarditis.

BACKGROUND: There are unique challenges in the diagnosis and management of multi drug resistant tuberculosis (MDR-TB) in children. It is difficult to obtain confirmatory microbiological diagnosis in TB pericarditis. It is essential to differentiate between drug sensitive and drug resistant forms of TB as it has a major bearing on the regimen used, and inappropriate TB treatment combined with steroid use for pericarditis can lead to deterioration. With lack of samples, the treatment decision relies on the drug resistance pattern of the close contact if available. Therapeutic challenges of MDR-TB management in a child involve use of toxic drugs that need to be judiciously handled. We report a 2 years 4 months old male child who was diagnosed with TB pericarditis and treated based on the resistance pattern of his mother who was on treatment for pulmonary MDR-TB. CASE PRESENTATION: This 2 years 4 months old male child was diagnosed with TB involving his pericardium. Getting him started on an appropriate regimen was delayed due to the difficulty in establishing microbiological confirmation and drug susceptibility. He was commenced on a regimen based on his mother's drug resistance pattern and required surgery due to cardiac failure during the course of his treatment. He successfully completed 2 years of therapy. CONCLUSIONS: This child's case demonstrates that despite unique challenges in diagnosis and management of drug resistant extra pulmonary tuberculosis in children, treatment of even complex forms can be successful. The need for high suspicion of MDR-TB, especially when there is close contact with pulmonary TB, careful design of an effective regimen that is tolerated by the child, indications for invasive surgical management of pericarditis, appropriate follow-up and management of adverse effects are emphasised.

Standardised shorter regimens versus individualised longer regimens for rifampin- or multidrug-resistant tuberculosis.

We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the "shorter regimen") and individualised regimens of ≥20 months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.

Treatment Outcomes in Global Systematic Review and Patient Meta-Analysis of Children with Extensively Drug-Resistant Tuberculosis.

Extensively drug-resistant tuberculosis (XDR TB) has extremely poor treatment outcomes in adults. Limited data are available for children. We report on clinical manifestations, treatment, and outcomes for 37 children (<15 years of age) with bacteriologically confirmed XDR TB in 11 countries. These patients were managed during 1999-2013. For the 37 children, median age was 11 years, 32 (87%) had pulmonary TB, and 29 had a recorded HIV status; 7 (24%) were infected with HIV. Median treatment duration was 7.0 months for the intensive phase and 12.2 months for the continuation phase. Thirty (81%) children had favorable treatment outcomes. Four (11%) died, 1 (3%) failed treatment, and 2 (5%) did not complete treatment. We found a high proportion of favorable treatment outcomes among children, with mortality rates markedly lower than for adults. Regimens and duration of treatment varied considerably. Evaluation of new regimens in children is required.