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Background In 2019, the World Health Organization called for operational research on all-oral shortened regimens for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). We report safety and effectiveness of three 9-month all-oral regimens containing bedaquiline (Bdq), linezolid (Lzd), and levofloxacin (Lfx) and reinforced with cycloserine (Cs) and clofazimine (Cfz), delamanid (Dlm) and pyrazinamide (Z), or Dlm and Cfz. Methods We conducted a prospective cohort study of patients initiating treatment for pulmonary MDR/RR-TB under operational research conditions at public health facilities in Kazakhstan. Participants were screened monthly for adverse events. Participants with baseline resistance were excluded from the study and treated with a longer regimen. We analyzed clinically relevant adverse events of special interest in all participants and sputum culture conversion and end-of-treatment outcomes among individuals who were not excluded. Results Of 510 participants, 41% were women, the median age was 37 years (25th–75th percentile: 28–49), 18% had a body mass index <18.5 kg/m2, and 51% had cavitary disease. A total of 399 (78%) initiated Bdq-Lzd-Lfx-Cs-Cfz, 83 (16%) started Bdq-Lzd-Lfx-Dlm-Z, and 28 (5%) initiated Bdq-Lzd-Lfx-Dlm-Cfz. Fifty-eight individuals (11%) were excluded from the study, most commonly due to identification of baseline drug resistance (n = 52; 90%). Among the remaining 452 participants, treatment success frequencies were 92% (95% CI: 89–95%), 89% (95% CI: 80–94%), and 100% (95% CI: 86–100%) for regimens with Cs/Cfz, Dlm/Z, and Dlm/Cfz, respectively. Clinically relevant adverse events of special interest were uncommon. Conclusions All regimens demonstrated excellent safety and effectiveness, expanding the potential treatment options for patients, providers, and programs. [ABSTRACT FROM AUTHOR]

Rationale for review.Migrants to the WHO European Region are disproportionately affected by infections including tuberculosis, HIV and hepatitis B and C (HBV/HCV), compared with the host population. There are inequities in the accessibility and quality of health services available to refugees and migrants in the Region. This has consequences for health outcomes and will ultimately impact the ability to meet Regional infection elimination targets. We reviewed academic and grey literature to identify national policies and guidelines for tuberculosis/HIV/HBV/HCV specific to migrants in Member States of the WHO European Region, and identify: a) evidence informing policy and b) barriers and facilitators to policy implementation.Key Findings: Relatively few primary national policy/guideline documents were identified that related to migrants and tuberculosis (14 of 53 Member States (26%), HIV (n = 15, 28%) and HBV/HCV (n = 3, 6%), which often did not align with WHO recommendations and for some countries, violated migrants' human rights. We found extreme heterogeneity in the implementation of WHO- and European Centre for Disease Prevention and Control-advocated policies and recommendations on the prevention, diagnosis, treatment and care of TB/HIV/HBV/HCV infection in migrants across Member States of the WHO European Region.There is great heterogeneity in implementation of WHO- and European Centre for Disease Prevention and Control-advocated policies on the prevention, diagnosis, treatment and care of TB/HIV/HBV/HCV infection in migrants across Member States in the Region.Conclusions/recommendations: More transparent and accessible reporting of national policies and guidelines are required, together with the evidence base upon which these policy decisions are based. Political engagement is essential to drive changes in national legislation to ensure equitable and universal access to diagnosis and care for infectious diseases. [ABSTRACT FROM AUTHOR]

The article discusses the global tuberculosis response efforts, saved 60 million lives since 2000, TB remains one of the top infectious killers worldwide, affecting more than 10 million people. Topics include the global treatment success rate for multi drug-resistant TB and/or rifampicin-resistant TB patients; and the target 3.3 of the Sustainable Development Goals, confirmed by the WHO's End TB Strategy.

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. [ABSTRACT FROM AUTHOR]

To address the sub-optimal treatment outcomes among patients with multidrug-resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the National TB Programme in Belarus started using new drugs such as bedaquiline and delamanid in 2015-16. In this study, we assessed cardiovascular safety and effectiveness (culture conversion, treatment outcomes and post-treatment recurrence) of delamanid-containing regimens among adults (>18 years) with MDR-TB or XDR-TB from June 2016 to February 2018. This was a nationwide cohort study involving analysis of routinely collected programme data from the national and six regional TB hospitals. Cardiovascular adverse events (AEs) were classified as serious or not, based on international guidelines. We conducted Cox proportional hazards regression and calculated adjusted hazards ratio(aHR) and 95% confidence intervals (CI) to evaluate factors associated with AEs and unsuccessiul treatment outcomes (death, failure and lost-to-follow-up). Of 125 patients enrolled (35, 28% females; mean age 43 years), 85(68%) had XDR-TB. All the patients received delamanid and 20 patients received both delamanid and bedaquiline. Cardiovascular AEs (177 episodes in total) were observed in the majority (73%) of patients but were mild and managed easily. The most common cardiovascular AEs were QTcF prolongation (64/177, 36%) and other electrocardiography (ECG) abnormalities (40/177, 23%). There were two instances of serious AEs leading to death, both of which were not related to delamanid. In multivariable analysis, male sex (aHR 0.72; 95% CI 0.51-0.99), and baseline ECG abnormalities (aHR 1.68; 95% CI 1.19-2.36) were associated with cardiovascular AEs. Median time to culture conversion was 1.1 months (interquartile range: 1.0-2.1). Culture conversion was observed in 115 (92%) patients at six months of treatment and 110 (88%) completed the treatment successfully. Loss to follow-up, failure and death were observed in 6%, 4% and 2% patients respectively. Among those assessed at 12 months post-treatment (n=33), recurrence was seen in one patient. The only factor associated with unsuccessful treatment outcomes in multivariable analysis was baseline Hepatitis C co-infection (aHR 3.61; 95% CI 1.09-11.95). In conclusion, treatment using delamanid-containing regimens was effective and had a favourable safety profile. We hope our findings inform the development of national clinical guidelines and scale-up of new drugs in other countries. [ABSTRACT FROM AUTHOR]

There is limited evidence describing the safety and effectiveness of bedaquiline and delamanid containing regimens in children and adolescents with Multidrug-Resistant Tuberculosis (MDR-TB) and Extensively Drug-Resistant Tuberculosis (XDR-TB) globally. In this nationwide descriptive cohort study from Belarus, we examined adverse drug events, time to culture conversion, treatment outcomes including post-treatment recurrence among children and adolescents (<18 years of age) treated with bedaquiline and/or delamanid containing regimens from 2015 to 2019. Of the 40 participants included (55% females; age range 10 17 years), 20 (50%) had XDR-TB and 15 (38%) had resistance to either fluoroquinolone or second-line injectable. Half of the patients received delamanid and another half received bedaquiline with one patient receiving both drugs. AEs were reported in all the patients. A total of 224 AEs were reported, most of which (76%) were mild in nature. Only 10 (5%) AEs were graded severe and one AE was graded life-threatening. A total of 7 AEs (3%) were classified as 'serious' and only one patient required permanent discontinuation of the suspected drug (linezolid). Most of the AEs (94%) were resolved before the end of treatment. All patients culture-positive at baseline (n=34) became culture-negative within three months of treatment. Median time to culture conversion was 1.1 months (interquartile range: 0.9-1.6). Two patients were still receiving treatment at the time of analysis. The remaining 38 patients successfully completed treatment. Among those eligible and assessed at 6 (n=32) and 12 months (n=27) post-treatment, no recurrences were detected. In conclusion, treatment of children and adolescents with MDR-TB and XDR-TB using bedaquiline and/or delamanid containing regimens was effective and had favourable safety profile. Achieving such excellent outcomes under programmatic settings is encouraging for other national tuberculosis programmes, which are in the process of introducing or scaling-up the use of these new drugs in their countries. [ABSTRACT FROM AUTHOR]

Background. We sought to determine whether treatment with a "long aggressive regimen" was associated with lower rates of relapse among patients successfully treated for pulmonary multidrug-resistant tuberculosis (MDR-TB) in Tomsk, Russia. Methods. We conducted a retrospective cohort study of adult patients that initiated MDR-TB treatment with individualized regimens between September 2000 and November 2004, and were successfully treated. Patients were classified as having received "aggressive regimens" if their intensive phase consisted of at least 5 likely effective drugs (including a second-line injectable and a fluoroquinolone) used for at least 6 months post culture conversion, and their continuation phase included at least 4 likely effective drugs. Patients that were treated with aggressive regimens for a minimum duration of 18 months post culture conversion were classified as having received "long aggressive regimens." We used recurrence as a proxy for relapse because genotyping was not performed. After treatment, patients were classified as having disease recurrence if cultures grew MDR-TB or they re-initiated MDR-TB therapy. Data were analyzed using Cox proportional hazard regression. Results. Of 408 successfully treated patients, 399 (97.5%) with at least 1 follow-up visit were included. Median duration of follow-up was 42.4 months (interquartile range: 20.5-59.5), and there were 27 recurrence episodes. In a multivariable complete case analysis (n = 371 [92.9%]) adjusting for potential confounders, long aggressive regimens were associated with a lower rate of recurrence (adjusted hazard ratio: 0.22, 95% confidence interval, .05-.92). Conclusions. Long aggressive regimens for MDR-TB treatment are associated with lower risk of disease recurrence. [ABSTRACT FROM AUTHOR]

In this retrospective cohort study of patients treated for multidrug-resistant tuberculosis in the Russian Federation, we found that monthly exposure to an aggressive multidrug-resistant tuberculosis regimen was a robust predictor of decreased risk of death or failure during treatment.Background. Evidence is sparse regarding the optimal construction of regimens to treat multidrug-resistant (MDR) tuberculosis disease due to strains of Mycobacterium tuberculosis resistant to at least both isoniazid and rifampin. Given the low potency of many second-line antituberculous drugs, we hypothesized that an aggressive regimen of at least 5 likely effective drugs during the intensive phase, including a fluoroquinolone and a parenteral agent, would be associated with a reduced risk of death or treatment failure.Methods. We conducted a retrospective cohort study of patients initiating MDR tuberculosis treatment between 2000 and 2004 in Tomsk, Russian Federation. We used a multivariate Cox proportional hazards model to assess whether monthly exposure to an aggressive regimen was associated with the risk of death or treatment failure.Results. Six hundred fourteen individuals with confirmed MDR tuberculosis were eligible for analysis. On multivariable analysis that adjusted for extensively drug-resistant (XDR) tuberculosis—MDR tuberculosis isolates resistant to fluoroquinolones and parenteral agents—we found that monthly exposure to an aggressive regimen was significantly associated with a lower risk of death or treatment failure (hazard ratio, 0.52 [95% confidence interval, .29–.94]; P = .030).Conclusions. Receipt of an aggressive treatment regimen was a robust predictor of decreased risk of death or failure during MDR tuberculosis treatment. These findings further support the use of this regimen definition as the benchmark for the standard of care of MDR tuberculosis patients and should be used as the basis for evaluating novel therapies. [ABSTRACT FROM AUTHOR]