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.

Safety and effectiveness of three novel all-oral shortened regimens for rifampicin- or multidrug-resistant tuberculosis in Kazakhstan.

BACKGROUND: In 2019, WHO 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 nine-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, median age was 37 years (interquartile range: 28-49), 18% had a body mass index <18·5 kg/m2, and 51% had cavitary disease. Three hundred and ninety-nine (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% confidence interval [CI]: 89 to 95), 89% (95%CI: 80 to 94), and 100% (95%CI: 86 to 100) for regimens with Cs/Cfz, Dlm/Z, and Dlm/Cfz respectively. Clinically-relevant adverse events of special interest were uncommon. CONCLUSION: All regimens demonstrated excellent safety and effectiveness, expanding the potential treatment options for patients, providers, and programs.

Tuberculosis Co-Infection Is Common in Patients Requiring Hospitalization for COVID-19 in Belarus: Mixed-Methods Study.

A significant drop in tuberculosis (TB) case-finding has been widely reported during the period of the COVID-19 pandemic. To address a decrease in TB notification, Belarus introduced laboratory TB testing in patients with the laboratory-confirmed coronavirus disease 2019 (COVID-19). We conducted a secondary analysis of health records among 844 patients with laboratory-confirmed COVID-19 diagnosis who were admitted to repurposed departments at TB hospitals and who were tested by Xpert MTB/RIF (Cepheid Inc., Sunnyvale, CA, USA) in five Belarus regions between April and October 2021. Quantitative analysis followed by 13 individual interviews with health managers, physicians, and nurses participating in the intervention. Most patients were male (64%) and mean age was 43.5 ± 16 years. One in twenty (n = 47, 5.6%) patients were co-infected with active pulmonary TB, and over one-third of them (n = 18) had rifampicin resistance. In-hospital mortality was comparable in patients with and without TB co-infection (2.1% and 2.3% respectively, p > 0.99). Laboratory TB testing among patients with COVID-19 at repurposed departments of TB hospitals is feasible in Belarus and may improve TB case-finding.

Factors Associated with Unfavourable Treatment Outcomes in Patients with Tuberculosis: A 16-Year Cohort Study (2005-2020), Republic of Karakalpakstan, Uzbekistan.

Tuberculosis (TB) remains a public health burden in the Republic of Karakalpakstan, Uzbekistan. This region-wide retrospective cohort study reports the treatment outcomes of patients registered in the TB electronic register and treated with first-line drugs in the TB Programme of the Republic of Karakalpakstan from 2005-2020 and factors associated with unfavourable outcomes. Among 35,122 registered patients, 24,394 (69%) patients were adults, 2339 (7%) were children, 18,032 (51%) were male and 19,774 (68%) lived in rural areas. Of these patients, 29,130 (83%) had pulmonary TB and 7497 (>22%) had been previously treated. There were 7440 (21%) patients who had unfavourable treatment outcomes. Factors associated with unfavourable treatment outcomes included: increasing age, living in certain parts of the republic, disability, pensioner status, unemployment, being HIV-positive, having pulmonary TB, and receiving category II treatment. Factors associated with death included: being adult and elderly, living in certain parts of the republic, having a disability, pensioner status, being HIV-positive, and receiving category II treatment. Factors associated with failure included: being adolescent, female, having pulmonary TB. Factors associated with loss to follow-up included: being male, disability, pensioner status, unemployment, receiving category II treatment. In summary, there are sub-groups of patients who need special attention in order to decrease unfavourable treatment outcomes.

Operational Research to Inform Programmatic Approaches to the Management of Tuberculosis in Uzbekistan.

Globally, an estimated 10 million people fell ill with tuberculosis (TB) in 2019, a number that has been declining very slowly in recent years [...].

Tuberculosis Notification Trends and Treatment Outcomes in Penitentiary and Civilian Health Care Sectors in the WHO European Region.

SETTING: Tuberculosis (TB) morbidity in penitentiary sectors is one of the major barriers to ending TB in the World Health Organization (WHO) European Region. OBJECTIVES AND DESIGN: a comparative analysis of TB notification rates during 2014-2018 and of treatment outcomes in the civilian and penitentiary sectors in the WHO European Region, with an assessment of risks of developing TB among people experience incarceration. RESULTS: in the WHO European Region, incident TB rates in inmates were 4-24 times higher than in the civilian population. In 12 eastern Europe and central Asia (EECA) countries, inmates compared to civilians had higher relative risks of developing TB (RR = 25) than in the rest of the region (RR = 11), with the highest rates reported in inmates in Azerbaijan, Kazakhstan, Kyrgyzstan, Republic of Moldova, Russian Federation, and Ukraine. The average annual change in TB notification rates between 2014 and 2018 was -7.0% in the civilian sector and -10.9% in the penitentiary sector. A total of 15 countries achieved treatment success rates of over 85% for new penitentiary sector TB patients, the target for the WHO European Region. In 10 countries, there were no significant differences in treatment outcomes between civilian and penitentiary sectors. CONCLUSION: 42 out of 53 (79%) WHO European Region countries reported TB data for the selected time periods. Most countries in the region achieved a substantial decline in TB burden in prisons, which indicates the effectiveness of recent interventions in correctional institutions. Nevertheless, people who experience incarceration remain an at-risk population for acquiring infection, developing active disease and unfavourable treatment outcomes. Therefore, TB prevention and care practices in inmates need to be improved.

Trends, Characteristics and Treatment Outcomes of Patients with Drug-Resistant Tuberculosis in Uzbekistan: 2013-2018.

Uzbekistan has a high burden of drug-resistant tuberculosis (TB). Although conventional treatment for multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) has been available since 2013, there has been no systematic documentation about its use and effectiveness. We therefore documented at national level the trends, characteristics, and outcomes of patients with drug-resistant TB enrolled for treatment from 2013-2018 and assessed risk factors for unfavorable treatment outcomes (death, failure, loss to follow-up, treatment continuation, change to XDR-TB regimen) in patients treated in Tashkent city from 2016-2017. This was a cohort study using secondary aggregate and individual patient data. Between 2013 and 2018, MDR-TB numbers were stable between 2347 and 2653 per annum, while XDR-TB numbers increased from 33 to 433 per annum. At national level, treatment success (cured and treatment completed) for MDR-TB decreased annually from 63% to 57%, while treatment success for XDR-TB increased annually from 24% to 57%. On multivariable analysis, risk factors for unfavorable outcomes, death, and loss to follow-up in drug-resistant TB patients treated in Tashkent city included XDR-TB, male sex, increasing age, previous TB treatment, alcohol abuse, and associated comorbidities (cardiovascular and liver disease, diabetes, and HIV/AIDS). Reasons for these findings and programmatic implications are discussed.

Scaling Up Molecular Diagnostic Tests for Drug-Resistant Tuberculosis in Uzbekistan from 2012-2019: Are We on the Right Track?

Uzbekistan has a large burden of drug-resistant tuberculosis (TB). To deal with this public health threat, the National TB Program introduced rapid molecular diagnostic tests such as Xpert MTB/RIF (Xpert) and line probe assays (LPAs) for first-line and second-line drugs. We documented the scale-up of Xpert and LPAs from 2012-2019 and assessed whether this led to an increase in patients with laboratory-confirmed multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB) and extensively drug-resistant TB (XDR-TB). This was a descriptive study using secondary program data. The numbers of GeneXpert instruments cumulatively increased from six to sixty-seven, resulting in annual assays increasing from 5574 to 107,330. A broader use of the technology resulted in a lower proportion of tests detecting Mycobacterium tuberculosis with half of the positive results showing rifampicin resistance. LPA instruments cumulatively increased from two to thirteen; the annual first-line assays for MDR-TB increased from 2582 to 6607 while second-line assays increased from 1435 in 2016 to 6815 in 2019 with about one quarter to one third of diagnosed patients showing second-line drug resistance. Patient numbers with laboratory-confirmed MDR-TB remained stable (from 1728 to 2060) but there was a large increase in patients with laboratory-confirmed XDR-TB (from 31 to 696). Programmatic implications and ways forward are discussed.

Operational research as an instrument to address the critical gaps for effective treatment of tuberculosis in eastern Europe and central Asia.

Editorial.

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.