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.

Time to start of tuberculosis treatment in penitentiary system of Kyrgyz Republic: A retrospective cohort study.

BACKGROUND: Tuberculosis burden among the incarcerated population is generally higher than that of general population. Early diagnosis and prompt initiation of treatment are key strategies to contain disease transmission. The aim of this study was to determine the time to treatment initiation among inmates with new smear or Xpert MTB/RIF positive pulmonary tuberculosis and explore risk factors associated with delayed treatment initiation in prison settings. METHODS: We conducted a retrospective cohort study using routine health care data from prison settings in Kzrgyz Republic on new pulmonary tuberculosis patients confirmed by smear microscopy or GeneXpert MTB/RIF during 2014-2019. We computed delay in start of treatment-days from specimen collection to treatment initiation-for exposure variables. We dichotomized treatment delay using 10-day cut-off point,and used logistic regression to identify factors associated with treatment delay. RESULTS: Among 406 cases included into analysis, the median delay to treatment initiation was 7 days [IQR: 2-16 days]. Using 10-day cut-off, 189 (46.6%) patients had delayed treatment initiation. Treatment delay was negatively associated with smear positivity [adjusted OR (aOR) = 0.44, 95% CI 0.29-0.68] compared to smear negative patients, while patients with isoniazid resistant (aOR = 2.61, 95%CI 1.49-4.56) and rifampicin resistant tuberculosis (aOR = 4.14, 95%CI 2.56-6.77) had increased delay compared to patients who were sensitive for both rifampicin and isoniazid. CONCLUSION: Timely diagnosis and effective treatment remain the cornerstone of TB control program populations in the general and in prison settings in particular. Prison authorities need to address all potential areas of delay in TB diagnosis and treatment to strengthen their TB control efforts so that prisons remain free of TB for detainees, prison staff and visitors. These include improved supply of TB drugs, early detection of TB cases and improved collaboration with the health authorities outside the prison system.

Characteristics and Treatment Outcomes of Patients with Tuberculosis Receiving Adjunctive Surgery in Uzbekistan.

Surgical interventions are performed as an adjunct to pharmacological treatment in Uzbekistan in 10-12% of diagnosed tuberculosis (TB) patients. In this study among patients with respiratory TB who had surgical interventions in Republican Specialized Scientific-Practical Medical Centre of Phthisiology and Pulmonology of Uzbekistan (RSSPMCPP) from January to May 2017, we describe (i) reasons and types of surgical intervention, (ii) post-surgical complications, (iii) histological diagnosis before and after surgery, and (iv) treatment outcomes. There were 101 patients included in the analysis (mean age 36 years; 51% male; 71% lived in rural areas). The main indications for surgical intervention included pulmonary tuberculoma (40%), fibrocavitary, or cavernous pulmonary TB (23%) and massive hemoptysis (20%). Pulmonary resections were the most frequent surgical procedures: segmentectomy (41%), lobectomy or bilobectomy (19%), and combined resection (17%). Ten patients (9%) suffered post-surgery complications. According to histological examination after surgery, TB was confirmed in 81 (80%) patients. For the other 20 patients, the confirmed diagnoses were: lung cancer (n = 6), echinococcosis (n = 5), post-TB fibrosis (n = 5), non-tuberculous pleurisy (n = 2), hamartoma (n = 1), and pneumonia (n = 1). The majority of patients (94%), who underwent surgery, were considered successfully treated. In conclusion, adjunctive surgical therapy can be an option for TB treatment, especially in cases of complicated TB.

Incidence Rate and Risk Factors for Tuberculosis among People Living with HIV: A 2015-2017 Cohort from Tashkent, Uzbekistan.

People living with the human immunodeficiency virus (PLHIV) have a higher risk of developing active tuberculosis (TB) disease, and TB remains a major cause of death in PLHIV. Uzbekistan is facing a substantial TB epidemic, which increases the risk of PLHIV developing active TB. Our retrospective cohort study aimed to evaluate the incidence rate and assess the risk factors for developing active TB among PLHIV. We collected secondary data extracted from medical charts of all patients, newly diagnosed at the AIDS Center in Tashkent, during the period of 2015-2017. The incidence rate of TB among PLHIV was 5.1 (95% CI: 4.5-6.0) per 1000 person/month. Adjusted regression analysis showed three major risk factors for TB, namely, being less than 15 years old (hazard ratio (HR) 5.83; 95% CI: 3.24-10.50, p value = 0.001),low CD4 count (adjusted hazard ratio(aHR) 21.0; 95% CI: 9.25-47.7, p value < 0.001), and antiretroviral therapy (ART) interruption/not receiving ART (aHR 5.57; 95% CI: 3.46-8.97 and aHR 6.2; 95% CI: 3.75-10.24, p value < 0.001, respectively) were significantly associated with developing active TB among PLHIV. Our findings indicate that taking prescribed ART without interruptions and maintaining CD4cell counts higher than 320 cells/µL are essential to prevent the development of active TB among PLHIV.

Diagnostic Procedures, Diagnoses, and Treatment Outcomes of Patients with Presumptive Tuberculosis Pleural Effusion in Uzbekistan.

Tuberculosis (TB) pleural effusion (TPE) is the second most common manifestation of extrapulmonary TB (EPTB), which remains a great diagnostic challenge worldwide. In Uzbekistan, there has been no formal evaluation of the actual practices of diagnosing and treating TPE. Our cohort study therefore aimed to describe the frequency and types of different diagnostic procedures of TPE during 2017-2018 and assess the association of baseline characteristics and establish diagnostic methods with TB treatment outcomes. In total, 187 patients with presumptive TPE were assessed, and 149 had a confirmed diagnosis of TPE (other diagnoses included cancer n = 8, pneumonia n = 17, and 13 cases were unspecified). TB was bacteriologically confirmed in 22 (14.8%), cytologically confirmed in 64 (43.0%), and histologically confirmed in 16 (10.7%) patients. Hepatitis was the only co-morbidity significantly associated with unsuccessful treatment outcomes (RR 4.8; 95%CI: 1.44-15.98, p value 0.011). Multivariable regression analysis showed that drug-resistant TB was independently associated with unsuccessful TB treatment outcome. (RR 3.83; 95%CI: 1.05-14.02, p value 0.04). Multidisciplinary approaches are required to maximize the diagnostic accuracy of TPE and minimize the chances of misdiagnosis. TPE patients with co-infections and those with drug resistance should be more closely monitored to try and ensure successful TB treatment outcomes.

Effectiveness and Safety of a Shorter Treatment Regimen in a Setting with a High Burden of Multidrug-Resistant Tuberculosis.

Treatment of drug-resistant tuberculosis is lengthy, insufficiently effective, and toxic. Since 2016, the World Health Organization has recommended shorter treatment regimens (STR). We assessed effectiveness and predictors of drug adverse events (DAE) among patients treated with STR. There were 95 consecutive rifampicin-resistant patients enrolled in STR in Tashkent between June 2018 and September 2019. Of these, 66.3% were successfully treated, 17.9% suffered failed treatment, 7.4% died, 5.3% were lost to follow-up and 3.2% were not evaluated. No recurrence was identified in 54 patients after 12 months of successful treatment completion. There were 47 reported DAE: the incidence rate was 6.15 DAE per 100 person-months-of-treatment. Any DAE was reported in 38 (40%) patients and grade 3/4 DAE were recorded in 21 (22.1%) patients. Median time to DAE was 101 (interquartile range 64-139) days. The most frequently encountered DAE were gastro-intestinal disorders, followed by hepatotoxicity and ototoxicity. The most commonly offending drug inducing DAE was protionamide. The dose was temporarily interrupted in 55.3% of DAE, reduced in 8.5% of DAE and permanently withdrawn in another 8.5% of DAE. HIV status was the only predictor associated with increased hazard of DAE. In Uzbekistan STR showed moderate effectiveness and safety, although treatment failure was high.

Incidence rate and time to serious adverse events among rifampicin resistant tuberculosis patients in Georgia treated with new and repurposed anti-tuberculosis drugs, 2016-2018.

Considering the complexity of second-line anti-tuberculosis (TB) treatment regimens, the management of drug-resistant TB (DR-TB) in Georgia remains a major challenge. Since the introduction of new and repurposed anti-TB medications, the implementation of active TB Drug Safety Monitoring (aDSM) was a critical program component to help establish safety and manage all treatment related Serious Adverse Events (SAEs). In our study, we aimed to describe the occurrence, characteristics and timing of SAE among patients with Rifampicin Resistant and Multi-Drug Resistant TB (RR/MDR-TB) receiving new and/or repurposed anti-TB medications (bedaquiline, delamanid, linezolid, clofazimine, imipenem) during the period of 2016-2018 in Georgia and identify predictors of SAE. The data were obtained from the medical charts, electronic database and standardized aDSM reports During 2016-2018 period in total 970 people with RR/MDR-TB were notified in Georgia and 388 of them received new and/or repurposed TB drugs as part of their treatment regimen and all were included into the study. The results showed a total of 73 SAEs registered among 49 (12.6%) patients receiving new and/or repurposed drugs. The overall SAE incidence rate per 100 person-months was 1.16. The severity of the majority of the SAEs (46.6%) was grade III and 21.9% were grade IV. The most common SAE reported was hepatotoxicity, with an incidence of 0.26 per 100 person-month (n=16, 21.9%) followed by cardiotoxicity with an incidence of 0.16 per 100 person-month (n=10, 13.7%). Median time to SAE occurrence was 183 days (IQR 84 - 334) after treatment initiation. Resistance profile was the only predictor associated with occurrence of a SAEs. There was increased hazard of SAEs among patients with XDR-TB (adjusted HR=2.18, 95% CI: 1.12-4.23). Our findings on SAEs among patients treated with new or repurposed anti-TB drugs are echoing the findings available in the literature. They highlight the need for close monitoring of patients and underlines the importance of the aDSM during the whole treatment. Safety profile of the medications and combinations used are yet to be established and larger datasets comprised of patients receiving same treatment regimens need to be utilized.

Effectiveness and safety of fully oral modified shorter treatment regimen for multidrug-resistant tuberculosis in Georgia, 2019-2020.

Tuberculosis treatment is challenging, especially among people with drug-resistant forms of tuberculosis. The introduction of fully oral modified short treatment regimen has a great potential to shorten duration of treatment, improve safety and ultimately increase treatment success rate. In 2019 Georgia has piloted the modified fully oral shorter treatment regimen in a routine programmatic condition. Our study aimed to evaluate effectiveness and safety of the modified shorter treatment regimen in Georgia among the first 25 consecutively enrolled patients with rifampicin-resistant tuberculosis with proven sensitivity to fluoroquinolone and without prior exposure to second-line tuberculosis drugs. Regimen consisted of 9-month daily administration of bedaquilline, linezolid, levofloxacin, clofazimine and cycloserine. Study patients were enrolled between March-August 2019. We used a national electronic surveillance system, medical records and active TB drug-safety monitoring and management database to extract study related data. The mean age of the study participants was 48 years, 68% were male, 8% were HIV positive, 16% had diabetes and 12% tested positive for hepatitis C infection. The median time to culture conversion among 16 patients who were culture positive at treatment initiation was 1.0 (95% CI: 1.0-2.0) month. Of those, by the end of treatment 15 patients converted to negative. Out of the 25 patients in the study cohort 22 (88%) had successful treatment outcome, one patient (4%) died and two (8%) were lost to follow up. The regimen was largely well tolerated. Three patients (12%) experienced serious adverse events, of which in two cases were possibly related to TB drugs in the regimen. Seven patients developed adverse events of interest in eight instances, including musculoskeletal (twice), psychiatric, gastrointestinal disorders, hepatotoxicity, peripheral neuropathy, cardiotoxicity and myelosuppression (once each). In four patients (16%) the duration of the treatment was extended beyond nine months due to insufficient radiological improvements. Our findings demonstrate that good treatment outcomes are achievable in people with fluoroquinolone-sensitive tuberculosis within routine programmatic conditions using fully oral modified short treatment regimen. The extensive use of fully oral modified shorter treatment regimen in Georgia and other high priority countries in the World Health Organization European Region is warranted.

Drug-resistant tuberculosis in eastern Europe and central Asia: a time-series analysis of routine surveillance data.

BACKGROUND: Among all WHO regions, the WHO European Region has the highest proportion of drug-resistant tuberculosis among new and retreated cases. The 18 high-priority countries in eastern Europe and central Asia account for 85% of the tuberculosis incidence and more than 90% of drug-resistant tuberculosis cases emerging in the region. We aimed to analyse time-series trends in notification rates of drug-resistant tuberculosis among new tuberculosis cases in the 18 high-priority countries in the WHO European Region. METHODS: We used country data stored in WHO's global tuberculosis database. For each country, we calculated annual notification rates per 100 000 population of new tuberculosis cases and of drug-resistant tuberculosis among new cases reported from Jan 1, 2000, to Dec 31, 2017. We computed annual percentage changes of notification rates and identified time-points of significant change in trends using the joinpoint regression method. FINDINGS: All 17 countries with data (no data available from Turkmenistan) showed a significant decline in new tuberculosis notification rates in the most recent years since the last joinpoint if one was identified. Notification rates of drug-resistant tuberculosis showed diverse trends, with substantial year-to-year variation. In the most recent years, notification rates of drug-resistant tuberculosis among new tuberculosis cases were decreasing in two countries (Estonia and Latvia), increasing in eight countries (Azerbaijan, Kyrgyzstan, Moldova [Republic of Moldova], Romania, Russia [Russian Federation], Tajikistan, Ukraine, and Uzbekistan), and stable in seven countries (Armenia, Belarus, Bulgaria, Georgia, Kazakhstan, Lithuania, and Turkey). INTERPRETATION: Our findings suggest that countries in the WHO European Region are more successful in controlling drug-susceptible tuberculosis than drug-resistant forms, and as a result, the proportion of drug-resistant strains among newly notified patients with tuberculosis is increasing in many settings. Two countries showed that it is possible to decrease incidence of both drug-susceptible and drug-resistant tuberculosis. If no additional efforts are made in prevention and care of patients with drug-resistant tuberculosis, further decline of the tuberculosis burden will be halted. Further studies are needed to investigate the success stories and document the most effective interventions to reach the target to end tuberculosis by 2030. FUNDING: United States Agency for International Development.

Behavior change communication model enhancing parental practices for improved early childhood growth and development outcomes in rural Armenia - A quasi-experimental study.

The latest evidence demonstrates the importance of nurturing care from conception to lay a strong foundation for children's cognitive, socio-emotional and physical well-being. The interventions enhancing parental practices in children's health and growth, protection from neglect, abuse, and injury have lifelong impact on health, learning, economic productiveness outcomes. Existing maternal and child health delivery platforms might potentially be utilized to integrate Early Childhood Development interventions. However, there is a dearth of studies demonstrating the feasibility and effectiveness of an integrated MCH and ECD model. ECD component was integrated into MCH program activities, implemented and tested in Armenia. For 14 months, all mothers of children aged 0 to 23 months (1300) living in 43 communities in Gegharkunik province (Armenia) participated in the study. Twenty-three intervention communities (680 children) received added ECD package to MCH intervention, and 20 control communities (630 children) received only MCH intervention. We used a quasi-experimental intervention-control design, with pre-and post-data collected. Variables measured and compared were related to child development, nutrition status, parental child care (stimulation, discipline) and nutrition practices. Intervention sites showed 83% higher odd of total ECD composite score (cognitive, language, motor) compared to children in the control sites. Child caregivers had better child care, nutrition practices and early learning support than controls. No change was found in discipline practices and stunting rates. MCH-ECD integrated model is an effective delivery platform for improving parenting behavior, child growth, and development.