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 [...].

Adverse Drug Reactions among Children with Tuberculosis in Tashkent, Uzbekistan, 2019.

The treatment of childhood tuberculosis can be challenging due to the lack of pediatric drug formulations and monitoring of drug-toxicity in routine settings. There are no published studies from Uzbekistan on the adverse drug reactions (ADR) associated with anti-tuberculosis treatment in children. In this study, we aimed to investigate the ADR associated with anti-tuberculosis treatment in children. This was a cohort study using secondary program data of children treated at the city and regional tuberculosis clinics in Tashkent, Uzbekistan. Of the 302 patients evaluated, 135 (44.7%) reported ADR. New tuberculosis was registered in 277 (92%) patients and 262 (87%) had extrapulmonary tuberculosis. Factors associated with ADR included treatment at a regional hospital (adjusted odds ratio, aOR = 1.75; p = 0.026), female sex (aOR = 2.2; p = 0.004), and treatment with second-line drugs (aOR = 8.82; p < 0.001). The most common ADRs were gastrointestinal disorders (28.5%) followed by hepatitis (8.9%) and dermatologic reactions (8.6%). Most of the ADRs were mild (55.6%) or moderate (43.7%), only one child had severe ADR. Patients with the identified risk factors should be closely monitored during the treatment. We also recommend expansion of ADR surveillance throughout the country for more representative data in the future.

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.

Hospitalizations and Treatment Outcomes in Patients with Urogenital Tuberculosis in Tashkent, Uzbekistan, 2016-2018.

Despite the global shift to ambulatory tuberculosis (TB) care, hospitalizations remain common in Uzbekistan. This study examined the duration and determinants of hospitalizations among adult patients (≥18 years) with urogenital TB (UGTB) treated with first-line anti-TB drugs during 2016-2018 in Tashkent, Uzbekistan. This was a cohort study based on the analysis of health records. Of 142 included patients, 77 (54%) were males, the mean (±standard deviation) age was 40 ± 16 years, and 68 (48%) were laboratory-confirmed. A total of 136 (96%) patients were hospitalized during the intensive phase, and 12 (8%) had hospital admissions during the continuation phase of treatment. The median length of stay (LOS) during treatment was 56 days (Interquartile range: 56-58 days). LOS was associated with history of migration (adjusted incidence rate ratio (aIRR): 0.46, 95% confidence interval (CI): 0.32-0.69, p < 0.001); UGTB-related surgery (aIRR: 1.18, 95% CI: 1.01-1.38, p = 0.045); and hepatitis B comorbidity (aIRR: 3.18, 95% CI: 1.98-5.39, p < 0.001). The treatment success was 94% and it was not associated with the LOS. Hospitalization was almost universal among patients with UGTB in Uzbekistan. Future research should focus on finding out what proportion of hospitalizations were not clinically justified and could have been avoided.

Treatment Outcomes of Isoniazid-Resistant (Rifampicin Susceptible) Tuberculosis Patients in Uzbekistan, 2017-2018.

Tuberculosis patients "resistant to isoniazid and susceptible to rifampicin (Hr-TB)" remain neglected, despite a high burden and poor outcomes. The World Health Organization (WHO) recommends a 6 month regimen consisting of levofloxacin, rifampicin, ethambutol, and pyrazinamide (LRZE) to treat Hr-TB. In contrast, Uzbekistan uses a 9 month regimen (LRZE plus a second-line injectable in the first 3 months). We aimed to assess the treatment outcomes of this novel regimen among Hr-TB patients treated in two regions of Uzbekistan (Fergana and Bukhara) in 2017-2018. We conducted a cohort study involving secondary analysis of routine surveillance data. Of 132 Hr-TB patients, 105 (80%) were successfully treated. Death was the predominant unsuccessful outcome (13, 10%) followed by "treatment failure" (10, 8%) and "lost to follow-up" (4, 2%). High treatment success is an indicator of the potential effectiveness of the novel regimen and adds to the limited global evidence on this issue. However, the sample size was small and there was no comparison group. Since the study was conducted in two regions of Uzbekistan only, the findings have limited generalizability. We recommend future research using an adequate sample size and an appropriate study design (randomized controlled trial or prospective cohort with a control group receiving the WHO-recommended regimen).

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.

Treatment Compliance of Multidrug Resistant Tuberculosis in Uzbekistan: Does Practice Follow Policy?

Compliance with treatment guidelines is essential to achieve successful outcomes in tuberculosis patients. Thus, we assessed if multidrug-resistant tuberculosis treatment practices from 2012-2018 in Uzbekistan were compliant with national guidelines in terms of regimens prescribed, weight-based drug dosages used, and documentation of treatment changes (such as prolongation of intensive phase, change of drugs, and their reasons) in the treatment card and Consilium form. A total of 1481 patients were included. Of them, only 25% received standardized regimens as per guidelines and the remaining received individualized regimens. There was an increasing trend in using standardized regimens from 2% in 2012 to 44% in 2018. Compliance to recommended weight-based drug dosages was observed in 85% of the patients during the intensive phase and 84% in the continuation phase-ranged 71-91% over the years. Prolongation of the intensive phase was done in 42% of patients. The treatment was changed in 44% of patients during the intensive phase and 34% of patients during the continuation phase. The documentation of treatment changes was suboptimal (42-75%) during the initial years (2012-2014); however, it improved significantly during later years (86-100%). Future research should explore reasons for non-compliance so that the quality of patient care can be improved.

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.

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.

Risk Factors for Unfavorable Treatment Outcomes among the Human Immunodeficiency Virus-Associated Tuberculosis Population in Tashkent City, Uzbekistan: 2013-2017.

Tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection poses a growing clinical challenge. People living with HIV have a higher chance of developing TB, and once the disease has progressed, are at greater risk of having unfavorable TB treatment outcomes. Data on TB treatment outcomes among the HIV-associated TB population in Uzbekistan are limited. Thus, we conducted a cohort study among 808 adult patients with HIV-associated TB registered at the Tashkent TB referral hospital from 2013-2017 to document baseline characteristics and evaluate risk factors for unfavorable TB treatment outcomes. The data were collected from medical records and ambulatory cards. About 79.8% of the study population had favorable treatment outcomes. Antiretroviral therapy (ART) coverage at the admission was 26.9%. Information on CD4-cell counts and viral loads were largely missing. Having extrapulmonary TB (aOR 2.21, 95% CI: 1.38-3.53, p = 0.001), positive sputum smear laboratory results on admission (aOR 1.62, 95% CI: 1.07-2.40), diabetes (aOR 5.16, 95% CI: 1.77-14.98), and hepatitis C (aOR 1.68, 95% CI: 1.14-2.46) were independent risk factors for developing unfavorable TB treatment outcomes. The study findings provide evidence for targeted clinical management in co-infected patients with risk factors. Strengthening the integration of TB/HIV services may improve availability of key data to improve co-infection management.

Recurrent tuberculosis and associated factors: A five - year countrywide study in Uzbekistan.

BACKGROUND: In Uzbekistan, despite stable and relatively high tuberculosis treatment success rates, relatively high rates of recurrent tuberculosis have recently been reported. Recurrent tuberculosis is when a patient who was treated for pulmonary tuberculosis and cured, later develops the disease again. This requires closer analysis to identify possible causes and recommend interventions to improve the situation. Using countrywide data, this study aimed to analyse trends in recurrent tuberculosis cases and describe their associations with socio-demographic and clinical factors. METHOD: Countrywide retrospective cohort study comparing recurrent tuberculosis patients with all new tuberculosis patients registered within the NTP between January 2006 and December 2010 using routinely collected data. Determinants studied were baseline characteristics and treatment outcomes. RESULTS: Of 107,380 registered patients during the period January 2006 and December 2010, 9358 (8.7%) were recurrent cases. Between 2006 and 2008, the number of recurrent cases per annum increased from 1530 to 2081, then fell slightly thereafter from 2081 to 1888 cases. The proportion of all notified cases during this period increased from 6.5% to 9.9%. Factors associated with recurrent tuberculosis included age (35-55 years old), having smear positive pulmonary tuberculosis, residing in certain areas of Uzbekistan, having particular co-morbidities (including chronic obstructive pulmonary disease and HIV), and being unemployed, a pensioner or disabled. Recurrent tuberculosis patients also had a higher likelihood of having an unfavourable treatment outcome. CONCLUSION: Despite signs of declining national tuberculosis notifications between 2006 and 2010, the relative proportion of recurrent cases appears to have increased. These findings, together with the identification of possible risk factors associated with recurrent tuberculosis, highlight various areas where Uzbekistan needs to focus its tuberculosis control efforts, particularly in light of the country's rapidly emerging multi drug resistant tuberculosis epidemic.