A 10-year review of isoniazid-resistant TB management in Uzbekistan 2009-2020.

BACKGROUND: Isoniazid (INH, H) resistance is the most common drug-resistant TB pattern, with treatment success rates lower than those in drug-susceptible TB. The WHO recommends a 6-month regimen of rifampicin (RIF, R), ethambutol (EMB, E), pyrazinamide (PZA, Z), and levofloxacin (Lfx) (6REZLfx) for INH-resistant, RIF-susceptible TB (HRRS-TB). Uzbekistan has a high burden of TB (62/100,000 population) and multidrug-resistant TB (12/100,000 population). METHODS: We conducted a retrospective, descriptive study of microbiologically confirmed HRRS-TB using routinely collected programmatic data from 2009 to 2020. RESULTS: We included 854 HRRS-TB cases. Treatment success was 80.2% overall. For REZLfx, the treatment success rate was 92.0% over a short treatment duration, with no amplifications to RIF or second-line anti-TB drug resistance. We documented 46 regimens with REZLfx plus linezolid (success 87.0%) and 539 regimens using kanamycin or capreomycin (success 76.6%). We identified 37 treatment failures (4.3%), 30 deaths (3.5%), 25 resistance amplifications (2.9%), including eight to RIF (0.9%), and 99 lost to follow-up (LTFU) cases (11.6%). Unsuccessful outcomes were more common with older age, diabetes, chest X-ray cavities, smear positivity, smear-positive persistence, and male sex. LTFU was more common with injection-containing regimens. CONCLUSIONS: REZLfx is a safe and effective first-line treatment for INH-resistant, RIF-susceptible TB. Treatment success was lower and LTFU was higher for injection-containing regimens.

CONTEXTE: La résistance à l'isoniazide (INH, H) est la forme de TB pharmacorésistante la plus courante, avec des taux de réussite thérapeutique inférieurs à ceux de la TB pharmacosensible. L'OMS recommande un traitement de six mois à base de rifampicine (RIF, R), d'éthambutol (EMB, E), de pyrazinamide (PZA, Z) et de lévofloxacine (LFx) (6REZLfx) pour la TB résistante à l'INH et sensible au RIF (HRRS-TB). En Ouzbékistan, la prévalence de la TB est élevée, avec un taux de 62 cas pour 100 000 habitants, ainsi que de la TB multirésistante, avec un taux de 12 cas pour 100 000 habitants. MÉTHODES: Une étude rétrospective et descriptive de la HRRS-TB confirmée microbiologiquement a été réalisée en utilisant des données programmatiques collectées de manière routinière de 2009 à 2020. RÉSULTATS: Nous avons inclus 854 cas de HRRS-TB. Le taux de réussite du traitement global était de 80,2%. Pour le traitement avec REZLfx, le taux de réussite était de 92,0% sur une courte durée, sans résistance au RIF ni aux médicaments antituberculeux de deuxième ligne. Nous avons observé 46 schémas thérapeutiques associant REZLfx et linézolide avec un taux de réussite de 87,0%, ainsi que 539 schémas thérapeutiques utilisant la kanamycine ou la capréomycine avec un taux de réussite de 76,6 %. Nous avons enregistré 37 échecs thérapeutiques (4,3%), 30 décès (3,5%), 25 cas de résistance amplifiée (2,9%), dont huit au RIF (0,9%), et 99 cas de perte de suivi (LTFU, pour l'anglais « loss to follow-up ¼) (11,6%). Les échecs étaient plus fréquents chez les patients âgés, diabétiques, présentant des cavités à la radiographie thoracique, un frottis positif persistant et de sexe masculin. La prolongation de la durée d'utilisation était plus fréquente avec les schémas contenant des injections. CONCLUSIONS: REZLfx est un traitement de première intention sûr et efficace contre la TB résistante à l'INH et sensible aux RIF. Le succès du traitement était plus faible et le nombre de LTFU était plus élevé pour les schémas contenant des injections.

Second-line drug-resistant TB and associated risk factors in Karakalpakstan, Uzbekistan.

BACKGROUND: Drug-resistant TB (DR-TB) remains a major public health threat. In 2022, Uzbekistan reported 2,117 cases of DR-TB, with 69% tested for fluoroquinolone resistance. Limited information is available on the prevalence of resistance to bedaquiline, linezolid, and fluoroquinolone, which are key components of the all-oral treatment regimen for rifampicin-resistant TB in Uzbekistan. METHODS: A retrospective study was conducted using extensive programmatic data from 2019 to 2023 in Uzbekistan. We assessed second-line drug-resistant TB (SLDR-TB) rates using phenotypic drug susceptibility testing (pDST). Demographic and clinical characteristics associated with SLDR-TB were analysed using multivariable logistic regression models based on the Allen-Cady approach. RESULTS: In total, 2,405 patients with TB who had undergone pDST were included (median age 40 years, 47% female). The overall SLDR-TB resistance rate was 24% (95% CI 22-26). Prevalence of resistance to bedaquiline, linezolid, moxifloxacin, levofloxacin, and amikacin were respectively 3.1%, 0.8%, 15%, 13%, and 12%. Risk factors for SLDR-TB were resistance to rifampicin and/or isoniazid, exposure to clofazimine, retreatment status, contact with drug-susceptible TB case or DR-TB case, and diabetes. CONCLUSIONS: The high prevalence of SLDR-TB is of major concern, emphasising the need for baseline pDST in RR-TB treatment. Identified risk factors can aid early detection of at-risk individuals and inform clinical practice.

CONTEXTE: La TB résistante aux médicaments (DR-TB) reste une menace majeure pour la santé publique. En 2022, l'Ouzbékistan a signalé 2 117 cas de DR-TB, dont 69% ont été testés pour la résistance aux fluoroquinolones. Les informations sur la prévalence de la résistance à la bédaquiline, au linézolide et aux fluoroquinolones, qui sont des composants clés du traitement entièrement oral de la TB résistante à la rifampicine en Ouzbékistan, sont limitées. MÉTHODES: Une étude rétrospective a été menée en utilisant des données programmatiques exhaustives de 2019 à 2023 en Ouzbékistan. Nous avons évalué les taux de TB résistante aux médicaments de deuxième ligne (SLDR-TB, pour l'anglais, « second-line drug-resistant TB ¼) en utilisant des tests de sensibilité phénotypique aux médicaments (pDST). Les caractéristiques démographiques et cliniques associées à la SLDR-TB ont été analysées à l'aide de modèles de régression logistique multivariés basés sur l'approche Allen-Cady. RÉSULTATS: Au total, 2 405 patients atteints de TB ayant subi un pDST ont été inclus (âge médian de 40 ans, 47% de femmes). Le taux global de résistance à la SLDR-TB était de 24% (CI à 95% 22­26). La prévalence de la résistance à la bédaquiline, au linézolide, à la moxifloxacine, à la lévofloxacine et à l'amikacine était respectivement de 3,1%, 0,8%, 15%, 13% et 12%. Les facteurs de risque de SLDR-TB comprenaient la résistance à la rifampicine et/ou à l'isoniazide, l'exposition à la clofazimine, le statut de retraitement, le contact avec un cas de TB sensible aux médicaments ou de DR-TB, et le diabète. CONCLUSIONS: La prévalence élevée de la SLDR-TB est une source de préoccupation majeure, soulignant la nécessité de réaliser des pDST de base dans le traitement de la TB résistante à la rifampicine. Les facteurs de risque identifiés peuvent aider à la détection précoce des individus à risque et à informer la pratique clinique.

[Evaluation of the efficacy of antiparasitic drugs in the treatment of concurrent parasitic diseases in patients with HIV infection and in those with pulmonary tuberculosis].

The efficacy of albendazole (400 mg taken once), mebendazole (100 mg taken once), and metronidazole (0.5 g thrice daily for 7 days) was evaluated when treating ascariasis, enterobiosis, and blastocystosis, respectively, in patients with HIV infection and in those with pulmonary tuberculosis. Metronidazole-resistant lambliasis was treated with exdisten (5 mg four times for 10 days) in 30.4% of the patients with HIV infection and in 43.3% of those with tuberculosis. Most HIV infected patients received antiretroviral therapy (ARVT). All the tuberculosis patients took isoniazid, ethambutol, pyrazinamide, rifampicin, and streptomycin. Efficiency was monitored by triple coproscopy at an interval of 5-7 days and by additional examinations using the method of Ritchii et al. There was parasitological cure (decreased infection rate for blastocystosis) and clinical improvement as positive changes in symptoms, such as nausea, weakness, headache, weight loss, and others, in all the patients with concomitant ascariasis, enterobiosis, and lambliasis. ARVT and antituberculosis drugs were observed to be better tolerated in all cases.

Acquired bedaquiline resistance in Karakalpakstan, Uzbekistan.

BACKGROUND: The WHO recommends the use of bedaquiline (BDQ) in longer, as well as shorter, multidrug-resistant TB (MDR-TB) treatment regimens. However, resistance to this new drug is now emerging. We aimed to describe the characteristics of patients in Karakalpakstan, Uzbekistan, who were treated for MDR-TB and acquired BDQ resistance during treatment.METHODS: We performed a retrospective study of routinely collected data for patients treated for MDR-TB in Karakalpakstan between January 2015 and December 2020. We included patients on BDQ-containing regimens with baseline susceptibility to BDQ who developed BDQ resistance at any point after treatment initiation. Patients resistant to BDQ at baseline or with no confirmed susceptibility to BDQ at baseline were excluded.RESULTS: Of the 523 patients who received BDQ-containing regimens during the study period, BDQ resistance was detected in 31 patients (5.9%); 20 patients were excluded-16 with no prior confirmation of BDQ susceptibility and 4 who were resistant at baseline. Eleven patients with acquired BDQ resistance were identified. We discuss demographic variables, resistance profiles, treatment-related variables and risk factors for unfavourable outcomes for these patients.CONCLUSION: Our programmatic data demonstrated the acquisition of BDQ resistance during or subsequent to receiving a BDQ-containing regimen in a patient cohort from Uzbekistan. We highlight the need for individualised treatment regimens with optimised clinical and laboratory follow up to prevent resistance acquisition.

Capacity of Abbott RealTime MTB RIF/INH to detect rifampicin- and isoniazid-resistant tuberculosis.

Abbott RealTime MTB RIF/INH Resistance (RT RIF/INH) is a new assay for the detection of resistance to rifampicin (RIF) and isoniazid (INH) in tuberculosis (TB) patients. To evaluate the capacity of RT RIF/INH to detect resistance-associated mutations in target genes. A total of 311 Mycobacterium tuberculosis strains that had been pre-characterised using genotypic methods (GenoType® MTBDRplus, Sanger sequencing) and phenotypic drug susceptibility testing were subjected to DNA extraction on Abbott m2000sp and analysed using RT RIF/INH. Detection of heteroresistant mutations was studied with artificial mixtures of wild-type and mutant DNA. Overall sensitivity and specificity values of RT RIF/INH to detect resistance were respectively 87.2% and 98.4% for RIF and respectively 90.1% and 99.2% for INH. The capacity of RT RIF/INH to detect specific mutations was 100% for katG, inhA and frequent rpoB mutations, and 76% for rare rpoB mutations. Among the latter, two rare mutations were not consistently detected. With heteroresistant samples, RT RIF/INH reported resistance if samples contained at least 75-90% of mutant DNA. RT RIF/INH is a reliable high-throughput assay for the detection of RIF and INH resistance markers. The ability to detect INH resistance also may be of benefit in areas with high rates of INH-resistant, non-multidrug-resistant TB. .

Impact of pyrazinamide resistance on multidrug-resistant tuberculosis in Karakalpakstan, Uzbekistan.

SETTING: The World Health Organization (WHO) recommends the inclusion of pyrazinamide (PZA) in treatment regimens for multidrug-resistant tuberculosis (MDR-TB) unless resistance has been confirmed. OBJECTIVE: To investigate the association between PZA susceptibility and MDR-TB treatment outcome among patients treated with a PZA-containing regimen and whether the duration of the intensive phase of the PZA-containing regimen affected treatment outcome. DESIGN: We conducted a retrospective cohort study including all eligible MDR-TB patients starting treatment in 2003-2013 in the TB programme in Karakalpakstan, Uzbekistan. PZA drug susceptibility testing (DST) using liquid culture was performed, and outcomes were classified according to the WHO 2013 definitions. RESULTS: Of 2446 MDR-TB patients included, 832 (34.0%) had an available baseline PZA DST result, 612 (73.6%) of whom were PZA-resistant. We found no association between treatment success and PZA susceptibility (adjusted odds ratio [aOR] 0.86, 95%CI 0.51-1.44, P = 0.6) in patients treated with PZA. Furthermore, among patients with no baseline PZA DST result, no evidence was seen of an association between treatment success and PZA treatment duration (aOR 0.86, 95%CI 0.49-1.51, P = 0.6). CONCLUSION: Treatment of MDR-TB with a standard PZA regimen does not appear to improve treatment outcomes, regardless of PZA susceptibility or duration of treatment.

'They prefer hidden treatment': anti-tuberculosis drug-taking practices and drug regulation in Karakalpakstan.

SETTING: The joint Médecins Sans Frontières/Ministry of Health Multidrug-Resistant Tuberculosis (MDR-TB) Programme, Karakalpakstan, Uzbekistan. OBJECTIVE: Uzbekistan has high rates of MDR-TB. We aimed to understand patients' and prescribers' attitudes to anti-tuberculosis drug prescription, regulation and drug-taking behaviour. METHODS: Participants (12 patients, 12 practitioners) were recruited purposively. Data were gathered qualitatively using field notes and in-depth interviews and analysed thematically. FINDINGS: Our analysis highlighted two main themes. First, shame and stigma were reported to increase the likelihood of self-treatment and incorrect use of anti-tuberculosis drugs, most commonly at the initial stages of illness. A health system failure to promote health information was perceived, leading to wrong diagnoses and inappropriate therapies. Motivated by shame, patients hid their condition by resorting to drug treatment options outside the programme, compounding the risk of chaotic management and dissemination of erroneous information through lay networks. Second, positive influences on treatment were reported through patients, practitioners and peers working effectively together to deliver the correct information and support, which acted to normalise TB, reduce stigma and prevent misuse of anti-tuberculosis drugs. CONCLUSION: Effective case finding, patient support and community education strategies are essential. Patients, practitioners and peers working together can help reduce stigma and prevent misuse of anti-tuberculosis drugs.

[Features of disruption of certain components of carbohydrate metabolism in a combination of pulmonary tuberculosis and diabetes mellitus in people with haptoglobin phenotypes]. / Osobennosti narushenii nekotorykh zven'ev uglevodnogo obmena pri sochetanii tuberkuleza legkikh i sakharnogo diabeta u lits s raznymi fenotipami gaptoglobina.

Sugar level in blood, the activity of lactate dehydrogenase (LDH), glucose-6-phosphate dehydrogenase (G-6-PDH), 2,3-BPG content, HbA1C and the phenotype of haptoglobin were studied in 180 patients with lung tuberculosis and diabetes mellitus. The increased (2-4.2-fold) blood sugar level was found in 77.2% patients. It was accompanied by decreased activity of LDH (by 1.3-1.7 times), G-6-PDH (by 15-45% in 87% patients). In patients with various haptoglobin phenotypes the content of HbA1C and 2.3-BPG was increased by 1.5-1.7 and 2-3 times, respectively. Clear differences in the studied parameters were found in patients with various phenotypes of haptoglobin (Hp). The most serious impairments of the studied parameters of carbohydrate metabolism were found in untreated patients with homozygote Hp phenotypes 2-2 and 1-1. Alterations found in the present study can be used for evaluating the depth of impairments of the carbohydrate metabolism in patients with combination of lung tuberculosis and diabetes mellitus.

[Diagnostic criteria of carbohydrate metabolism disorders in pulmonary tuberculosis complicated by diabetes mellitus in patients with various haptoglobin phenotypes]. / Diagnosticheskie kriterii narusheniia uglevodnogo obmena pri sochetanii tuberkuleza legkikh s sakharnym diabetom u bol'nykh s raznymi fenotipami gaptoglobina.

A total of 180 patients with various haptoglobin (Hp) phenotypes were examined in order to detect specific features of carbohydrate metabolism disorders in pulmonary tuberculosis concomitant with diabetes mellitus. Blood sugar levels, G-6-PDH and LDH, acid-base balance, and 2,3-DPG and HbA1c were evaluated. LDH activity was decreased 1.3-1.7 times in comparison with the norm, G-6-PDH was decreased by 15-45% vs. the norm in 87% patients, acid-base status was imbalanced, HbA1c content was increased 1.5-1.7 times vs. the norm, and 2.3-DPG content was increased 2-3-fold in comparison with the norm in 83% patients. Increased levels of HbA1c and 2,3-DPG in the studied combination of diseases augmented disorders of O2 binding to hemoglobin, which led to hypoxia. The most pronounced shifts in the studied parameters were observed in patients with Hp 2-2 and Hp 1-1. Changes in the studied parameters should be used for the diagnosis of the severity of carbohydrate metabolism disorders in diabetics with pulmonary tuberculosis.

[Manifestations of pulmonary tuberculosis concurrent with diabetes mellitus and various haptoglobin phenotypes]. / Proiavlenie tuberkuleza legkikh pri sochetanii s sakharnym diabetom i raznykh fenotipakh gaptoglobina.

For diagnosis, detection of the specific manifestations of pulmonary tuberculosis (PT) concurrent with diabetes mellitus, 48 patients with insulin-dependent diabetes (IDD) and 132 with noninsulin-dependent diabetes (NIDD), who carry various haptoglobin (Hp) phenotypes were studied. It has been found that PT develops in IDD mainly in 5-10 years and in NIDD in 1-4 years. The gravest course of both types of diabetes is frequently encountered in those having Hp 2-2 phenotypes and slightly less frequently in those with Hp 1-1. The patients having these phenotypes have abnormalities in the levels of glycaric hemoglobin, 2.3-diphosphoglycerol phosphate, in the activity of the enzymes lactate dehydrogenase and glucose-6-phosphate dehydrogenase and acid-alkali imbalance. It is expedient to determine Hp phenotypes to evaluate the severity and prognosis and to choose a treatment policy for comorbidity and the proposed biochemical indices should be more widely used to evaluate carbohydrate metabolic disturbances in PT concurrent with diabetes mellitus.