Impact of Prior Tuberculosis Treatment With New/Companion Drugs on Clinical Outcomes in Patients Receiving Concomitant Bedaquiline and Delamanid for Multidrug- and Rifampicin-Resistant Tuberculosis.

BACKGROUND: There are scarce data on the clinical outcomes of persons retreated with new/companion anti-tuberculosis (TB) drugs for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). We sought to evaluate the efficacy and safety of bedaquiline and delamanid containing regimens among patients with and without prior exposure to the new/companion drugs (bedaquiline, delamanid, linezolid, clofazimine, and fluoroquinolones). METHODS: We conducted a retrospective cohort study among patients with pulmonary MDR/RR-TB in Georgia who received bedaquiline and delamanid combination as a part of a salvage regimen from November 2017 to December 2020 in a programmatic setting. RESULTS: Among 106 persons with a median age of 39.5 years, 44 (41.5%) were previously treated with new/companion TB drugs. Patients with prior exposure to new/companion drugs had higher rates of baseline resistance compared to those without exposure to new/companion TB drugs (bedaquiline 15.2% vs 1.8%, linezolid 22.2% vs 16.7%). Sputum culture conversion rates among patients exposed and not exposed to new/companion drugs were 65.9% vs 98.0%, respectively (P < .001). Among patients with and without prior new/companion TB drug use, favorable outcome rates were 41.0% and 82.3%, respectively (P < .001). Treatment adherence in 32 (30.2%) patients was ≤80%. Five of 21 patients (23.8%) who had a baseline and repeat susceptibility test had acquired bedaquiline resistance. QTC/F prolongation (>500 ms) was rare (2.8%). CONCLUSIONS: Prior exposure to new/companion TB drugs was associated with poor clinical outcomes and acquired drug resistance. Tailoring the TB regimen to each patient's drug susceptibility test results and burden of disease and enhancing adherence support may improve outcomes.

Low BMI increases all-cause mortality rates in patients with drug-resistant TB.

BACKGROUND: Loss to follow-up (LTFU) is common among patients with drug-resistant TB (DR-TB) receiving second-line TB treatment; however, little is known about outcomes after LTFU, including mortality.OBJECTIVE: To determine rates of and factors associated with all-cause mortality among patients with DR-TB who were LTFU.METHODS: Retrospective cohort study of adult patients with DR-TB in Georgia who initiated second-line TB treatment during 2011-2014 and were LTFU. Survival analyses were used to estimate all-cause mortality rates and adjusted hazard ratios (aHR).RESULTS: During 2011-2014, 2,437 second-line treatment episodes occurred and 695 patients were LTFU. Among 695 LTFU patients, 143 (21%) died during 2,686 person-years (PY) post-LTFU (all-cause mortality rate 5.1%, 95% CI 4.3-6.0 per 100 PY). In multivariable analysis, low weight (BMI < 18.5 kg/m²) at treatment initiation (aHR 3.2, 95% CI 2.2-4.7), return to treatment after LTFU (aHR 3.1, 95% CI 2.2-4.4), <12 months of treatment (aHR 2.4, 95% CI 1.4-4.1) and a pre-LTFU positive culture (aHR 3.3, 95% CI 2.2-4.9) were associated with all-cause mortality.CONCLUSION: High all-cause mortality occurred among patients with DR-TB after LTFU despite a low HIV prevalence. Providing additional assistance for patients during DR-TB treatment to prevent LTFU and use of new and shorter treatment regimens may reduce mortality among LTFU.

Clinical outcomes among patients with tuberculous meningitis receiving intensified treatment regimens.

SETTING: National Center for Tuberculosis and Lung Diseases (NCTLD), Tbilisi, Georgia.OBJECTIVE: To determine clinical outcomes of patients with tuberculous meningitis (TBM) treated with an intensified regimen including a fluoroquinolone (FQ) and an injectable agent.DESIGN: Prospective cohort of patients aged ≥16 years initiating treatment for TBM at the NCTLD from January 2018 to December 2019. Treatment outcomes and neurologic disability at 1, 6 and 12 months after treatment initiation were assessed.RESULTS: Among 77 patients with median follow-up time of 363 days (IQR 269-374), 97% received a FQ, 62% an injectable agent, 44% linezolid and 39% a carbapenem. Fifty-seven patients (74%) successfully completed treatment, 2 (2.6%) had treatment failure, 6 (7.8%) died, and the remainder (12%) were lost to follow up. Among 11 patients treated for multidrug-resistant TBM, the median follow-up time was 467 days and one patient (8%) died. Regarding neurologic outcomes, 14/76 (18%) patients had Modified Rankin Scores of 0 at baseline, improving to 85% (56/66) and 94% (47/50) at 6 and 12 months, respectively.CONCLUSION: Intensified multidrug treatment regimens including a FQ and an injectable agent in all patients and newly implemented drugs in patients with multidrug-resistant TBM resulted in low mortality and favorable neurologic outcomes.

THE RELATIONSHIP BETWEEN TYPE-2 DIABETES AND TUBERCULOSIS.

According to the experimental and clinical investigations, innate and adaptive immune disorders play a significant role in T2-D subjects to become more susceptible to TB. It was shown that the functions of neutrophils, macrophages, NK cells and other components of innate immunity areis markedly compromised by metabolic disorders in T2-D. The number of evidences suggests that reduction in TH1:TH2 cytokines ratios may have significant influence on susceptibility of TB infection in T2-D subjects. Hormonal changes in T2-D also may increase susceptibility to TB, including 2 hormones -ghrelin and leptin that are involved to in controlling blood glucose levels related to malnutrition during TB. According Based on the experimental and clinical results resistin, being a key molecule that links obesity and TB2-D, is considered as a protein contributing contributor to the development of insulin resistance, being a key molecule that links obesity and TB2-D. Subjects with T2-D showed higher levels of resistin in serum associated with reduced possibility of human macrophages to enhance the production of reactive oxygen species (ROS) in vitro against a challenge with TB. Immunological impairment has an important role in susceptibility to TB infection for patients with T2-D. It has been revealed that IFN-y and IL-22 markedly discriminate diabetes from nondiabetic individuals. It was also established that aside from this many cytokines such as IL-17A, IFN-B, TNFα, IL-10, IL-18, IFN-Y and IL-22 are the most significant and consequently potentially related to the effects caused by diabetes caused effects in the pathogenesis of active pulmonary TB. The endothelial system plays significant role in the pathogenesis and progression of TB infection. It was demonstrated that endothelin "B" receptor antagonist leads to vasoconstriction precluding inflammatory cell infiltration in lung tissue, suggesting that ET-1 proinflammatory action involves ET "B" receptor. It was also shown that sputum endothelin-1 level is associated with active pulmonary tuberculosis and effectiveness of treatment. Reduction ins sputum ET-1 level has significant role in the assessment of anti-tuberculosis treatment efficacy. Alterations in microbiota in T2-D subjects may influence on immunity against TB infection. As it was established the amount of bacteria producing short-chain fatty acids (SCFA) markedly decrease in T2-D, and treatment with SCFA reduced induction of TFN-α, IL-10 and IL-17 cytokines in contrast to IL-6, IFN-y and IL-22, without modification of their induction after using of SCFA. Vitamin "D" deficiency in T2-D may also play a role ion the immune response against TB. A number of evidences suggest the correlation between its diminished levels and TB or TB-T2-D. In conclusion it is suggested that different risk factors, including immunological and hormonal changes as well as alterations in different cytokine production and microbiota, endothelial dysfunction and vitamin "D" deficiency are the main contributors leading to comorbidity of T2-D and in TB.

Linezolid use for drug-resistant tuberculosis in Georgia: a retrospective cohort study.

SETTING: Data on the long-term use of linezolid (LZD) in the treatment of drug-resistant pulmonary tuberculosis (DR-PTB) are limited.OBJECTIVE: To assess safety, tolerability and efficacy of LZD-containing regimens for the treatment of DR-PTB in the country of Georgia.DESIGN: A retrospective study was conducted among DR-PTB patients receiving LZD 600 mg/day as part of newly implemented regimens (bedaquiline or delamanid, repurposed and second-line drugs) from July 2014 to October 2015 in programmatic conditions and following WHO recommendations.RESULTS: One hundred mostly male (82%) patients with a median age of 33 years received LZD. Most patients (77%) had previously been treated for TB; 57% had extensively drug-resistant TB. The median duration of LZD use was 503 days (interquartile range 355-616). LZD-associated adverse events occurred in 12 patients, leading to discontinuation in 4 (2 each due to peripheral neuropathy and cytopenias), and dose reduction to 300 mg/day in 6 cases (4 due to peripheral neuropathy and 2 for cytopenias). Almost all patients (95%) achieved culture conversion and 79% had a successful treatment outcomes.CONCLUSION: Treatment regimens including lengthy LZD use showed fairly good safety and tolerability and were associated with high rates of culture conversion and favorable outcomes.

Clinical Outcomes Among Patients With Drug-resistant Tuberculosis Receiving Bedaquiline- or Delamanid-Containing Regimens.

BACKGROUND: Bedaquiline and delamanid are newly available drugs for treating multidrug-resistant tuberculosis (MDR-TB); however, there are limited data guiding their use and no comparison studies. METHODS: We conducted a prospective, observational study among patients with MDR-TB in Georgia who were receiving a bedaquiline- or delamanid-based treatment regimen. Monthly sputum cultures, minimal inhibitory concentration testing, and adverse event monitoring were performed. Primary outcomes were culture conversion rates and clinical outcomes. Targeted maximum likelihood estimation and super learning were utilized to produce a covariate-adjusted proportion of outcomes for each regimen. RESULTS: Among 156 patients with MDR-TB, 100 were enrolled and 95 were receiving a bedaquiline-based (n = 64) or delamanid-based (n = 31) regimen. Most were male (82%) and the median age was 38 years. Rates of previous treatment (56%) and cavitary disease (61%) were high. The most common companion drugs included linezolid, clofazimine, cycloserine, and a fluoroquinolone. The median numbers of effective drugs received among patients on bedaquiline-based (4; interquartile range [IQR], 4-4) and delamanid-based (4; IQR, 3.5-5) regimens were similar. Rates of acquired drug resistance were significantly higher among patients receiving delamanid versus bedaquiline (36% vs 10%, respectively; P < .01). Adjusted rates of sputum culture conversion at 2 months (67% vs 47%, respectively; P = .10) and 6 months (95% vs 74%, respectively; P < .01), as well as more favorable clinical outcomes (96% vs 72%, respectively; P < .01), were higher among patients receiving bedaquiline versus delamanid. CONCLUSIONS: Among patients with MDR-TB, bedaquiline-based regimens were associated with higher rates of sputum culture conversion, more favorable outcomes, and a lower rate of acquired drug resistance versus delamanid-based regimens.

A survey of the tuberculosis physician workforce in the country of Georgia.

SETTING: A well-trained and sufficient tuberculosis (TB) workforce is essential for disease control, especially in an era of newly implemented diagnostics and medications. However, there are few reports on the status of the TB workforce in many endemic countries. OBJECTIVE: To evaluate the demographics, salary, career satisfaction, and attitudes towards the field of TB among the physician TB workforce in the country of Georgia. DESIGN: A cross-sectional study of physicians in the current Georgian National TB Programme (NTP) using an anonymous 31-item questionnaire. RESULTS: Among 184 NTP physicians countrywide, 142 (77%) were contacted and 138 (75%) completed questionnaires. The median age was 56 years (interquartile range 50-64); most (81%) were female. The monthly salary from TB work was USD205 for 50% of respondents. Nearly half (47%) received an additional salary from another source. Many physicians (65%) indicated that they were satisfied with their work, but over half (55%) were unsatisfied with reimbursement. While most physicians (78%) were concerned about the lack of interest in TB, only 36% would recommend a career in TB care. CONCLUSION: While the current TB workforce in Georgia finds their work fulfilling, an ageing workforce, low salaries and perceived lack of interest in the field are a matter of concern for future TB control.

Is 6 months of bedaquiline enough? Results from the compassionate use of bedaquiline in Armenia and Georgia.

BACKGROUND AND SETTING: Bedaquiline (BDQ) was initially only available through compassionate use programmes. OBJECTIVE: To assess the effectiveness and safety of multidrug-resistant tuberculosis (MDR-TB) treatment containing BDQ. METHOD: Retrospective analysis of data from patients receiving BDQ through compassionate use in Armenia and Georgia from April 2013 to April 2015. Logistic regression was used to assess the risk factors associated with unsuccessful treatment outcomes. RESULTS: Of 82 patients included, 84.2% (69/82) had fluoroquinolone-resistant MDR-TB and 43.4% (23/53) were seropositive for the hepatitis C virus (HCV). The culture conversion rate was 84.4% (54/64), and 18.5% (10/54) reverted back to positive. In total, 79.3% (65/82) of the patients reported at least one adverse event. Serious adverse events were reported in 14 patients, with 10/14 patients experiencing fatal outcomes-6/10 related to advanced TB and 2/10 assessed as possibly related to BDQ. Treatment outcomes were as follows: 58.5% treatment success, 12.2% deaths, 7.3% failures and 21.9% lost to follow-up. HCV coinfection was associated with unsuccessful outcomes (adjusted OR 4.45, 95%CI 1.23-16.13). CONCLUSION: BDQ through compassionate use showed relatively good success rates and safety profiles in a cohort with difficult-to-treat MDR-TB. High rates of reversion may indicate that >24 weeks of BDQ is necessary in some cases. HCV coinfection should be diagnosed and treatment considered in MDR-TB patients.

Examples of bedaquiline introduction for the management of multidrug-resistant tuberculosis in five countries.

BACKGROUND: For the first time in almost 50 years, there are new drugs available for the treatment of tuberculosis (TB), including bedaquiline (BDQ) and delamanid (DLM). The rate of introduction, however, has not kept pace with patient needs. It is estimated that as many as 23% of multidrug-resistant TB (MDR-TB) patients have an indication for receiving BDQ. As this is the first time the MDR-TB community is introducing new medications, it is important to understand how implementation can be developed in a variety of settings. METHODS: A qualitative assessment of country TB programs in which more than 5% of MDR-TB patients were started on BDQ under program conditions. RESULTS: National TB programs in Belarus, France, Georgia, South Africa, and Swaziland all started sizeable cohorts of patients on BDQ in 2015. Common factors observed in these programs included experience with compassionate use/expanded access, support from implementing partners, and adequate national or donor-supported budgets. Barriers to introduction included restriction of BDQ to the in-patient setting, lack of access to companion drugs, and the development of systems for pharmacovigilance. CONCLUSION: The five countries in this paper are examples of the introduction of new therapeutic options for the treatment of TB.

A comparison of the Xpert(®) MTB/RIF and GenoType(®) MTBDRplus assays in Georgia.

Few studies have directly compared the performance of rapid molecular diagnostic tests for tuberculosis (TB). We found that the commercially available molecular diagnostic tests Xpert(®) MTB/RIF and GenoType(®) MTBDRplus both provided timely and accurate results compared to conventional phenotypic tests in detecting TB and rifampicin resistance.

[Morphological changes of cardiovascular system at experimental hypertension, caused by no inhibition in condition of the laser irradiation of low-frequency].

The aim of our study was the investigation of the morphological changes of cardiovascular system, caused by NO inhibition during the laser irradiation of low-frequency. On reception of L NAME and a low-frequency laser irradiation arterial pressure during all experiment remains within the norm. At slight increase of phonic arterial pressure the laser irradiation proved to be less effective, while on a background of high arterial pressure the irradiation does not interfere the further development of hypertension and persistency. Immediately after reception of L NAME and at a low-frequency laser irradiation, the fibrosis and inflammatory changes of myocardium have not been observed; on the background of the slight enhancement of arterial pressure, laser irradiation causes insignificantly expressed fibrosis, inflammatory changes in myocardium; while on the background of increased arterial pressure a laser irradiation doesn't interfere development of fibrosis, myocardium and inflammatory changes in it. Immediately after reception L NAME and at a laser irradiation of low-frequency from the third day, a damage of cardiovascular walls, inflammatory changes, perivascular fibrosis have not been developed, while on the background of increased arterial pressure the irritation doesn't interfere the development of the above mentioned changes. Thus, the irradiation of a low-frequency laser might be recommended to prevent the development of hypertension and to avoid the complications of pre-clinical phase of hypertension. Though, the analogous recommendations are not foreseen for involvement in algorithm of the treatment of hypertension and correction of clinical evidence of the disease.