Iagor Kalandadze

Use of a Molecular Diagnostic Test in AFB Smear Positive Tuberculosis Suspects Greatly Reduces Time to Detection of Multidrug Resistant Tuberculosis

Background The WHO has recommended the implementation of rapid diagnostic tests to detect and help combat M/XDR tuberculosis (TB). There are limited data on the performance and impact of these tests in field settings. Methods The performance of the commercially available Genotype MTBDRplus molecular assay was compared to conventional methods including AFB smear, culture and drug susceptibility testing (DST) using both an absolute concentration method on Löwenstein-Jensen media and broth-based method using the MGIT 960 system. Sputum specimens were obtained from TB suspects in the country of Georgia who received care through the National TB Program. Results Among 500 AFB smear-positive sputum specimens, 458 (91.6%) had both a positive sputum culture for Mycobacterium tuberculosis and a valid MTBDRplus assay result. The MTBDRplus assay detected isoniazid (INH) resistance directly from the sputum specimen in 159 (89.8%) of 177 specimens and MDR-TB in 109 (95.6%) of 114 specimens compared to conventional methods. There was high agreement between the MTBDRplus assay and conventional DST results in detecting MDR-TB (kappa = 0.95, p<0.01). The most prevalent INH resistance mutation was S315T (78%) in the katG codon and the most common rifampicin resistance mutation was S531L (68%) in the rpoB codon. Among 13 specimens from TB suspects with negative sputum cultures, 7 had a positive MTBDRplus assay (3 with MDR-TB). The time to detection of MDR-TB was significantly less using the MTBDRplus assay (4.2 days) compared to the use of standard phenotypic tests (67.3 days with solid media and 21.6 days with broth-based media). Conclusions Compared to conventional methods, the MTBDRplus assay had high accuracy and significantly reduced time to detection of MDR-TB in an area with high MDR-TB prevalence. The use of rapid molecular diagnostic tests for TB and drug resistance should increase the proportion of patients promptly placed on appropriate therapy.

Adjunctive surgery improves treatment outcomes among patients with multidrug-resistant and extensively drug-resistant tuberculosis.

OBJECTIVES To determine risk factors for poor outcomes among patients with pulmonary multidrug- or extensively drug-resistant (M/XDR) tuberculosis (TB) in Georgia. METHODS This was a prospective, population-based observational cohort study. RESULTS Among 380M/XDR-TB patients (mean age 38 years), 179 (47%) had a poor outcome: 59 (16%) died, 37 (10%) failed, and 83 (22%) defaulted. Newly diagnosed M/XDR-TB cases were significantly more likely to have a favorable outcome than retreatment cases (odds ratio (OR) 4.26, 95% confidence interval (CI) 1.99-9.10, p<0.001). In the multivariable analysis, independent risk factors for a poor treatment outcome included previous treatment history (OR 2.92, 95% CI 1.29-6.58), bilateral disease (OR 1.90, 95% CI 1.20-3.01), body mass index (BMI, kg/m(2)) ≤18.5 (OR 1.91, 95% CI 1.11-3.29), and XDR-TB (OR 2.28, 95% CI 1.11-4.71). Patients who underwent surgical resection (OR 0.27, 95% CI 0.11-0.64) and had sputum culture conversion by 4 months (OR 0.33, 95% CI 0.21-0.52) were significantly less likely to have poor treatment outcomes. CONCLUSIONS Adjunctive surgery appeared to be beneficial in treating patients with M/XDR-TB. Retreatment cases, XDR-TB, bilateral disease, and low BMI were associated with a poor outcome. Additional studies are needed to further define the apparent beneficial role of surgery in the treatment of M/XDR-TB.

Additional drug resistance in Mycobacterium tuberculosis isolates from resected cavities among patients with multidrug-resistant or extensively drug-resistant pulmonary tuberculosis.

The pathogenesis of increasing drug resistance among patients with multidrug-resistant or extensively drug-resistant tuberculosis undergoing treatment is poorly understood. Increasing drug resistance found among Mycobacterium tuberculosis recovered from cavitary isolates compared with paired sputum isolates suggests pulmonary cavities may play a role in the development of worsening tuberculosis drug resistance.

Outcomes among tuberculosis patients with isoniazid resistance in Georgia, 2007-2009.

BACKGROUND The optimal management strategy for patients with isoniazid (INH) monoresistant forms of tuberculosis (TB) has been widely debated. The current daily 9-month regimen of rifampin, pyrazinamide and ethambutol was established based largely on trials in settings with low TB rates and low rates of drug resistance. OBJECTIVE To explore the outcomes of patients with INH-monoresistant TB in the country of Georgia, a setting with both high TB rates and drug-resistant forms of the disease. METHODS Retrospective record review of all patients diagnosed with smear-positive pulmonary TB resistant to either INH or INH+SM (streptomycin) in Georgia between 2007 and 2009. RESULTS Of 8752 patients with pulmonary TB registered in Georgia, 909 were found to have INH or INH+SM resistance. Treatment outcomes were relatively poor in this group, with only 71% treatment success. Outcomes were significantly worse among patients with older age and a history of previous treatment. CONCLUSIONS INH or INH+SM resistance in pulmonary TB patients in Georgia is common. The low rates of treatment success suggest the need for an improved treatment regimen for patients with resistance to these first-line drugs; this need is particularly pronounced among the subset of patients with a history of previous treatment.

Outcomes of children treated for tuberculosis with second-line medications in Georgia, 2009-2011.

BACKGROUND Drug-resistant tuberculosis (DR-TB) is a major public threat in countries of the former Soviet Union, including Georgia. There are few studies of pediatric DR-TB cases, especially at a national level. OBJECTIVE To report the characteristics and treatment outcomes of pediatric multidrug-resistant TB (MDR-TB) cases in Georgia. METHODS We extracted data on all pediatric (age <16 years) MDR-TB cases notified in Georgia from 2009 to 2011. We assessed the baseline and treatment characteristics and treatment outcomes of this cohort. RESULTS Between 2009 and 2011, there were 45 notified pediatric DR-TB cases in Georgia. Just over half had previously received anti-tuberculosis treatment and the median age was 7.7 years. Time from diagnosis to treatment was short (median 16 days), and the median length of treatment was 20.2 months. Of those not still on treatment, 77.1% (95%CI 61.0-87.9) had a successful outcome. CONCLUSIONS One of the first reports of pediatric DR-TB treatment outcomes at a national level, this study demonstrates that successful outcomes can be achieved.

Tobacco smoking and tuberculosis treatment outcomes: a prospective cohort study in Georgia

Abstract Objective To assess the effect of tobacco smoking on the outcome of tuberculosis treatment in Tbilisi, Georgia. Methods We conducted a prospective cohort study of adults with laboratory-confirmed tuberculosis from May 2011 to November 2013. History of tobacco smoking was collected using a standardized questionnaire adapted from the global adult tobacco survey. We considered tuberculosis therapy to have a poor outcome if participants defaulted, failed treatment or died. We used multivariable regressions to estimate the risk of a poor treatment outcome. Findings Of the 591 tuberculosis patients enrolled, 188 (31.8%) were past smokers and 271 (45.9%) were current smokers. Ninety (33.2%) of the current smokers and 24 (18.2%) of the participants who had never smoked had previously been treated for tuberculosis (P < 0.01). Treatment outcome data were available for 524 of the participants, of whom 128 (24.4%) – including 80 (32.9%) of the 243 current smokers and 21 (17.2%) of the 122 individuals who had never smoked – had a poor treatment outcome. Compared with those who had never smoked, current smokers had an increased risk of poor treatment outcome (adjusted relative risk, aRR: 1.70; 95% confidence interval, CI: 1.00–2.90). Those who had ceased smoking more than two months before enrolment did not have such an increased risk (aRR: 1.01; 95% CI: 0.51–1.99). Conclusion There is a high prevalence of smoking among patients with tuberculosis in Georgia and smoking increases the risk of a poor treatment outcome.

Geographical heterogeneity of multidrug-resistant tuberculosis in Georgia, January 2009 to June 2011

In 2011, Georgia, in the Caucasus, reported that 11% of new and 32% of previously treated tuberculosis (TB) cases nationally had multidrug-resistant TB (MDR-TB). To help understand the mechanisms driving these high risks of drug-resistance and plan for targeted interventions, we identified geographical variability in the MDR-TB burden in Georgia and patient-level MDR-TB risk factors. We used routinely collected surveillance data on notified TB cases to estimate the MDR-TB incidence/100,000 people and the percentage of TB cases with MDR-TB for each of 65 districts and regression modelling to identify patient-level MDR-TB risk factors. 1,795 MDR-TB cases were reported (January 2009–June 2011); the nationwide notified MDR-TB incidence was 16.2/100,000 but far higher (837/100,000) in the penitentiary system. We found substantial geographical heterogeneity between districts in the average annual MDR-TB incidence/100,000 (range: 0.0–5.0 among new and 0.0–18.9 among previously treated TB cases) and the percentage of TB cases with MDR-TB (range: 0.0%–33.3% among new and 0.0%–75.0% among previously treated TB cases). Among treatment-naïve individuals, those in cities had greater MDR-TB risk than those in rural areas (increased odds: 43%; 95% confidence interval: 20%–72%). These results suggest that interventions for interrupting MDR-TB transmission are urgently needed in prisons and urban areas.

Eliminating the category II retreatment regimen from National Tuberculosis Programme guidelines: the Georgian experience

PROBLEM The category II retreatment regimen for management of tuberculosis in previously treated patients was first introduced in the early 1990s. It consists of 8 months of total therapy with the addition of streptomycin to standard first-line medications. A review of 6500 patients on category II therapy in Georgia showed poor outcomes and high rates of streptomycin resistance. APPROACH The National Tuberculosis Program used an evidence-based analysis of national data to convince policy-makers that category II therapy should be eliminated from national guidelines in Georgia. LOCAL SETTING The World Health Organization tuberculosis case-notification rate in Georgia is 102 per 100,000 population. All patients receive culture and drug susceptibility testing as a standard part of tuberculosis diagnosis. In 2009, routine surveillance found multidrug-resistant tuberculosis in 10.6% of newly diagnosed patients and 32.5% of previously treated cases. RELEVANT CHANGES Category II retreatment regimen is no longer used in Georgia. Treatment is guided by results of drug susceptibility testing--using rapid, molecular tests where possible--for all previously treated tuberculosis patients. LESSONS LEARNT There was little resistance to policy change because the review was initiated and led by the National Tuberculosis Program. This experience can serve as a successful model for other countries to make informed decisions about the use of category II therapy.