Title Participants Abstract "Unexpected high prevalence of resistance-associated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline" "Cristina Villellas, Nele Coeck, Conor Meehan, Nacer Lounis, Bouke de Jong, Leen Rigouts, Koen Andries" "OBJECTIVES: Resistance-associated variants (RAVs) in Rv0678, a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines.METHODS: Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDR-TB sequences of a population-based cohort.RESULTS: Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (> 0.24 mg/L, n = 8), normal (0.03-0.24 mg/L, n = 11) or low (" "Genetic variability of Mycobacterium tuberculosis complex in patients with no known risk factors for MDR-TB in the North-eastern part of Lima, Peru" "F. Barletta, L. Otero, J. Collantes, B. Asto, Bouke de Jong, C. Seas, Leen Rigouts" "BACKGROUND: The aim of this study was to investigate the genetic diversity among Mycobacterium tuberculosis complex circulating in patients with no known risk factors for multi-drug resistant (MDR) tuberculosis (TB) living in a high MDR burden area and analyze the relationship between genotypes, primary drug resistance and age. METHODS: Samples were collected during January-July 2009. Isolates were tested for drug susceptibility to first-line drugs and were genotyped by spoligotyping and the 15-loci Mycobacterial Interspersed Repetitive Unit. RESULTS: Among the 199 isolates analyzed, 169 (84.9%) were identified in the SpolDB4.0 and 30 (15.1%) could not be matched to any lineage. The most prevalent lineage was Haarlem (29.6%), followed by T (15.6%), Beijing (14.1%), Latin American Mediterranean (12.6%) and U (8.5%). A few isolates belonged to the X and S clades (4.5%). Spoligotype analysis identified clustering among 148 of 169 isolates, whereas with MIRU15 all isolates were unique. Out of 197 strains; 31.5% were resistant to at least one drug, 7.5% were MDR and 22.3% showed any resistance to isoniazid. CONCLUSION: In contrast with other Latin-American countries where LAM lineage is the most predominant, we found the spoligotype 50 from the Haarlem lineage as the most common. None of the prevailing lineages showed a significant association with age or resistance to isoniazid and/or rifampicin." "Genetic variability of mycobacterium tuberculosis complex in patients with no known risk factors for MDR-TB in the North-eastern part of Lima, Peru" "Francesca Barletta, Larissa Otero, Jimena Collantes, Belisa Asto, Bouke C. de Jong, Carlos Seas, Leen Rigouts" "Background: The aim of this study was to investigate the genetic diversity among Mycobacterium tuberculosis complex circulating in patients with no known risk factors for multi-drug resistant (MDR) tuberculosis (TB) living in a high MDR burden area and analyze the relationship between genotypes, primary drug resistance and age. Methods: Samples were collected during January-July 2009. Isolates were tested for drug susceptibility to first-line drugs and were genotyped by spoligotyping and the 15-loci Mycobacterial Interspersed Repetitive Unit (MIRU15). Results: Among the 199 isolates analyzed, 169 (84.9%) were identified in the SpolDB4.0 and 30 (15.1%) could not be matched to any lineage. The most prevalent lineage was Haarlem (29.6%), followed by T (15.6%), Beijing (14.1%), Latin American Mediterranean (12.6%) and U (8.5%). A few isolates belonged to the X and S clades (4.5%). Spoligotype analysis identified clustering among 148 of 169 isolates, whereas with MIRU15 all isolates were unique. Out of 197 strains; 31.5% were resistant to at least one drug, 7.5% were MDR and 22.3% showed any resistance to isoniazid. Conclusion: In contrast with other Latin-American countries where LAM lineage is the most predominant, we found the spoligotype 50 from the Haarlem lineage as the most common. None of the prevailing lineages showed a significant association with age or resistance to isoniazid and/or rifampicin." "Short-course treatment outcomes and adverse events in adults and children-adolescents with MDR-TB in Niger" "S. H. Harouna, N. Ortuno-Gutierrez, M. B. Souleymane, W. Kizito, S. Morou, AR Boukary, Maria Zolfo, Guido Benedetti, A Piubello" "Setting: Niger National Tuberculosis Programme.Objective: To describe the outcomes and adverse events (AEs) in a cohort of adults, children and adolescents with multidrug-resistant tuberculosis (MDR-TB) who were treated with the 'short-course regimen'.Design: The regimen comprised an intensive phase of 4-6 months with kanamycin, medium-high dose of isoniazid and prothionamide, and high doses of gatifloxacin, clofazimine, ethambutol and pyrazinamide throughout. Sixty-five patients were treated with a regimen of 12-14 months and 55 patients with a regimen of 9-11 months.Results: Of the 120 patients evaluated, 110 (92%) were adults (median age 31 years) and 10 (8%) were children or adolescents (median age 17 years). The treatment success rate was respectively 88% and 83% with the 9-month regimen, and 90% and 75% with the 12-month regimen in adults and children/adolescents. Initial resistance to ethambutol and prothionamide did not affect treatment success rates but resistance to fluoroquinolones did, although this was not statistically significant. Vomiting was the most frequently encountered AE, followed by ototoxicity and hepatotoxicity. AEs experienced were mild or moderate in severity in most patients, and did not lead to treatment interruption.Conclusion: These results confirm the programmatic effectiveness and tolerability of the shorter regimen in second-line drug-naive patients." "Analysis of multi drug resistant tuberculosis (MDR-TB) financial protection policy: MDR-TB health insurance schemes, in Chhattisgarh state, India" "Lai Jiang" "INTRODUCTION: There are significant financial barriers to access treatment for multi drug resistant tuberculosis (MDR-TB) in India. To address these challenges, Chhattisgarh state in India has established a MDR-TB financial protection policy by creating MDR-TB benefit packages as part of the universal health insurance scheme that the state has rolled out in their effort towards attaining Universal Health Coverage for all its residents. In these schemes the state purchases health insurance against set packages of services from third party health insurance agencies on behalf of all its residents. Provider payment reform by strategic purchasing through output based payments (lump sum fee is reimbursed as per the MDR-TB benefit package rates) to the providers - both public and private health facilities empanelled under the insurance scheme was the key intervention. AIM: To understand the implementation gap between policy and practice of the benefit packages with respect to equity in utilization of package claims by the poor patients in public and private sector. METHODS: Data from primary health insurance claims from January 2013 to December 2015, were analysed using an extension of 'Kingdon's multiple streams for policy implementation framework' to explain the implementation gap between policy and practice of the MDR-TB benefit packages. RESULTS: The total number of claims for MDR-TB benefit packages increased over the study period mainly from poor patients treated in public facilities, particularly for the pre-treatment evaluation and hospital stay packages. Variations and inequities in utilizing the packages were observed between poor and non-poor beneficiaries in public and private sector. Private providers participation in the new MDR-TB financial protection mechanism through the universal health insurance scheme was observed to be much lower than might be expected given their share of healthcare provision overall in India. CONCLUSION: Our findings suggest that there may be an implementation gap due to weak coupling between the problem and the policy streams, reflecting weak coordination between state nodal agency and the state TB department. There is a pressing need to build strong institutional capacity of the public and private sector for improving service delivery to MDR-TB patients through this new health insurance mechanism." "Procurement and supply management system for MDR-TB in Nigeria" "Bolajoko Jatau, Yohanna Avong, Olumide Ogundahunsi, Safieh Shah, Katherine Tayler-Smith, Rafael Van den Bergh, Rony Zachariah, Johan van Griensven, Ernest Ekong, Patrick Dakum" "BACKGROUND: The World Health Organisation (WHO) introduced the twelve early warning indicators for monitoring and evaluating drug Procurement and Supply management (PSM) systems, intended to prevent drug stock-outs and overstocking. Nigeria--one of the high Multi Drug Resistant Tuberculosis (MDR-TB) burden countries, scaled-up treatment in 2012 with the concurrent implementation of a PSM system.METHOD: We evaluated how well this system functioned using the WHO indicators, including all seven MDR-TB treatment centres in the country that were functional throughout 2013.RESULTS: The quantity of MDR-TB drugs ordered for 2013 matched the annual forecast and all central orders placed during the year were delivered in full and on time. Drug consumption was 81%-106% of the quantity allocated for routine consumption. Timely submission of complete inventory reports ranged from 86-100%, late submissions being 5-15 days late. Forty to 71% of treatment centres placed a drug order when stock was below the minimum level of three months. The proportion of drug orders received at the treatment centres in full and on time ranged from 29-80%, late orders being 1-19 days late.CONCLUSION: The PSM was found to be performing well in terms of forecasting and procurement of MDR-TB drugs, but there were shortcomings in drug distribution, reporting at treatment centre level and in drug order placements. Despite these gaps, there were no stock outs. These findings indicate that where it matters most, namely ensuring that no drug stock outs affect patient management, the PSM system is effective. Addressing the observed shortcomings will help to strengthen the existing PSM system in anticipation of a growing MDR-TB case burden in the country." "Diverse clinical and social circumstances: developing patient-centred care for DR-TB patients in South Africa" "L Mitrani, L Dickson-Hall, S Le Roux, J Hill, M Loveday, Alison D. Grant, Karina Kielmann, K Mlisana, Mosa Moshabela, M P Nicol, Jim Black, H Cox" "OBJECTIVE: To describe the medical, socio-economic and geographical profiles of patients with rifampicin-resistant TB (RR-TB) and the implications for the provision of patient-centred care.SETTING: Thirteen districts across three South African provinces.DESIGN: This descriptive study examined laboratory and healthcare facility records of 194 patients diagnosed with RR-TB in the third quarter of 2016.RESULTS: The median age was 35 years; 120/194 (62%) of patients were male. Previous TB treatment was documented in 122/194 (63%) patients and 56/194 (29%) had a record of fluoroquinolone and/or second-line injectable resistance. Of 134 (69%) HIV-positive patients, viral loads were available for 68/134 (51%) (36/68 [53%] had viral loads of >1000 copies/ml) and CD4 counts were available for 92/134 (69%) (20/92 [22%] had CD4" "Specific gyrA gene mutations predict poor treatment outcome in MDR-TB" "Leen Rigouts, Nele Coeck, Mourad Gumusboga, Pim De Rijk, K.J.M. Aung, M.A. Hossain, Kristina Fissette, H L Rieder, Conor Meehan, Bouke de Jong, Armand Van Deun" "OBJECTIVES: Mutations in the gyrase genes cause fluoroquinolone resistance in Mycobacterium tuberculosis. However, the predictive value of these markers for clinical outcomes in patients with MDR-TB is unknown to date. The objective of this study was to determine molecular markers and breakpoints predicting second-line treatment outcomes in M. tuberculosis patients treated with fourth-generation fluoroquinolones.METHODS: We analysed treatment outcome data in relation to the gyrA and gyrB sequences and MICs of ofloxacin, gatifloxacin and moxifloxacin for pretreatment M. tuberculosis isolates from 181 MDR-TB patients in Bangladesh whose isolates were susceptible to injectable drugs.RESULTS: The gyrA 90Val, 94Gly and 94Ala mutations were most frequent, with the highest resistance levels for 94Gly mutants. Increased pretreatment resistance levels (>2 mg/L), related to specific mutations, were associated with lower cure percentages, with no cure in patients whose isolates were resistant to gatifloxacin at 4 mg/L. Any gyrA 94 mutation, except 94Ala, predicted a significantly lower proportion of cure compared with all other gyrA mutations taken together (all non-94 mutants + 94Ala) [OR = 4.3 (95% CI 1.4-13.0)]. The difference in treatment outcome was not explained by resistance to the other drugs.CONCLUSIONS: Our study suggests that gyrA mutations at position 94, other than Ala, predict high-level resistance to gatifloxacin and moxifloxacin, as well as poor treatment outcome, in MDR-TB patients in whom an injectable agent is still effective." "Genetic variations in GLI-1 and MDR-1 do not predict disease progression in patients with ulcerative colitis" "Marc Ferrante, Tamara Coopmans, Isabelle Cleynen, Nathalie Vermeulen, Marie Joossens, Ingrid Arijs, Gert A. Van Assche, Paul Rurgeerts, Severine Vermeire" "A cross-sectional study of tuberculosis drug resistance among previously treated patients in a tertiary hospital in Accra, Ghana; public health implications of standardized regimens" "Audrey Forson, Awewura Kwara, Samuel Kudzawu, Michael Omari, Jacob Otu, Florian Gehre, Bouke de Jong, Martin Antonio" "Background: Mycobacterium tuberculosis drug resistance is a major challenge to the use of standardized regimens for tuberculosis (TB) therapy, especially among previously treated patients. We aimed to investigate the frequency and pattern of drug resistance among previously treated patients with smear-positive pulmonary tuberculosis at the Korle-Bu Teaching Hospital Chest Clinic, Accra.Methods: This was a cross-sectional survey of mycobacterial isolates from previously treated patients referred to the Chest Clinic Laboratory between October 2010 and October 2013. The Bactec MGIT 960 system for mycobactrerial culture and drug sensitivity testing (DST) was used for sputum culture of AFB smear-positive patients with relapse, treatment failure, failure of smear conversion, or default. Descriptive statistics were used to summarize patient characteristics, and frequency and patterns of drug resistance.Results: A total of 112 isolates were studied out of 155 from previously treated patients. Twenty contaminated (12.9%) and 23 non-viable isolates (14.8%) were excluded. Of the 112 studied isolates, 53 (47.3%) were pan-sensitive to all first-line drugs tested Any resistance (mono and poly resistance) to isoniazid was found in 44 isolates (39.3%) and any resistance to streptomycin in 43 (38.4%). Thirty-one (27.7%) were MDR-TB. Eleven (35.5%) out of 31 MDR-TB isolates were pre-XDR. MDR-TB isolates were more likely than non-MDR isolates to have streptomycin and ethambutol resistance.Conclusions: The main findings of this study were the high prevalence of MDR-TB and streptomycin resistance among previously treated TB patients, as well as a high prevalence of pre-XDR-TB among the MDR-TB patients, which suggest that first-line and second-line DST is essential to aid the design of effective regimens for these groups of patients in Ghana."