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1. 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.

Author

Mikiashvili, L, Kempker, R R, Chakhaia, T S, Bablishvili, N, Avaliani, Z, Lomtadze, N, Schechter, M C, and Kipiani, M

Subjects
DRUG therapy for tuberculosis, COMBINATION drug therapy, RESEARCH funding, PATIENT safety, QUESTIONNAIRES, RETROSPECTIVE studies, DESCRIPTIVE statistics, ANTITUBERCULAR agents, LONGITUDINAL method, DRUG efficacy, RIFAMPIN, DRUG resistance
Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Healthcare delivery for HIV-positive people with tuberculosis in Europe

Author

Bentzon, A, Panteleev, A, Mitsura, V, Borodulina, E, Skrahina, A, Denisova, E, Tetradov, S, Podlasin, R, Riekstina, V, Kancauskiene, Z, Paduto, D, Mocroft, A, Trofimova, T, Miller, R, Post, F, Grezesczuk, A, Lundgren, J, Inglot, M, Podlekareva, D, Bolokadze, N, Kirk, O, Karpov, I, Vassilenko, A, Klimuk, D, Skrahin, A, Kondratenko, O, Zalutskaya, A, Bondarenko, V, Kozorez, E, Tumash, O, Suetnov, O, Iljina, V, Kummik, T, Mshvidobadze, K, Lanchava, N, Goginashvili, L, Mikiashvili, L, Bablishvili, N, Rozentale, B, Zeltina, I, Janushkevich, I, Caplinskiene, I, Caplinskas, S, Wiercinska-Drapalo, A, Thompson, M, Kozlowska, J, Bura, M, Knysz, B, Garlicki, A, Loster, J, Duiculescu, D, Rakhmanova, A, Panteleeva, O, Yakovlev, A, Kozlov, A, Tyukalova, A, Vlasova, Y, Trofimov, T, Kyselyova, G, Obel, N, Gerstoft, J, Kronborg, G, Payen, M, Kabeya, K, Necsoi, C, Dabis, F, Tsaranazy, A, Cazanave, C, Furrer, H, Sagette, M, Rickenbach, M, Elzi, L, Battegay, M, Sculier, D, Calmy, A, Cavassini, M, Bruno, A, Bernasconi, E, Hoffmann, M, Vernazza, P, Fehr, J, Weber, R, Vora, N, Cooke, G, Mullaney, S, Wilkins, E, George, V, Collini, P, Dockrell, D, Campbell, L, Brum, R, Mabonga, E, Saigal, P, Kegg, S, Ainsworth, J, Waters, A, Dhar, J, Ellis, K, Spallanzani, O, Girardi, E, Rianda, A, Galati, V, Pinnetti, C, Tommasi, C, San Gerardo, A, Lapadula, G, Di Biagio, A, Parisini, A, Carbonara, S, Angarano, G, Purgatorio, M, Matteelli, A, Apostoli, A, Miro, J, Manzardo, C, Ligero, C, Gonzalez, J, Martinez-Martinez, J, Sanchez, F, Knobel, H, Salvado, M, Lopez-Colomes, J, Martinez-Lacasa, X, Cuchi, E, Falco, V, Curran, A, Tortola, M, Ocana, I, Vidal, R, Sambeat, M, Pomar, V, Coll, P, Pozamczer, D, Saumoy, M, Alcaide, F, Cayla, J, Moreno, A, Millet, J, Orcau, A, Fina, L, Romero, A, Roldan, L, Iribarren, J, Ibarguren, M, Moreno, S, Gonzalez, A, Miralles, P, Aldamiz-Echevarria, T, Losso, M, Toibaro, J, Gambardella, L, Ramos Mejia, J, Moreno Macias, L, Warley, E, Tavella, S, Garcia Messina, O, Gear, O, Laplume, H, Marson, C, Contarelia, J, Michaan, M, Scapellato, P, Bartoletti, B, Palmero, D, Elias, C, Cortes, C, Crabtree, B, Mosqueda Gomez, J, Villanueva, J, Gonzalez Hernandez, L, Badial, F, Bentzon A. K., Panteleev A., Mitsura V., Borodulina E., Skrahina A., Denisova E., Tetradov S., Podlasin R., Riekstina V., Kancauskiene Z., Paduto D., Mocroft A., Trofimova T., Miller R., Post F., Grezesczuk A., Lundgren J. D., Inglot M., Podlekareva D., Bolokadze N., Kirk O., Karpov I., Vassilenko A., Klimuk D., Skrahin A., Kondratenko O., Zalutskaya A., Bondarenko V., Kozorez E., Tumash O., Suetnov O., Iljina V., Kummik T., Mshvidobadze K., Lanchava N., Goginashvili L., Mikiashvili L., Bablishvili N., Rozentale B., Zeltina I., Janushkevich I., Caplinskiene I., Caplinskas S., Wiercinska-Drapalo A., Thompson M., Kozlowska J., Bura M., Knysz B., Garlicki A., Loster J., Duiculescu D., Rakhmanova A., Panteleeva O., Yakovlev A., Kozlov A., Tyukalova A., Vlasova Y., Trofimov T., Kyselyova G., Obel N., Gerstoft J., Kronborg G., Payen M. C., Kabeya K., Necsoi C., Dabis F., Tsaranazy A., Cazanave C., Furrer H., Sagette M., Rickenbach M., Elzi L., Battegay M., Sculier D., Calmy A., Cavassini M., Bruno A., Bernasconi E., Hoffmann M., Vernazza P., Fehr J., Weber R., Vora N., Cooke G., Mullaney S., Wilkins E., George V., Collini P., Dockrell D., Campbell L., Brum R., Mabonga E., Saigal P., Kegg S., Ainsworth J., Waters A., Dhar J., Ellis K., Spallanzani O. L., Girardi E., Rianda A., Galati V., Pinnetti C., Tommasi C., San Gerardo A. O., Lapadula G., Di Biagio A., Parisini A., Carbonara S., Angarano G., Purgatorio M., Matteelli A., Apostoli A., Miro J. M., Manzardo C., Ligero C., Gonzalez J., Martinez-Martinez J. A., Sanchez F., Knobel H., Salvado M., Lopez-Colomes J. L., Martinez-Lacasa X., Cuchi E., Falco V., Curran A., Tortola M. T., Ocana I., Vidal R., Sambeat M. A., Pomar V., Coll P., Pozamczer D., Saumoy M., Alcaide F., Cayla J., Moreno A., Millet J. P., Orcau A., Fina L., Romero A., Roldan L. L., Iribarren J. A., Ibarguren M., Moreno S., Gonzalez A., Miralles P., Aldamiz-Echevarria T., Losso M., Toibaro J., Gambardella L., Ramos Mejia J. M., Moreno Macias L., Warley E., Tavella S., Garcia Messina O., Gear O., Laplume H., Marson C., Contarelia J., Michaan M., Scapellato P., Bartoletti B., Palmero D., Elias C., Cortes C., Crabtree B., Mosqueda Gomez J. L., Villanueva J. A., Gonzalez Hernandez L. A., Badial F., Bentzon, A, Panteleev, A, Mitsura, V, Borodulina, E, Skrahina, A, Denisova, E, Tetradov, S, Podlasin, R, Riekstina, V, Kancauskiene, Z, Paduto, D, Mocroft, A, Trofimova, T, Miller, R, Post, F, Grezesczuk, A, Lundgren, J, Inglot, M, Podlekareva, D, Bolokadze, N, Kirk, O, Karpov, I, Vassilenko, A, Klimuk, D, Skrahin, A, Kondratenko, O, Zalutskaya, A, Bondarenko, V, Kozorez, E, Tumash, O, Suetnov, O, Iljina, V, Kummik, T, Mshvidobadze, K, Lanchava, N, Goginashvili, L, Mikiashvili, L, Bablishvili, N, Rozentale, B, Zeltina, I, Janushkevich, I, Caplinskiene, I, Caplinskas, S, Wiercinska-Drapalo, A, Thompson, M, Kozlowska, J, Bura, M, Knysz, B, Garlicki, A, Loster, J, Duiculescu, D, Rakhmanova, A, Panteleeva, O, Yakovlev, A, Kozlov, A, Tyukalova, A, Vlasova, Y, Trofimov, T, Kyselyova, G, Obel, N, Gerstoft, J, Kronborg, G, Payen, M, Kabeya, K, Necsoi, C, Dabis, F, Tsaranazy, A, Cazanave, C, Furrer, H, Sagette, M, Rickenbach, M, Elzi, L, Battegay, M, Sculier, D, Calmy, A, Cavassini, M, Bruno, A, Bernasconi, E, Hoffmann, M, Vernazza, P, Fehr, J, Weber, R, Vora, N, Cooke, G, Mullaney, S, Wilkins, E, George, V, Collini, P, Dockrell, D, Campbell, L, Brum, R, Mabonga, E, Saigal, P, Kegg, S, Ainsworth, J, Waters, A, Dhar, J, Ellis, K, Spallanzani, O, Girardi, E, Rianda, A, Galati, V, Pinnetti, C, Tommasi, C, San Gerardo, A, Lapadula, G, Di Biagio, A, Parisini, A, Carbonara, S, Angarano, G, Purgatorio, M, Matteelli, A, Apostoli, A, Miro, J, Manzardo, C, Ligero, C, Gonzalez, J, Martinez-Martinez, J, Sanchez, F, Knobel, H, Salvado, M, Lopez-Colomes, J, Martinez-Lacasa, X, Cuchi, E, Falco, V, Curran, A, Tortola, M, Ocana, I, Vidal, R, Sambeat, M, Pomar, V, Coll, P, Pozamczer, D, Saumoy, M, Alcaide, F, Cayla, J, Moreno, A, Millet, J, Orcau, A, Fina, L, Romero, A, Roldan, L, Iribarren, J, Ibarguren, M, Moreno, S, Gonzalez, A, Miralles, P, Aldamiz-Echevarria, T, Losso, M, Toibaro, J, Gambardella, L, Ramos Mejia, J, Moreno Macias, L, Warley, E, Tavella, S, Garcia Messina, O, Gear, O, Laplume, H, Marson, C, Contarelia, J, Michaan, M, Scapellato, P, Bartoletti, B, Palmero, D, Elias, C, Cortes, C, Crabtree, B, Mosqueda Gomez, J, Villanueva, J, Gonzalez Hernandez, L, Badial, F, Bentzon A. K., Panteleev A., Mitsura V., Borodulina E., Skrahina A., Denisova E., Tetradov S., Podlasin R., Riekstina V., Kancauskiene Z., Paduto D., Mocroft A., Trofimova T., Miller R., Post F., Grezesczuk A., Lundgren J. D., Inglot M., Podlekareva D., Bolokadze N., Kirk O., Karpov I., Vassilenko A., Klimuk D., Skrahin A., Kondratenko O., Zalutskaya A., Bondarenko V., Kozorez E., Tumash O., Suetnov O., Iljina V., Kummik T., Mshvidobadze K., Lanchava N., Goginashvili L., Mikiashvili L., Bablishvili N., Rozentale B., Zeltina I., Janushkevich I., Caplinskiene I., Caplinskas S., Wiercinska-Drapalo A., Thompson M., Kozlowska J., Bura M., Knysz B., Garlicki A., Loster J., Duiculescu D., Rakhmanova A., Panteleeva O., Yakovlev A., Kozlov A., Tyukalova A., Vlasova Y., Trofimov T., Kyselyova G., Obel N., Gerstoft J., Kronborg G., Payen M. C., Kabeya K., Necsoi C., Dabis F., Tsaranazy A., Cazanave C., Furrer H., Sagette M., Rickenbach M., Elzi L., Battegay M., Sculier D., Calmy A., Cavassini M., Bruno A., Bernasconi E., Hoffmann M., Vernazza P., Fehr J., Weber R., Vora N., Cooke G., Mullaney S., Wilkins E., George V., Collini P., Dockrell D., Campbell L., Brum R., Mabonga E., Saigal P., Kegg S., Ainsworth J., Waters A., Dhar J., Ellis K., Spallanzani O. L., Girardi E., Rianda A., Galati V., Pinnetti C., Tommasi C., San Gerardo A. O., Lapadula G., Di Biagio A., Parisini A., Carbonara S., Angarano G., Purgatorio M., Matteelli A., Apostoli A., Miro J. M., Manzardo C., Ligero C., Gonzalez J., Martinez-Martinez J. A., Sanchez F., Knobel H., Salvado M., Lopez-Colomes J. L., Martinez-Lacasa X., Cuchi E., Falco V., Curran A., Tortola M. T., Ocana I., Vidal R., Sambeat M. A., Pomar V., Coll P., Pozamczer D., Saumoy M., Alcaide F., Cayla J., Moreno A., Millet J. P., Orcau A., Fina L., Romero A., Roldan L. L., Iribarren J. A., Ibarguren M., Moreno S., Gonzalez A., Miralles P., Aldamiz-Echevarria T., Losso M., Toibaro J., Gambardella L., Ramos Mejia J. M., Moreno Macias L., Warley E., Tavella S., Garcia Messina O., Gear O., Laplume H., Marson C., Contarelia J., Michaan M., Scapellato P., Bartoletti B., Palmero D., Elias C., Cortes C., Crabtree B., Mosqueda Gomez J. L., Villanueva J. A., Gonzalez Hernandez L. A., and Badial F.

Abstract

Background: In a 2013 survey, we reported distinct discrepancies in delivery of tuberculosis (TB) and HIV services in eastern Europe (EE) vs. western Europe (WE). Objectives: To verify the differences in TB and HIV services in EE vs. WE. Methods: Twenty-three sites completed a survey in 2018 (EE, 14; WE, nine; 88% response rate). Results were compared across as well as within the two regions. When possible, results were compared with the 2013 survey. Results: Delivery of healthcare was significantly less integrated in EE: provision of TB and HIV services at one site (36% in EE vs. 89% in WE; P = 0.034), and continued TB follow-up in one location (42% vs. 100%; P = 0.007). Although access to TB diagnostics, standard TB and HIV drugs was generally good, fewer sites in EE reported unlimited access to rifabutin/multi-drug-resistant TB (MDR-TB) drugs, HIV integrase inhibitors and opioid substitution therapy (OST). Compared with 2013, routine usage of GeneXpert was more common in EE in 2018 (54% vs. 92%; P = 0.073), as was access to moxifloxacin (46% vs. 91%; P = 0.033), linezolid (31% vs. 64%; P = 0.217), and bedaquiline (0% vs. 25%; P = 0.217). Integration of TB and HIV services (46% vs. 39%; P = 1.000) and provision of OST to patients with opioid dependency (54% vs. 46%; P = 0.695) remained unchanged. Conclusion: Delivery of TB and HIV healthcare, including integration of TB and HIV care and access to MDR-TB drugs, still differs between WE and EE, as well as between individual EE sites.

Published
2021

6. Delayed diagnosis of tuberculosis in persons living with HIV in Eastern Europe: associated factors and effect on mortality—a multicentre prospective cohort study

Author

Kraef, C, Bentzon, A, Panteleev, A, Skrahina, A, Bolokadze, N, Tetradov, S, Podlasin, R, Karpov, I, Borodulina, E, Denisova, E, Azina, I, Lundgren, J, Johansen, I, Mocroft, A, Podlekareva, D, Kirk, O, Vassilenko, A, Klimuk, D, Kondratenko, O, Zalutskaya, A, Bondarenko, V, Mitsura, V, Kozorez, E, Tumash, O, Suetnov, O, Paduto, D, Iljina, V, Kummik, T, Mshvidobadze, K, Lanchava, N, Goginashvili, L, Mikiashvili, L, Bablishvili, N, Rozentale, B, Zeltina, I, Janushkevich, I, Caplinskiene, I, Caplinskas, S, Kancauskiene, Z, Wiercinska-Drapalo, A, Thompson, M, Kozlowska, J, Grezesczuk, A, Bura, M, Knysz, B, Inglot, M, Garlicki, A, Loster, J, Uiculescu, D, Rakhmanova, A, Panteleev, O, Yakovlev, A, Kozlov, A, Tyukalova, A, Vlasova, Y, Rofimov, T, Kyselyova, G, Obel, N, Gerstoft, J, Kronborg, G, Payen, M, Abeya, K, Necsoi, C, Dabis, F, Tsaranazy, A, Cazanave, C, Furrer, H, Sagette, M, Rickenbach, M, Sculier, D, Calmy, A, Cavassini, M, Bruno, A, Bernasconi, E, Hoffmann, M, Vernazza, P, Fehr, J, Weber, R, Miller, R, Vora, N, Cooke, G, Mullaney, S, Wilkins, E, George, V, Collini, P, Dockrell, D, Post, F, Campbell, L, Brum, R, Mabonga, E, Saigal, P, Kegg, S, Ainsworth, J, Waters, A, Dhar, J, Ellis, K, Girardi, E, Rianda, A, Galati, V, Pinnetti, C, Tommasi, C, Lapadula, G, Di Biagio, A, Parisini, A, Carbonara, S, Angarano, G, Purgatorio, M, Matteelli, A, Apostoli, A, Miro, J, Manzardo, C, Ligero, C, Gonzalez, J, Martinez-Martinez, J, Sanchez, F, Knobel, H, Salvado, M, Lopez-Colomes, J, Martinez-Lacasa, X, Cuchi, E, Falco, V, Curran, A, Tortola, M, Ocana, I, Vidal, R, Sambeat, M, Pomar, V, Coll, P, Pozamczer, D, Saumoy, M, Alcaide, F, Cayla, J, Moreno, A, Millet, J, Orcau, A, Fina, L, Romero, A, Roldan, L, Iribarren, J, Ibarguren, M, Moreno, S, Gonzalez, A, Miralles, P, Aldamiz-Echevarria, T, Losso, M, Toibaro, J, Gambardella, L, Moreno Macias, L, Warley, E, Tavella, S, Garcia Messina, O, Gear, O, Laplume, H, Marson, C, Contarelia, J, Michaan, M, Scapellato, P, Bartoletti, B, Palmero, D, Elias, C, Cortes, C, Crabtree, B, Mosqueda Gomez, J, Villanueva, J, Gonzalez Hernandez, L, Badial, F, Kraef C., Bentzon A., Panteleev A., Skrahina A., Bolokadze N., Tetradov S., Podlasin R., Karpov I., Borodulina E., Denisova E., Azina I., Lundgren J., Johansen I. S., Mocroft A., Podlekareva D., Kirk O., Vassilenko A., Klimuk D., Kondratenko O., Zalutskaya A., Bondarenko V., Mitsura V., Kozorez E., Tumash O., Suetnov O., Paduto D., Iljina V., Kummik T., Mshvidobadze K., Lanchava N., Goginashvili L., Mikiashvili L., Bablishvili N., Rozentale B., Zeltina I., Janushkevich I., Caplinskiene I., Caplinskas S., Kancauskiene Z., Wiercinska-Drapalo A., Thompson M., Kozlowska J., Grezesczuk A., Bura M., Knysz B., Inglot M., Garlicki A., Loster J., uiculescu D. D., Rakhmanova A., Panteleev O., Yakovlev A., Kozlov A., Tyukalova A., Vlasova Y., rofimov T. T., Kyselyova G., Obel N., Gerstoft J., Kronborg G., Payen M. C., abeya K. K., Necsoi C., Dabis F., Tsaranazy A., Cazanave C., Furrer H., Sagette M., Rickenbach M., Sculier D., Calmy A., Cavassini M., Bruno A., Bernasconi E., Hoffmann M., Vernazza P., Fehr J., Weber R., Miller R., Vora N., Cooke G., Mullaney S., Wilkins E., George V., Collini P., Dockrell D., Post F., Campbell L., Brum R., Mabonga E., Saigal P., Kegg S., Ainsworth J., Waters A., Dhar J., Ellis K., Girardi E., Rianda A., Galati V., Pinnetti C., Tommasi C., Lapadula G., Di Biagio A., Parisini A., Carbonara S., Angarano G., Purgatorio M., Matteelli A., Apostoli A., Miro J. M., Manzardo C., Ligero C., Gonzalez J., Martinez-Martinez J. A., Sanchez F., Knobel H., Salvado M., Lopez-Colomes J. L., Martinez-Lacasa X., Cuchi E., Falco V., Curran A., Tortola M. T., Ocana I., Vidal R., Sambeat M. A., Pomar V., Coll P., Pozamczer D., Saumoy M., Alcaide F., Cayla J., Moreno A., Millet J. P., Orcau A., Fina L., Romero A., Roldan L. L., Iribarren J. A., Ibarguren M., Moreno S., Gonzalez A., Miralles P., Aldamiz-Echevarria T., Losso M., Toibaro J., Gambardella L., Moreno Macias L., Warley E., Tavella S., Garcia Messina O., Gear O., Laplume H., Marson C., Contarelia J., Michaan M., Scapellato P., Bartoletti B., Palmero D., Elias C., Cortes C., Crabtree B., Mosqueda Gomez J. L., Villanueva J. A., Gonzalez Hernandez L. A., Badial F., Kraef, C, Bentzon, A, Panteleev, A, Skrahina, A, Bolokadze, N, Tetradov, S, Podlasin, R, Karpov, I, Borodulina, E, Denisova, E, Azina, I, Lundgren, J, Johansen, I, Mocroft, A, Podlekareva, D, Kirk, O, Vassilenko, A, Klimuk, D, Kondratenko, O, Zalutskaya, A, Bondarenko, V, Mitsura, V, Kozorez, E, Tumash, O, Suetnov, O, Paduto, D, Iljina, V, Kummik, T, Mshvidobadze, K, Lanchava, N, Goginashvili, L, Mikiashvili, L, Bablishvili, N, Rozentale, B, Zeltina, I, Janushkevich, I, Caplinskiene, I, Caplinskas, S, Kancauskiene, Z, Wiercinska-Drapalo, A, Thompson, M, Kozlowska, J, Grezesczuk, A, Bura, M, Knysz, B, Inglot, M, Garlicki, A, Loster, J, Uiculescu, D, Rakhmanova, A, Panteleev, O, Yakovlev, A, Kozlov, A, Tyukalova, A, Vlasova, Y, Rofimov, T, Kyselyova, G, Obel, N, Gerstoft, J, Kronborg, G, Payen, M, Abeya, K, Necsoi, C, Dabis, F, Tsaranazy, A, Cazanave, C, Furrer, H, Sagette, M, Rickenbach, M, Sculier, D, Calmy, A, Cavassini, M, Bruno, A, Bernasconi, E, Hoffmann, M, Vernazza, P, Fehr, J, Weber, R, Miller, R, Vora, N, Cooke, G, Mullaney, S, Wilkins, E, George, V, Collini, P, Dockrell, D, Post, F, Campbell, L, Brum, R, Mabonga, E, Saigal, P, Kegg, S, Ainsworth, J, Waters, A, Dhar, J, Ellis, K, Girardi, E, Rianda, A, Galati, V, Pinnetti, C, Tommasi, C, Lapadula, G, Di Biagio, A, Parisini, A, Carbonara, S, Angarano, G, Purgatorio, M, Matteelli, A, Apostoli, A, Miro, J, Manzardo, C, Ligero, C, Gonzalez, J, Martinez-Martinez, J, Sanchez, F, Knobel, H, Salvado, M, Lopez-Colomes, J, Martinez-Lacasa, X, Cuchi, E, Falco, V, Curran, A, Tortola, M, Ocana, I, Vidal, R, Sambeat, M, Pomar, V, Coll, P, Pozamczer, D, Saumoy, M, Alcaide, F, Cayla, J, Moreno, A, Millet, J, Orcau, A, Fina, L, Romero, A, Roldan, L, Iribarren, J, Ibarguren, M, Moreno, S, Gonzalez, A, Miralles, P, Aldamiz-Echevarria, T, Losso, M, Toibaro, J, Gambardella, L, Moreno Macias, L, Warley, E, Tavella, S, Garcia Messina, O, Gear, O, Laplume, H, Marson, C, Contarelia, J, Michaan, M, Scapellato, P, Bartoletti, B, Palmero, D, Elias, C, Cortes, C, Crabtree, B, Mosqueda Gomez, J, Villanueva, J, Gonzalez Hernandez, L, Badial, F, Kraef C., Bentzon A., Panteleev A., Skrahina A., Bolokadze N., Tetradov S., Podlasin R., Karpov I., Borodulina E., Denisova E., Azina I., Lundgren J., Johansen I. S., Mocroft A., Podlekareva D., Kirk O., Vassilenko A., Klimuk D., Kondratenko O., Zalutskaya A., Bondarenko V., Mitsura V., Kozorez E., Tumash O., Suetnov O., Paduto D., Iljina V., Kummik T., Mshvidobadze K., Lanchava N., Goginashvili L., Mikiashvili L., Bablishvili N., Rozentale B., Zeltina I., Janushkevich I., Caplinskiene I., Caplinskas S., Kancauskiene Z., Wiercinska-Drapalo A., Thompson M., Kozlowska J., Grezesczuk A., Bura M., Knysz B., Inglot M., Garlicki A., Loster J., uiculescu D. D., Rakhmanova A., Panteleev O., Yakovlev A., Kozlov A., Tyukalova A., Vlasova Y., rofimov T. T., Kyselyova G., Obel N., Gerstoft J., Kronborg G., Payen M. C., abeya K. K., Necsoi C., Dabis F., Tsaranazy A., Cazanave C., Furrer H., Sagette M., Rickenbach M., Sculier D., Calmy A., Cavassini M., Bruno A., Bernasconi E., Hoffmann M., Vernazza P., Fehr J., Weber R., Miller R., Vora N., Cooke G., Mullaney S., Wilkins E., George V., Collini P., Dockrell D., Post F., Campbell L., Brum R., Mabonga E., Saigal P., Kegg S., Ainsworth J., Waters A., Dhar J., Ellis K., Girardi E., Rianda A., Galati V., Pinnetti C., Tommasi C., Lapadula G., Di Biagio A., Parisini A., Carbonara S., Angarano G., Purgatorio M., Matteelli A., Apostoli A., Miro J. M., Manzardo C., Ligero C., Gonzalez J., Martinez-Martinez J. A., Sanchez F., Knobel H., Salvado M., Lopez-Colomes J. L., Martinez-Lacasa X., Cuchi E., Falco V., Curran A., Tortola M. T., Ocana I., Vidal R., Sambeat M. A., Pomar V., Coll P., Pozamczer D., Saumoy M., Alcaide F., Cayla J., Moreno A., Millet J. P., Orcau A., Fina L., Romero A., Roldan L. L., Iribarren J. A., Ibarguren M., Moreno S., Gonzalez A., Miralles P., Aldamiz-Echevarria T., Losso M., Toibaro J., Gambardella L., Moreno Macias L., Warley E., Tavella S., Garcia Messina O., Gear O., Laplume H., Marson C., Contarelia J., Michaan M., Scapellato P., Bartoletti B., Palmero D., Elias C., Cortes C., Crabtree B., Mosqueda Gomez J. L., Villanueva J. A., Gonzalez Hernandez L. A., and Badial F.

Abstract

Background: Early diagnosis of tuberculosis (TB) is important to reduce transmission, morbidity and mortality in people living with HIV (PLWH). Methods: PLWH with a diagnosis of TB were enrolled from HIV and TB clinics in Eastern Europe and followed until 24 months. Delayed diagnosis was defined as duration of TB symptoms (cough, weight-loss or fever) for ≥ 1 month before TB diagnosis. Risk factors for delayed TB diagnosis were assessed using multivariable logistic regression. The effect of delayed diagnosis on mortality was assessed using Kaplan–Meier estimates and Cox models. Findings: 480/740 patients (64.9%; 95% CI 61.3–68.3%) experienced a delayed diagnosis. Age ≥ 50 years (vs. < 50 years, aOR = 2.51; 1.18–5.32; p = 0.016), injecting drug use (IDU) (vs. non-IDU aOR = 1.66; 1.21–2.29; p = 0.002), being ART naïve (aOR = 1.77; 1.24–2.54; p = 0.002), disseminated TB (vs. pulmonary TB, aOR = 1.56, 1.10–2.19, p = 0.012), and presenting with weight loss (vs. no weight loss, aOR = 1.63; 1.18–2.24; p = 0.003) were associated with delayed diagnosis. PLWH with a delayed diagnosis were at 36% increased risk of death (hazard ratio = 1.36; 1.04–1.77; p = 0.023, adjusted hazard ratio 1.27; 0.95–1.70; p = 0.103). Conclusion: Nearly two thirds of PLWH with TB in Eastern Europe had a delayed TB diagnosis, in particular those of older age, people who inject drugs, ART naïve, with disseminated disease, and presenting with weight loss. Patients with delayed TB diagnosis were subsequently at higher risk of death in unadjusted analysis. There is a need for optimisation of the current TB diagnostic cascade and HIV care in PLWH in Eastern Europe.

Published
2021

8. Delayed diagnosis of tuberculosis in persons living with HIV in Eastern Europe:associated factors and effect on mortality—a multicentre prospective cohort study

Author

Kraef, Christian, Bentzon, Adrian, Panteleev, Alexander, Skrahina, Alena, Bolokadze, Natalie, Tetradov, Simona, Podlasin, Regina, Karpov, Igor, Borodulina, Elena, Denisova, Elena, Azina, Inga, Lundgren, Jens, Johansen, Isik Somuncu, Mocroft, Amanda, Podlekareva, Daria, Kirk, Ole, Vassilenko, A., Klimuk, D., Kondratenko, O., Zalutskaya, A., Bondarenko, V., Mitsura, V., Kozorez, E., Tumash, O., Suetnov, O., Paduto, D., Iljina, V., Kummik, T., Mshvidobadze, K., Lanchava, N., Goginashvili, L., Mikiashvili, L., Bablishvili, N., Rozentale, B., Zeltina, I., Janushkevich, I., Caplinskiene, I., Caplinskas, S., Kancauskiene, Z., Wiercinska-Drapalo, A., Thompson, M., Kozlowska, J., Grezesczuk, A., Bura, M., Knysz, B., Inglot, M., Garlicki, A., Obel, N., Gerstoft, J., Kronborg, G., Kraef, Christian, Bentzon, Adrian, Panteleev, Alexander, Skrahina, Alena, Bolokadze, Natalie, Tetradov, Simona, Podlasin, Regina, Karpov, Igor, Borodulina, Elena, Denisova, Elena, Azina, Inga, Lundgren, Jens, Johansen, Isik Somuncu, Mocroft, Amanda, Podlekareva, Daria, Kirk, Ole, Vassilenko, A., Klimuk, D., Kondratenko, O., Zalutskaya, A., Bondarenko, V., Mitsura, V., Kozorez, E., Tumash, O., Suetnov, O., Paduto, D., Iljina, V., Kummik, T., Mshvidobadze, K., Lanchava, N., Goginashvili, L., Mikiashvili, L., Bablishvili, N., Rozentale, B., Zeltina, I., Janushkevich, I., Caplinskiene, I., Caplinskas, S., Kancauskiene, Z., Wiercinska-Drapalo, A., Thompson, M., Kozlowska, J., Grezesczuk, A., Bura, M., Knysz, B., Inglot, M., Garlicki, A., Obel, N., Gerstoft, J., and Kronborg, G.

Abstract

Background: Early diagnosis of tuberculosis (TB) is important to reduce transmission, morbidity and mortality in people living with HIV (PLWH). Methods: PLWH with a diagnosis of TB were enrolled from HIV and TB clinics in Eastern Europe and followed until 24 months. Delayed diagnosis was defined as duration of TB symptoms (cough, weight-loss or fever) for ≥ 1 month before TB diagnosis. Risk factors for delayed TB diagnosis were assessed using multivariable logistic regression. The effect of delayed diagnosis on mortality was assessed using Kaplan–Meier estimates and Cox models. Findings: 480/740 patients (64.9%; 95% CI 61.3–68.3%) experienced a delayed diagnosis. Age ≥ 50 years (vs. < 50 years, aOR = 2.51; 1.18–5.32; p = 0.016), injecting drug use (IDU) (vs. non-IDU aOR = 1.66; 1.21–2.29; p = 0.002), being ART naïve (aOR = 1.77; 1.24–2.54; p = 0.002), disseminated TB (vs. pulmonary TB, aOR = 1.56, 1.10–2.19, p = 0.012), and presenting with weight loss (vs. no weight loss, aOR = 1.63; 1.18–2.24; p = 0.003) were associated with delayed diagnosis. PLWH with a delayed diagnosis were at 36% increased risk of death (hazard ratio = 1.36; 1.04–1.77; p = 0.023, adjusted hazard ratio 1.27; 0.95–1.70; p = 0.103). Conclusion: Nearly two thirds of PLWH with TB in Eastern Europe had a delayed TB diagnosis, in particular those of older age, people who inject drugs, ART naïve, with disseminated disease, and presenting with weight loss. Patients with delayed TB diagnosis were subsequently at higher risk of death in unadjusted analysis. There is a need for optimisation of the current TB diagnostic cascade and HIV care in PLWH in Eastern Europe.

Published
2021

9. Healthcare delivery for HIV-positive people with tuberculosis in Europe

Author

Bentzon, A. K., Panteleev, A., Mitsura, V., Borodulina, E., Skrahina, A., Denisova, E., Tetradov, S., Podlasin, R., Riekstina, V., Kancauskiene, Z., Paduto, D., Mocroft, A., Trofimova, T., Miller, R., Post, F., Grezesczuk, A., Lundgren, J. D., Inglot, M., Podlekareva, D., Bolokadze, N., Kirk, O., Karpov, I., Vassilenko, A., Klimuk, D., Skrahin, A., Kondratenko, O., Zalutskaya, A., Bondarenko, V., Kozorez, E., Tumash, O., Suetnov, O., Iljina, V., Kummik, T., Mshvidobadze, K., Lanchava, N., Goginashvili, L., Mikiashvili, L., Bablishvili, N., Rozentale, B., Zeltina, I., Janushkevich, I., Caplinskiene, I., Caplinskas, S., Wiercinska-Drapalo, A., Obel, N., Gerstoft, J., Kronborg, G., Hoffmann, M., Campbell, L., González, A., Bentzon, A. K., Panteleev, A., Mitsura, V., Borodulina, E., Skrahina, A., Denisova, E., Tetradov, S., Podlasin, R., Riekstina, V., Kancauskiene, Z., Paduto, D., Mocroft, A., Trofimova, T., Miller, R., Post, F., Grezesczuk, A., Lundgren, J. D., Inglot, M., Podlekareva, D., Bolokadze, N., Kirk, O., Karpov, I., Vassilenko, A., Klimuk, D., Skrahin, A., Kondratenko, O., Zalutskaya, A., Bondarenko, V., Kozorez, E., Tumash, O., Suetnov, O., Iljina, V., Kummik, T., Mshvidobadze, K., Lanchava, N., Goginashvili, L., Mikiashvili, L., Bablishvili, N., Rozentale, B., Zeltina, I., Janushkevich, I., Caplinskiene, I., Caplinskas, S., Wiercinska-Drapalo, A., Obel, N., Gerstoft, J., Kronborg, G., Hoffmann, M., Campbell, L., and González, A.

Abstract

Background: In a 2013 survey, we reported distinct discrepancies in delivery of tuberculosis (TB) and HIV services in eastern Europe (EE) vs. western Europe (WE). Objectives: To verify the differences in TB and HIV services in EE vs. WE. Methods: Twenty-three sites completed a survey in 2018 (EE, 14; WE, nine; 88% response rate). Results were compared across as well as within the two regions. When possible, results were compared with the 2013 survey. Results: Delivery of healthcare was significantly less integrated in EE: provision of TB and HIV services at one site (36% in EE vs. 89% in WE; P = 0.034), and continued TB follow-up in one location (42% vs. 100%; P = 0.007). Although access to TB diagnostics, standard TB and HIV drugs was generally good, fewer sites in EE reported unlimited access to rifabutin/multi-drug-resistant TB (MDR-TB) drugs, HIV integrase inhibitors and opioid substitution therapy (OST). Compared with 2013, routine usage of GeneXpert was more common in EE in 2018 (54% vs. 92%; P = 0.073), as was access to moxifloxacin (46% vs. 91%; P = 0.033), linezolid (31% vs. 64%; P = 0.217), and bedaquiline (0% vs. 25%; P = 0.217). Integration of TB and HIV services (46% vs. 39%; P = 1.000) and provision of OST to patients with opioid dependency (54% vs. 46%; P = 0.695) remained unchanged. Conclusion: Delivery of TB and HIV healthcare, including integration of TB and HIV care and access to MDR-TB drugs, still differs between WE and EE, as well as between individual EE sites.

Published
2021

10. Healthcare delivery for HIV-positive people with tuberculosis in Europe

Author

Bentzon, A. K., Panteleev, A., Mitsura, V., Borodulina, E., Skrahina, A., Denisova, E., Tetradov, S., Podlasin, R., Riekstina, V., Kancauskiene, Z., Paduto, D., Mocroft, A., Trofimova, T., Miller, R., Post, F., Grezesczuk, A., Lundgren, J. D., Inglot, M., Podlekareva, D., Bolokadze, N., Kirk, O., Karpov, I., Vassilenko, A., Klimuk, D., Skrahin, A., Kondratenko, O., Zalutskaya, A., Bondarenko, V., Kozorez, E., Tumash, O., Suetnov, O., Iljina, V., Kummik, T., Mshvidobadze, K., Lanchava, N., Goginashvili, L., Mikiashvili, L., Bablishvili, N., Rozentale, B., Zeltina, I., Janushkevich, I., Caplinskiene, I., Caplinskas, S., Wiercinska-Drapalo, A., Thompson, M., Kozlowska, J., Bura, M., Knysz, B., Garlicki, A., Loster, J., Duiculescu, D., Rakhmanova, A., Panteleeva, O., Yakovlev, A., Kozlov, A., Tyukalova, A., Vlasova, Y., Trofimov, T., Kyselyova, G., Obel, N., Gerstoft, J., Kronborg, G., Payen, M. C., Kabeya, K., Necsoi, C., Dabis, F., Tsaranazy, A., Cazanave, C., Furrer, H., Sagette, M., Rickenbach, M., Elzi, L., Battegay, M., Sculier, D., Calmy, A., Cavassini, M., Bruno, A., Bernasconi, E., Hoffmann, M., Vernazza, P., Fehr, J., Weber, R., Vora, N., Cooke, G., Mullaney, S., Wilkins, E., George, V., Collini, P., Dockrell, D., Campbell, L., Brum, R., Mabonga, E., Saigal, P., Kegg, S., Ainsworth, J., Waters, A., Dhar, J., Ellis, K., Spallanzani, O. L., Girardi, E., Rianda, A., Galati, V., Pinnetti, C., Tommasi, C., San Gerardo, A. O., Lapadula, G., Di Biagio, A., Parisini, A., Carbonara, S., Angarano, G., Purgatorio, M., Matteelli, A., Apostoli, A., Miro, J. M., Manzardo, C., Ligero, C., Gonzalez, J., Martinez-Martinez, J. A., Sanchez, F., Knobel, H., Salvado, M., Lopez-Colomes, J. L., Martinez-Lacasa, X., Cuchi, E., Falco, V., Curran, A., Tortola, M. T., Ocana, I., Vidal, R., Sambeat, M. A., Pomar, V., Coll, P., Pozamczer, D., Saumoy, M., Alcaide, F., Cayla, J., Moreno, A., Millet, J. P., Orcau, A., Fina, L., Romero, A., Roldan, L. L., Iribarren, J. A., Ibarguren, M., Moreno, S., Gonzalez, A., Miralles, P., Aldamiz-Echevarria, T., Losso, M., Toibaro, J., Gambardella, L., Ramos Mejia, J. M., Moreno Macias, L., Warley, E., Tavella, S., Garcia Messina, O., Gear, O., Laplume, H., Marson, C., Contarelia, J., Michaan, M., Scapellato, P., Bartoletti, B., Palmero, D., Elias, C., Cortes, C., Crabtree, B., Mosqueda Gomez, J. L., Villanueva, J. A., Gonzalez Hernandez, L. A., and Badial, F.

Subjects
0301 basic medicine, medicine.medical_specialty, Rifabutin, Tuberculosis, Tuberculosi, Epidemiology, Antitubercular Agents, HIV Infections, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Moxifloxacin, Internal medicine, medicine, clinical management, VIH (Virus), Humans, Pharmacology (medical), 030212 general & internal medicine, Epidemiologia, coinfection, eastern Europe, HIV, tuberculosis, western Europe, Response rate (survey), GeneXpert MTB/RIF, business.industry, HIV (Viruses), Health Policy, medicine.disease, 030112 virology, Europe, Infectious Diseases, HIV-positive people, chemistry, Coinfection, Bedaquiline, business, Europa, Delivery of Health Care, medicine.drug
Abstract

Background: In a 2013 survey, we reported distinct discrepancies in delivery of tuberculosis (TB) and HIV services in eastern Europe (EE) vs. western Europe (WE). Objectives: To verify the differences in TB and HIV services in EE vs. WE. Methods: Twenty-three sites completed a survey in 2018 (EE, 14; WE, nine; 88% response rate). Results were compared across as well as within the two regions. When possible, results were compared with the 2013 survey. Results: Delivery of healthcare was significantly less integrated in EE: provision of TB and HIV services at one site (36% in EE vs. 89% in WE; P = 0.034), and continued TB follow-up in one location (42% vs. 100%; P = 0.007). Although access to TB diagnostics, standard TB and HIV drugs was generally good, fewer sites in EE reported unlimited access to rifabutin/multi-drug-resistant TB (MDR-TB) drugs, HIV integrase inhibitors and opioid substitution therapy (OST). Compared with 2013, routine usage of GeneXpert was more common in EE in 2018 (54% vs. 92%; P = 0.073), as was access to moxifloxacin (46% vs. 91%; P = 0.033), linezolid (31% vs. 64%; P = 0.217), and bedaquiline (0% vs. 25%; P = 0.217). Integration of TB and HIV services (46% vs. 39%; P = 1.000) and provision of OST to patients with opioid dependency (54% vs. 46%; P = 0.695) remained unchanged. Conclusion: Delivery of TB and HIV healthcare, including integration of TB and HIV care and access to MDR-TB drugs, still differs between WE and EE, as well as between individual EE sites.

Published
2020

13. Management of MDR-TB in HIV co-infected patients in Eastern Europe: Results from the TB:HIV study

Author

Efsen, A, Schultze, A, Miller, R, Panteleev, A, Skrahin, A, Podlekareva, D, Miro, J, Girardi, E, Furrer, H, Losso, M, Toibaro, J, Cayla, J, Mocroft, A, Lundgren, J, Post, F, Kirk, O, Karpov, I, Vassilenko, A, Skrahina, A, Klimuk, D, Kondratenko, O, Zalutskaya, A, Bondarenko, V, Mitsura, V, Kozorez, E, Tumash, O, Suetnov, O, Paduto, D, Iljina, V, Kummik, T, Bolokadze, N, Mshvidobadze, K, Lanchava, N, Goginashvili, L, Mikiashvili, L, Bablishvili, N, Rozentale, B, Zeltina, I, Janushkevich, I, Caplinskiene, I, Caplinskas, S, Kancauskiene, Z, Podlasin, R, Wiercinska-Drapalo, A, Thompson, M, Kozlowska, J, Grezesczuk, A, Bura, M, Knysz, B, Inglot, M, Garlicki, A, Loster, J, Tetradov, S, Duiculescu, D, Rakhmanova, A, Panteleeva, O, Yakovlev, A, Kozlov, A, Tyukalova, A, Vlasova, Y, Trofimov, T, Kyselyova, G, Andersen, A, Thorsteinsson, K, Payen, M, Kabeya, K, Necsoi, C, Dabis, F, Bruyand, M, Morlat, P, Dupont, A, Gerard, Y, Bonnal, F, Ceccaldi, J, De Witte, S, Monlun, E, Lataste, P, Chossat, I, Vora, N, Cooke, G, Mullaney, S, Wilkins, E, George, V, Collini, P, Dockrell, D, Campbell, L, Brum, R, Mabonga, E, Saigal, P, Kegg, S, Ainsworth, J, Waters, A, Dhar, J, Mashonganyika, L, Rianda, A, Galati, V, Pinnetti, C, Tommasi, C, Lapadula, G, Di Biagio, A, Parisini, A, Carbonara, S, Angarano, G, Purgatorio, M, Matteelli, A, Apostoli, A, Macias, L, Warley, E, Tavella, S, Garcia Messina, O, Gear, O, Laplume, H, Marson, C, Contarelia, J, Michaan, M, Scapellato, P, Alessandro, D, Bartoletti, B, Palmero, D, Elias, C, Cortes, C, Crabtree, B, Mosqueda Gomez, J, Villanueva, A, Gonzalez Hernandez, L, Efsen, AMW, Miller, RF, Podlekareva, DN, Miro, JM, Losso, MH, Cayla, JA, Lundgren, JD, Post, FA, Andersen, AB, Payen, MC, Macias, LM, Alessandro, DD, Mosqueda Gomez, JL, Gonzalez Hernandez, LA, Efsen, A, Schultze, A, Miller, R, Panteleev, A, Skrahin, A, Podlekareva, D, Miro, J, Girardi, E, Furrer, H, Losso, M, Toibaro, J, Cayla, J, Mocroft, A, Lundgren, J, Post, F, Kirk, O, Karpov, I, Vassilenko, A, Skrahina, A, Klimuk, D, Kondratenko, O, Zalutskaya, A, Bondarenko, V, Mitsura, V, Kozorez, E, Tumash, O, Suetnov, O, Paduto, D, Iljina, V, Kummik, T, Bolokadze, N, Mshvidobadze, K, Lanchava, N, Goginashvili, L, Mikiashvili, L, Bablishvili, N, Rozentale, B, Zeltina, I, Janushkevich, I, Caplinskiene, I, Caplinskas, S, Kancauskiene, Z, Podlasin, R, Wiercinska-Drapalo, A, Thompson, M, Kozlowska, J, Grezesczuk, A, Bura, M, Knysz, B, Inglot, M, Garlicki, A, Loster, J, Tetradov, S, Duiculescu, D, Rakhmanova, A, Panteleeva, O, Yakovlev, A, Kozlov, A, Tyukalova, A, Vlasova, Y, Trofimov, T, Kyselyova, G, Andersen, A, Thorsteinsson, K, Payen, M, Kabeya, K, Necsoi, C, Dabis, F, Bruyand, M, Morlat, P, Dupont, A, Gerard, Y, Bonnal, F, Ceccaldi, J, De Witte, S, Monlun, E, Lataste, P, Chossat, I, Vora, N, Cooke, G, Mullaney, S, Wilkins, E, George, V, Collini, P, Dockrell, D, Campbell, L, Brum, R, Mabonga, E, Saigal, P, Kegg, S, Ainsworth, J, Waters, A, Dhar, J, Mashonganyika, L, Rianda, A, Galati, V, Pinnetti, C, Tommasi, C, Lapadula, G, Di Biagio, A, Parisini, A, Carbonara, S, Angarano, G, Purgatorio, M, Matteelli, A, Apostoli, A, Macias, L, Warley, E, Tavella, S, Garcia Messina, O, Gear, O, Laplume, H, Marson, C, Contarelia, J, Michaan, M, Scapellato, P, Alessandro, D, Bartoletti, B, Palmero, D, Elias, C, Cortes, C, Crabtree, B, Mosqueda Gomez, J, Villanueva, A, Gonzalez Hernandez, L, Efsen, AMW, Miller, RF, Podlekareva, DN, Miro, JM, Losso, MH, Cayla, JA, Lundgren, JD, Post, FA, Andersen, AB, Payen, MC, Macias, LM, Alessandro, DD, Mosqueda Gomez, JL, and Gonzalez Hernandez, LA

Abstract

Objectives Mortality among HIV patients with tuberculosis (TB) remains high in Eastern Europe (EE), but details of TB and HIV management remain scarce. Methods In this prospective study, we describe the TB treatment regimens of patients with multi-drug resistant (MDR) TB and use of antiretroviral therapy (ART). Results A total of 105 HIV-positive patients had MDR-TB (including 33 with extensive drug resistance) and 130 pan-susceptible TB. Adequate initial TB treatment was provided for 8% of patients with MDR-TB compared with 80% of those with pan-susceptible TB. By twelve months, an estimated 57.3% (95%CI 41.5–74.1) of MDR-TB patients had started adequate treatment. While 67% received ART, HIV-RNA suppression was demonstrated in only 23%. Conclusions Our results show that internationally recommended MDR-TB treatment regimens were infrequently used and that ART use and viral suppression was well below the target of 90%, reflecting the challenging patient population and the environment in which health care is provided. Urgent improvement of management of patients with TB/HIV in EE, in particular for those with MDR-TB, is needed and includes widespread access to rapid TB diagnostics, better access to and use of second-line TB drugs, timely ART initiation with viral load monitoring, and integration of TB/HIV care.

Published
2018

14. Major differences in organization and availability of health care and medicines for HIV/TB coinfected patients across Europe

Author

Mansfeld, M, Skrahina, A, Shepherd, L, Schultze, A, Panteleev, A, Miller, R, Miro, J, Zeltina, I, Tetradov, S, Furrer, H, Kirk, O, Grzeszczuk, A, Bolokadze, N, Matteelli, A, Post, F, Lundgren, J, Mocroft, A, Efsen, A, Podlekareva, D, Losso, M, Toibaro, J, Palmero, D, Bartoletti, B, E., W, Gear, O, Messina, O, Michans, M, Laplume, H, David, D, Marson, C, Scapelatto, F, Dalessandro, D, Lupo, S, Costilla Campero, G, Herbst, M, Remondegui, C, Elias, C, Karpov, I, Vassilenko, A, Skrahina, E, Skrahin, A, Zalutskya, A, Kondratenko, O, Mitsura, V, Bondarenko, V, Suetnov, O, Paduto, D, Dewit, S, Payen, M, Noscoi, C, Kabeya, K, M., W, Cortes, C, Obel, N, Kronborg, G, Iljna, V, Kummik, T, Bryand, M, Dabis, F, Lanchava, N, Bablishvili, N, Goginashvili, L, Mikiashvili, L, Mshvidobadze, K, Girardi, E, Di Biagio, A, Apostoli, A, Barzoni, S, Lapadula, G, Purgatorio, M, Carbonara, S, Rozentale, B, Janushkevich, I, Caplinskas, S, Kancauskienne, Z, Caplinskienne, I, Crabtree, B, Pina, A, Madero, J, Mosqueda, J, Villanueva, J, Bura, M, Garlicki, A, Inglot, M, Knysz, B, Kozlowska, J, Loster, J, Mularska, E, Podlasin, R, Thompson, M, Wiercinska-Drapalo, A, Duiculescu, D, Rakhmanova, A, Yakovlev, A, Turkalova, A, Vlasova, Y, Trotimora, T, Borodulina, E, Chumanova, L, Mashkova, Y, Cayla, J, Moreno, A, Millet, J, Orcau, A, Fina, L, del Bano, L, Roldan, L, Romero, A, Martinez, J, Manzardo, C, Gonzalez, J, Tudo, G, Knobel, H, Sanchez, F, Salvado, M, Curran, A, Tortola, M, Pozamczer, D, Saumoy, M, Alcaide, F, Martinez-Lacasa, X, Cuchi, E, Sambeat, M, Pomar, V, Coll, P, Miralles, P, Moreno, S, Iribarren, J, Ibarguren, M, Aldamiz, T, Rickenbach, M, Sagette, M, Chapman, A, Dockrell, D, Wilkins, E, Cooke, G, Ainsworth, J, Macallen, D, Dhar, J, Vora, N, Mullaney, S, Kegg, S, Kyselyova, G, Mansfeld M., Skrahina A., Shepherd L., Schultze A., Panteleev A., Miller R., Miro J., Zeltina I., Tetradov S., Furrer H., Kirk O., Grzeszczuk A., Bolokadze N., Matteelli A., Post F., Lundgren J., Mocroft A., Efsen A., Podlekareva D., Losso M. H., Toibaro J. J., Palmero D., Bartoletti B. J., E. Warley, Gear O., Messina O. G., Michans M., Laplume H., David D., Marson C., Scapelatto F. P., Dalessandro D., Lupo S., Costilla Campero G., Herbst M., Remondegui C., Elias C., Karpov I., Vassilenko A., Skrahina E., Skrahin A., Zalutskya A., Kondratenko O., Mitsura V., Bondarenko V., Suetnov O., Paduto D., Dewit S., Payen M. C., Noscoi C., Kabeya K., M. Wolff, Cortes C., Obel N., Kronborg G., Iljna V., Kummik T., Bryand M., Dabis F., Lanchava N., Bablishvili N., Goginashvili L., Mikiashvili L., Mshvidobadze K., Girardi E., Di Biagio A., Apostoli A., Barzoni S., Lapadula G., Purgatorio M., Carbonara S., Rozentale B., Janushkevich I., Caplinskas S., Kancauskienne Z., Caplinskienne I., Crabtree B., Pina A., Madero J. S., Mosqueda J., Villanueva J. A., Bura M., Garlicki A., Inglot M., Knysz B., Kozlowska J., Loster J., Mularska E., Podlasin R., Thompson M., Wiercinska-Drapalo A., Duiculescu D., Rakhmanova A., Yakovlev A., Turkalova A., Vlasova Y., Trotimora T., Borodulina E., Chumanova L., Mashkova Y., Miro J. M., Cayla J. A., Moreno A., Millet J. P., Orcau A., Fina L., del Bano L., Roldan L. L., Romero A., Martinez J. A., Manzardo C., Gonzalez J., Tudo G., Knobel H., Sanchez F., Salvado M., Curran A., Tortola M. T., Pozamczer D., Saumoy M., Alcaide F., Martinez-Lacasa X., Cuchi E., Sambeat M. A., Pomar V., Coll P., Miralles P., Moreno S., Iribarren J. A., Ibarguren M., Aldamiz T., Rickenbach M., Sagette M., Post F. A., Miller R. F., Chapman A., Dockrell D., Wilkins E., Cooke G., Ainsworth J., Macallen D., Dhar J., Vora N., Mullaney S., Kegg S., Kyselyova G., Mansfeld, M, Skrahina, A, Shepherd, L, Schultze, A, Panteleev, A, Miller, R, Miro, J, Zeltina, I, Tetradov, S, Furrer, H, Kirk, O, Grzeszczuk, A, Bolokadze, N, Matteelli, A, Post, F, Lundgren, J, Mocroft, A, Efsen, A, Podlekareva, D, Losso, M, Toibaro, J, Palmero, D, Bartoletti, B, E., W, Gear, O, Messina, O, Michans, M, Laplume, H, David, D, Marson, C, Scapelatto, F, Dalessandro, D, Lupo, S, Costilla Campero, G, Herbst, M, Remondegui, C, Elias, C, Karpov, I, Vassilenko, A, Skrahina, E, Skrahin, A, Zalutskya, A, Kondratenko, O, Mitsura, V, Bondarenko, V, Suetnov, O, Paduto, D, Dewit, S, Payen, M, Noscoi, C, Kabeya, K, M., W, Cortes, C, Obel, N, Kronborg, G, Iljna, V, Kummik, T, Bryand, M, Dabis, F, Lanchava, N, Bablishvili, N, Goginashvili, L, Mikiashvili, L, Mshvidobadze, K, Girardi, E, Di Biagio, A, Apostoli, A, Barzoni, S, Lapadula, G, Purgatorio, M, Carbonara, S, Rozentale, B, Janushkevich, I, Caplinskas, S, Kancauskienne, Z, Caplinskienne, I, Crabtree, B, Pina, A, Madero, J, Mosqueda, J, Villanueva, J, Bura, M, Garlicki, A, Inglot, M, Knysz, B, Kozlowska, J, Loster, J, Mularska, E, Podlasin, R, Thompson, M, Wiercinska-Drapalo, A, Duiculescu, D, Rakhmanova, A, Yakovlev, A, Turkalova, A, Vlasova, Y, Trotimora, T, Borodulina, E, Chumanova, L, Mashkova, Y, Cayla, J, Moreno, A, Millet, J, Orcau, A, Fina, L, del Bano, L, Roldan, L, Romero, A, Martinez, J, Manzardo, C, Gonzalez, J, Tudo, G, Knobel, H, Sanchez, F, Salvado, M, Curran, A, Tortola, M, Pozamczer, D, Saumoy, M, Alcaide, F, Martinez-Lacasa, X, Cuchi, E, Sambeat, M, Pomar, V, Coll, P, Miralles, P, Moreno, S, Iribarren, J, Ibarguren, M, Aldamiz, T, Rickenbach, M, Sagette, M, Chapman, A, Dockrell, D, Wilkins, E, Cooke, G, Ainsworth, J, Macallen, D, Dhar, J, Vora, N, Mullaney, S, Kegg, S, Kyselyova, G, Mansfeld M., Skrahina A., Shepherd L., Schultze A., Panteleev A., Miller R., Miro J., Zeltina I., Tetradov S., Furrer H., Kirk O., Grzeszczuk A., Bolokadze N., Matteelli A., Post F., Lundgren J., Mocroft A., Efsen A., Podlekareva D., Losso M. H., Toibaro J. J., Palmero D., Bartoletti B. J., E. Warley, Gear O., Messina O. G., Michans M., Laplume H., David D., Marson C., Scapelatto F. P., Dalessandro D., Lupo S., Costilla Campero G., Herbst M., Remondegui C., Elias C., Karpov I., Vassilenko A., Skrahina E., Skrahin A., Zalutskya A., Kondratenko O., Mitsura V., Bondarenko V., Suetnov O., Paduto D., Dewit S., Payen M. C., Noscoi C., Kabeya K., M. Wolff, Cortes C., Obel N., Kronborg G., Iljna V., Kummik T., Bryand M., Dabis F., Lanchava N., Bablishvili N., Goginashvili L., Mikiashvili L., Mshvidobadze K., Girardi E., Di Biagio A., Apostoli A., Barzoni S., Lapadula G., Purgatorio M., Carbonara S., Rozentale B., Janushkevich I., Caplinskas S., Kancauskienne Z., Caplinskienne I., Crabtree B., Pina A., Madero J. S., Mosqueda J., Villanueva J. A., Bura M., Garlicki A., Inglot M., Knysz B., Kozlowska J., Loster J., Mularska E., Podlasin R., Thompson M., Wiercinska-Drapalo A., Duiculescu D., Rakhmanova A., Yakovlev A., Turkalova A., Vlasova Y., Trotimora T., Borodulina E., Chumanova L., Mashkova Y., Miro J. M., Cayla J. A., Moreno A., Millet J. P., Orcau A., Fina L., del Bano L., Roldan L. L., Romero A., Martinez J. A., Manzardo C., Gonzalez J., Tudo G., Knobel H., Sanchez F., Salvado M., Curran A., Tortola M. T., Pozamczer D., Saumoy M., Alcaide F., Martinez-Lacasa X., Cuchi E., Sambeat M. A., Pomar V., Coll P., Miralles P., Moreno S., Iribarren J. A., Ibarguren M., Aldamiz T., Rickenbach M., Sagette M., Post F. A., Miller R. F., Chapman A., Dockrell D., Wilkins E., Cooke G., Ainsworth J., Macallen D., Dhar J., Vora N., Mullaney S., Kegg S., and Kyselyova G.

Abstract

Objectives: The aim of the study was to investigate the organization and delivery of HIV and tuberculosis (TB) health care and to analyse potential differences between treatment centres in Eastern (EE) and Western Europe (WE). Methods: Thirty-eight European HIV and TB treatment centres participating in the TB:HIV study within EuroCoord completed a survey on health care management for coinfected patients in 2013 (EE: 17 respondents; WE:21; 76% of all TB:HIV centres). Descriptive statistics were obtained for regional comparisons. The reported data on health care strategies were compared with actual clinical practice at patient level via data derived from the TB:HIV study. Results: Respondent centres in EE comprised: Belarus (n=3), Estonia (1), Georgia (1), Latvia (1), Lithuania (1), Poland (4), Romania (1), the Russian Federation (4) and Ukraine (1); those in WE comprised: Belgium (1), Denmark (1), France (1), Italy (7), Spain (2), Switzerland (1) and UK (8). Compared with WE, treatment of HIV and TB in EE are less often located at the same site (47% in EE versus 100% in WE; P<0.001) and less often provided by the same doctors (41% versus 90%, respectively; P=0.002), whereas regular screening of HIV-infected patients for TB (80% versus 40%, respectively; P=0.037) and directly observed treatment (88% versus 20%, respectively; P<0.001) were more common in EE. The reported availability of rifabutin and second- and third-line anti-TB drugs was lower, and opioid substitution therapy (OST) was available at fewer centres in EE compared with WE (53% versus 100%, respectively; P<0.001). Conclusions: Major differences exist between EE and WE in relation to the organization and delivery of health care for HIV/TB-coinfected patients and the availability of anti-TB drugs and OST. Significant discrepancies between reported and actual clinical practices were found in EE.

Published
2015

15. Major differences in organization and availability of health care and medicines for HIV/TB coinfected patients across Europe

Author

Mansfeld M., Skrahina A., Shepherd L., Schultze A., Panteleev A., Miller R., Miro J., Zeltina I., Tetradov S., Furrer H., Kirk O., Grzeszczuk A., Bolokadze N., Matteelli A., Post F., Lundgren J., Mocroft A., Efsen A., Podlekareva D., Losso M. H., Toibaro J. J., Palmero D., Bartoletti B. J., E. Warley, Gear O., Messina O. G., Michans M., Laplume H., David D., Marson C., Scapelatto F. P., Dalessandro D., Lupo S., Costilla Campero G., Herbst M., Remondegui C., Elias C., Karpov I., Vassilenko A., Skrahina E., Skrahin A., Zalutskya A., Kondratenko O., Mitsura V., Bondarenko V., Suetnov O., Paduto D., Dewit S., Payen M. C., Noscoi C., Kabeya K., M. Wolff, Cortes C., Obel N., Kronborg G., Iljna V., Kummik T., Bryand M., Dabis F., Lanchava N., Bablishvili N., Goginashvili L., Mikiashvili L., Mshvidobadze K., Girardi E., Di Biagio A., Apostoli A., Barzoni S., Lapadula G., Purgatorio M., Carbonara S., Rozentale B., Janushkevich I., Caplinskas S., Kancauskienne Z., Caplinskienne I., Crabtree B., Pina A., Madero J. S., Mosqueda J., Villanueva J. A., Bura M., Garlicki A., Inglot M., Knysz B., Kozlowska J., Loster J., Mularska E., Podlasin R., Thompson M., Wiercinska-Drapalo A., Duiculescu D., Rakhmanova A., Yakovlev A., Turkalova A., Vlasova Y., Trotimora T., Borodulina E., Chumanova L., Mashkova Y., Miro J. M., Cayla J. A., Moreno A., Millet J. P., Orcau A., Fina L., del Bano L., Roldan L. L., Romero A., Martinez J. A., Manzardo C., Gonzalez J., Tudo G., Knobel H., Sanchez F., Salvado M., Curran A., Tortola M. T., Pozamczer D., Saumoy M., Alcaide F., Martinez-Lacasa X., Cuchi E., Sambeat M. A., Pomar V., Coll P., Miralles P., Moreno S., Iribarren J. A., Ibarguren M., Aldamiz T., Rickenbach M., Sagette M., Post F. A., Miller R. F., Chapman A., Dockrell D., Wilkins E., Cooke G., Ainsworth J., Macallen D., Dhar J., Vora N., Mullaney S., Kegg S., Kyselyova G., Mansfeld, M, Skrahina, A, Shepherd, L, Schultze, A, Panteleev, A, Miller, R, Miro, J, Zeltina, I, Tetradov, S, Furrer, H, Kirk, O, Grzeszczuk, A, Bolokadze, N, Matteelli, A, Post, F, Lundgren, J, Mocroft, A, Efsen, A, Podlekareva, D, Losso, M, Toibaro, J, Palmero, D, Bartoletti, B, E., W, Gear, O, Messina, O, Michans, M, Laplume, H, David, D, Marson, C, Scapelatto, F, Dalessandro, D, Lupo, S, Costilla Campero, G, Herbst, M, Remondegui, C, Elias, C, Karpov, I, Vassilenko, A, Skrahina, E, Skrahin, A, Zalutskya, A, Kondratenko, O, Mitsura, V, Bondarenko, V, Suetnov, O, Paduto, D, Dewit, S, Payen, M, Noscoi, C, Kabeya, K, M., W, Cortes, C, Obel, N, Kronborg, G, Iljna, V, Kummik, T, Bryand, M, Dabis, F, Lanchava, N, Bablishvili, N, Goginashvili, L, Mikiashvili, L, Mshvidobadze, K, Girardi, E, Di Biagio, A, Apostoli, A, Barzoni, S, Lapadula, G, Purgatorio, M, Carbonara, S, Rozentale, B, Janushkevich, I, Caplinskas, S, Kancauskienne, Z, Caplinskienne, I, Crabtree, B, Pina, A, Madero, J, Mosqueda, J, Villanueva, J, Bura, M, Garlicki, A, Inglot, M, Knysz, B, Kozlowska, J, Loster, J, Mularska, E, Podlasin, R, Thompson, M, Wiercinska-Drapalo, A, Duiculescu, D, Rakhmanova, A, Yakovlev, A, Turkalova, A, Vlasova, Y, Trotimora, T, Borodulina, E, Chumanova, L, Mashkova, Y, Cayla, J, Moreno, A, Millet, J, Orcau, A, Fina, L, del Bano, L, Roldan, L, Romero, A, Martinez, J, Manzardo, C, Gonzalez, J, Tudo, G, Knobel, H, Sanchez, F, Salvado, M, Curran, A, Tortola, M, Pozamczer, D, Saumoy, M, Alcaide, F, Martinez-Lacasa, X, Cuchi, E, Sambeat, M, Pomar, V, Coll, P, Miralles, P, Moreno, S, Iribarren, J, Ibarguren, M, Aldamiz, T, Rickenbach, M, Sagette, M, Chapman, A, Dockrell, D, Wilkins, E, Cooke, G, Ainsworth, J, Macallen, D, Dhar, J, Vora, N, Mullaney, S, Kegg, S, and Kyselyova, G

Subjects
Tuberculosi, Coinfection, Health Policy, Antitubercular Agents, HIV, 1103 Clinical Sciences, HIV Infections, Eastern, Health Surveys, Article, Europe, Infectious Diseases, Cross-Sectional Studies, Rifabutin, Delivery of health care, Integrated, Tuberculosis, Europe, Eastern, Humans, Opiate Substitution Treatment, Pharmacology (medical), Virology, 610 Medicine & health
Abstract

Objectives: The aim of the study was to investigate the organization and delivery of HIV and tuberculosis (TB) health care and to analyse potential differences between treatment centres in Eastern (EE) and Western Europe (WE). Methods: Thirty-eight European HIV and TB treatment centres participating in the TB:HIV study within EuroCoord completed a survey on health care management for coinfected patients in 2013 (EE: 17 respondents; WE:21; 76% of all TB:HIV centres). Descriptive statistics were obtained for regional comparisons. The reported data on health care strategies were compared with actual clinical practice at patient level via data derived from the TB:HIV study. Results: Respondent centres in EE comprised: Belarus (n=3), Estonia (1), Georgia (1), Latvia (1), Lithuania (1), Poland (4), Romania (1), the Russian Federation (4) and Ukraine (1); those in WE comprised: Belgium (1), Denmark (1), France (1), Italy (7), Spain (2), Switzerland (1) and UK (8). Compared with WE, treatment of HIV and TB in EE are less often located at the same site (47% in EE versus 100% in WE; P

Published
2015

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

Author

Kempker, R R, Mikiashvili, L, Zhao, Y, Benkeser, D, Barbakadze, K, Bablishvili, N, Avaliani, Z, Peloquin, C A, Blumberg, H M, and Kipiani, M

Subjects
ANTITUBERCULAR agents, DRUG side effects, IMIDAZOLES, LONGITUDINAL method, MICROBIAL sensitivity tests, SCIENTIFIC observation, QUINOLINE, SPUTUM, TREATMENT effectiveness, DESCRIPTIVE statistics
Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2020
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17. Management of MDR-TB in HIV co-infected patients in Eastern Europe: Results from the TB:HIV study

Author

Efsen, A.M.W., primary, Schultze, A., additional, Miller, R.F., additional, Panteleev, A., additional, Skrahin, A., additional, Podlekareva, D.N., additional, Miro, J.M., additional, Girardi, E., additional, Furrer, H., additional, Losso, M.H., additional, Toibaro, J., additional, Caylà, J.A., additional, Mocroft, A., additional, Lundgren, J.D., additional, Post, F.A., additional, Kirk, O., additional, Karpov, I., additional, Vassilenko, A., additional, Skrahina, A., additional, Klimuk, D., additional, Kondratenko, O., additional, Zalutskaya, A., additional, Bondarenko, V., additional, Mitsura, V., additional, Kozorez, E., additional, Tumash, O., additional, Suetnov, O., additional, Paduto, D., additional, Iljina, V., additional, Kummik, T., additional, Bolokadze, N., additional, Mshvidobadze, K., additional, Lanchava, N., additional, Goginashvili, L., additional, Mikiashvili, L., additional, Bablishvili, N., additional, Rozentale, B., additional, Zeltina, I., additional, Janushkevich, I., additional, Caplinskiene, I., additional, Caplinskas, S., additional, Kancauskiene, Z., additional, Podlasin, R., additional, Wiercinska-Drapalo, A., additional, Thompson, M., additional, Kozlowska, J., additional, Grezesczuk, A., additional, Bura, M., additional, Knysz, B., additional, Inglot, M., additional, Garlicki, A., additional, Loster, J., additional, Tetradov, S., additional, Duiculescu, D., additional, Rakhmanova, A., additional, Panteleeva, O., additional, Yakovlev, A., additional, Kozlov, A., additional, Tyukalova, A., additional, Vlasova, Y., additional, Trofimov, T., additional, Kyselyova, G., additional, Andersen, A.B., additional, Thorsteinsson, K., additional, Payen, M.C., additional, Kabeya, K., additional, Necsoi, C., additional, Dabis, F., additional, Bruyand, M., additional, Morlat, P., additional, Dupont, A., additional, Gerard, Y., additional, Bonnal, F., additional, Ceccaldi, J., additional, De Witte, S., additional, Monlun, E., additional, Lataste, P., additional, Chossat, I., additional, Miller, R., additional, Vora, N., additional, Cooke, G., additional, Mullaney, S., additional, Wilkins, E., additional, George, V., additional, Collini, P., additional, Dockrell, D., additional, Post, F., additional, Campbell, L., additional, Brum, R., additional, Mabonga, E., additional, Saigal, P., additional, Kegg, S., additional, Ainsworth, J., additional, Waters, A., additional, Dhar, J., additional, Mashonganyika, L., additional, Rianda, A., additional, Galati, V., additional, Pinnetti, C., additional, Tommasi, C., additional, Lapadula, G., additional, Di Biagio, A., additional, Parisini, A., additional, Carbonara, S., additional, Angarano, G., additional, Purgatorio, M., additional, Matteelli, A., additional, Apostoli, A., additional, Macias, L. Moreno, additional, Warley, E., additional, Tavella, S., additional, Garcia Messina, O., additional, Gear, O., additional, Laplume, H., additional, Marson, C., additional, Contarelia, J., additional, Michaan, M., additional, Scapellato, P., additional, Alessandro, D.D., additional, Bartoletti, B., additional, Palmero, D., additional, Elias, C., additional, Cortes, C., additional, Crabtree, B., additional, Mosqueda Gomez, J.L., additional, Villanueva, A., additional, and Gonzalez Hernandez, L.A., additional

Published
2018
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18. Tuberculosis-related mortality in people living with HIV in Europe and Latin America: An international cohort study

Author

Podlekareva Daria, N, Efsen Anne Marie, W, Schultze, A, Post Frank, A, Skrahina Alena, M, Panteleev, A, Furrer, H, Miller Robert, F, Losso, M. H, Toibaro, J, Miro Jose, M, Vassilenko, A, Girardi, Enrico, Bruyand, M, Obel, N, Lundgren Jens, D, Mocroft, A, Kirk, O, Karpov, I, Skrahina, A, Klimuk, D, Skrahin, A, Kondratenko, O, Zalutskaya, A, Bondarenko, V, Mitsura, V, Kozorez, E, Tumash, O, Suetnov, O, Paduto, D, Iljina, V, Kummik, T, Bolokadze, N, Mshvidobadze, K, Lanchava, N, Goginashvili, L, Mikiashvili, L, Bablishvili, N, Rozentale, B, Zeltina, I, Janushkevich, I, Caplinskiene, I, Caplinskas, S, Kancauskiene, Z, Podlasin, R, Wiercinska Drapalo, A, Thompson, M, Kozlowska, J, Grezesczuk, A, Bura, M, Knysz, B, Inglot, M, Garlicki, A, Loster, J, Duiculescu, D, Tetradov, S, Rakhmanova, A, Panteleeva, O, Yakovlev, A, Kozlov, A, Tyukalova, A, Vlasova, Y, Trofimov, T, Kyselyova, G, Thorsteinsson, K, Payen, Mc, Kabeya, K, Necsoi, C, Dabis, F, Morlat, P, Dupont, A, Gerard, Y, Bonnal, F, Ceccaldi, J, De Witte, S, Monlun, E, Lataste, P, Chossat, I, Sagette, M, Rickenbach, M, Elzi, L, Battegay, M, Sculier, D, Calmy, A, Cavassini, M, Bruno, A, Bernasconi, E, Hoffmann, M, Vernazza, P, Fehr, J, Weber, R, Aubert, V, Böni, J, Bucher, Hc, Burton Jeangros, C, Dollenmaier, G, Egger, M, Fellay, J, Fux, Ca, Gorgievski, M, Günthard, H, Haerry, D, Hasse, B, Hirsch, Hh, Hösli, I, Kahlert, C, Kaiser, L, Keiser, O, Klimkait, T, Kouyos, R, Kovari, H, Ledergerber, B, Martinetti, G, Martinez de Tejada, B, Metzner, K, Müller, N, Nadal, D, Nicca, D, Pantaleo, G, Rauch, A, Regenass, S, Rudin, C, Schöni Affolter, F, Schmid, P, Schüpbach, J, Speck, R, Tarr, P, Telenti, A, Trkola, A, Yerly, S, Miller, Rf, Vora, N, Cooke, G, Mullaney, S, Wilkins, E, George, V, Collini, P, Dockrell, D, Post, F, Campbell, L, Brum, R, Mabonga, E, Saigal, P, Kegg, S, Ainsworth, J, Waters, A, Dhar, J, Mashonganyika, L, Girardi, E, Rianda, A, Galati, V, Pinnetti, C, Tommasi, C, Lapadula, G, Di Biagio, A, Parisini, A, Carbonara, S, Angarano, G, Purgatorio, M, Matteelli, Alberto, Apostoli, A, Miro, Jm, Manzardo, C, Ligero, C, Gonzalez, J, Martinez Martinez, Ja, Sanchez, F, Knobel, H, Salvadó, M, Lopez Colomes, Jl, Martínez Lacasa, X, Cuchí, E, Falcó, V, Curran, A, Tortola, Mt, Ocaña, I, Vidal, R, Sambeat, Ma, Pomar, V, Coll, P, Pozamczer, D, Saumoy, M, Alcaide, F, Caylà, J, Moreno, A, Millet, Jp, Orcau, A, Fina, L, Romero, A, Roldan, Ll, Iribarren, Ja, Ibarguren, M, Moreno, S, González, A, Miralles, P, Aldámiz Echevarría, T, Losso, M, Gambardella, L, Macias, L, Warley, E, Tavella, S, Messina, O, Gear, O, Laplume, H, Marson, C, Contarelia, J, Michaan, M, Scapellato, P, Alessandro, D, Bartoletti, B, Palmero, D, Elias, C, Cortes, C, Crabtree, B, Gomez, Jl, Hernandez, La, and Badial, F.

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Latin Americans, Tuberculosis, Anti-HIV Agents, Epidemiology, 030106 microbiology, Population, Infectious Diseases, Immunology, Virology, Antitubercular Agents, HIV Infections, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Tuberculosis, Multidrug-Resistant, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Young adult, Epidemics, education, Prospective cohort study, education.field_of_study, AIDS-Related Opportunistic Infections, business.industry, Mortality rate, Middle Aged, medicine.disease, Europe, Latin America, Female, business, Developed country, Demography, Cohort study
Abstract

Management of tuberculosis in patients with HIV in eastern Europe is complicated by the high prevalence of multidrug-resistant tuberculosis, low rates of drug susceptibility testing, and poor access to antiretroviral therapy (ART). We report 1 year mortality estimates from a multiregional (eastern Europe, western Europe, and Latin America) prospective cohort study: the TB:HIV study.Consecutive HIV-positive patients aged 16 years or older with a diagnosis of tuberculosis between Jan 1, 2011, and Dec 31, 2013, were enrolled from 62 HIV and tuberculosis clinics in 19 countries in eastern Europe, western Europe, and Latin America. The primary endpoint was death within 12 months after starting tuberculosis treatment; all deaths were classified according to whether or not they were tuberculosis related. Follow-up was either until death, the final visit, or 12 months after baseline, whichever occurred first. Risk factors for all-cause and tuberculosis-related deaths were assessed using Kaplan-Meier estimates and Cox models.Of 1406 patients (834 in eastern Europe, 317 in western Europe, and 255 in Latin America), 264 (19%) died within 12 months. 188 (71%) of these deaths were tuberculosis related. The probability of all-cause death was 29% (95% CI 26-32) in eastern Europe, 4% (3-7) in western Europe, and 11% (8-16) in Latin America (p0·0001) and the corresponding probabilities of tuberculosis-related death were 23% (20-26), 1% (0-3), and 4% (2-8), respectively (p0·0001). Patients receiving care outside eastern Europe had a 77% decreased risk of death: adjusted hazard ratio (aHR) 0·23 (95% CI 0·16-0·31). In eastern Europe, compared with patients who started a regimen with at least three active antituberculosis drugs, those who started fewer than three active antituberculosis drugs were at a higher risk of tuberculosis-related death (aHR 3·17; 95% CI 1·83-5·49) as were those who did not have baseline drug-susceptibility tests (2·24; 1·31-3·83). Other prognostic factors for increased tuberculosis-related mortality were disseminated tuberculosis and a low CD4 cell count. 18% of patients were receiving ART at tuberculosis diagnosis in eastern Europe compared with 44% in western Europe and 39% in Latin America (p0·0001); 12 months later the proportions were 67% in eastern Europe, 92% in western Europe, and 85% in Latin America (p0·0001).Patients with HIV and tuberculosis in eastern Europe have a risk of death nearly four-times higher than that in patients from western Europe and Latin America. This increased mortality rate is associated with modifiable risk factors such as lack of drug susceptibility testing and suboptimal initial antituberculosis treatment in settings with a high prevalence of drug resistance. Urgent action is needed to improve tuberculosis care for patients living with HIV in eastern Europe.EU Seventh Framework Programme.

Published
2016

22. Optimizing multiplex SNP-based data analysis for genotyping of Mycobacterium tuberculosis isolates.

Author

Sengstake, S., Bablishvili, N., Schuitema, A., Bzekalava, N., Abadia, E., Beer, J. de, Tadumadze, N., Akhalaia, M., Tuin, K., Tukvadze, N., Aspindzelashvili, R., Bachiysk, a.E., Panaiotov, S., Sola, C., Soolingen, D. van, Klatser, P., Anthony, R., Bergval, I., Sengstake, S., Bablishvili, N., Schuitema, A., Bzekalava, N., Abadia, E., Beer, J. de, Tadumadze, N., Akhalaia, M., Tuin, K., Tukvadze, N., Aspindzelashvili, R., Bachiysk, a.E., Panaiotov, S., Sola, C., Soolingen, D. van, Klatser, P., Anthony, R., and Bergval, I.

Abstract

Contains fulltext : 136441.pdf (publisher's version ) (Open Access)

Published
2014

24. Combined species identification, genotyping, and drug resistance detection of Mycobacterium tuberculosis cultures by MLPA on a bead-based array

Author

Bergval, I., Sengstake, S., Brankova, N., Levterova, V., Abadia, E., Tadumaze, N., Bablishvili, N., Akhalaia, M., Tuin, K., Schuitema, A., Panaiotov, S., Bachiyska, E., Kantardjiev, T., Zwaan, R. de, Schurch, A., Soolingen, D. van, Hoog, A. van 't, Cobelens, F., Aspindzelashvili, R., Sola, C., Klatser, P., Anthony, R., Bergval, I., Sengstake, S., Brankova, N., Levterova, V., Abadia, E., Tadumaze, N., Bablishvili, N., Akhalaia, M., Tuin, K., Schuitema, A., Panaiotov, S., Bachiyska, E., Kantardjiev, T., Zwaan, R. de, Schurch, A., Soolingen, D. van, Hoog, A. van 't, Cobelens, F., Aspindzelashvili, R., Sola, C., Klatser, P., and Anthony, R.

Abstract

Contains fulltext : 124255.pdf (publisher's version ) (Open Access), The population structure of Mycobacterium tuberculosis is typically clonal therefore genotypic lineages can be unequivocally identified by characteristic markers such as mutations or genomic deletions. In addition, drug resistance is mainly mediated by mutations. These issues make multiplexed detection of selected mutations potentially a very powerful tool to characterise Mycobacterium tuberculosis. We used Multiplex Ligation-dependent Probe Amplification (MLPA) to screen for dispersed mutations, which can be successfully applied to Mycobacterium tuberculosis as was previously shown. Here we selected 47 discriminative and informative markers and designed MLPA probes accordingly to allow analysis with a liquid bead array and robust reader (Luminex MAGPIX technology). To validate the bead-based MLPA, we screened a panel of 88 selected strains, previously characterised by other methods with the developed multiplex assay using automated positive and negative calling. In total 3059 characteristics were screened and 3034 (99.2%) were consistent with previous molecular characterizations, of which 2056 (67.2%) were directly supported by other molecular methods, and 978 (32.0%) were consistent with but not directly supported by previous molecular characterizations. Results directly conflicting or inconsistent with previous methods, were obtained for 25 (0.8%) of the characteristics tested. Here we report the validation of the bead-based MLPA and demonstrate its potential to simultaneously identify a range of drug resistance markers, discriminate the species within the Mycobacterium tuberculosis complex, determine the genetic lineage and detect and identify the clinically most relevant non-tuberculous mycobacterial species. The detection of multiple genetic markers in clinically derived Mycobacterium tuberculosis strains with a multiplex assay could reduce the number of TB-dedicated screening methods needed for full characterization. Additionally, as a proportion of the marke

Published
2012

25. Combined species identification, genotyping, and drug resistance detection of mycobacterium tuberculosis cultures by mlpa on a bead-based array

Author

Bergval, I. (Indra), Sengstake, S. (Sarah), Brankova, N. (Nadia), Levterova, V. (Viktoria), Abadía, E. (Edgar), Tadumaze, N. (Nino), Bablishvili, N. (Nino), Akhalaia, M. (Maka), Tuin, K. (Kiki), Schuitema, A. (Anja), Panaiotov, S. (Stefan), Bachiyska, E. (Elizabeta), Kantardjiev, T. (Todor), Zwaan, R. (Rina) de, Schürch, A. (Anita), Soolingen, D. (Dick) van, Hoog, A. (Anja) van 't, Cobelens, F.G.J. (Frank), Aspindzelashvili, R. (Rusudan), Sola, C. (Christophe), Klatser, P.R. (Paul), Anthony, R. (Richard), Bergval, I. (Indra), Sengstake, S. (Sarah), Brankova, N. (Nadia), Levterova, V. (Viktoria), Abadía, E. (Edgar), Tadumaze, N. (Nino), Bablishvili, N. (Nino), Akhalaia, M. (Maka), Tuin, K. (Kiki), Schuitema, A. (Anja), Panaiotov, S. (Stefan), Bachiyska, E. (Elizabeta), Kantardjiev, T. (Todor), Zwaan, R. (Rina) de, Schürch, A. (Anita), Soolingen, D. (Dick) van, Hoog, A. (Anja) van 't, Cobelens, F.G.J. (Frank), Aspindzelashvili, R. (Rusudan), Sola, C. (Christophe), Klatser, P.R. (Paul), and Anthony, R. (Richard)

Abstract

The population structure of Mycobacterium tuberculosis is typically clonal therefore genotypic lineages can be unequivocally identified by characteristic markers such as mutations or genomic deletions. In addition, drug resistance is mainly mediated by mutations. These issues make multiplexed detection of selected mutations potentially a very powerful tool to characterise Mycobacterium tuberculosis. We used Multiplex Ligation-dependent Probe Amplification (MLPA) to screen for dispersed mutations, which can be successfully applied to Mycobacterium tuberculosis as was previously shown. Here we selected 47 discriminative and informative markers and designed MLPA probes accordingly to allow analysis with a liquid bead array and robust reader (Luminex MAGPIX technology). To validate the bead-based MLPA, we screened a panel of 88 selected strains, previously characterised by other methods with the developed multiplex assay using automated positive and negative calling. In total 3059 characteristics were screened and 3034 (99.2%) were consistent with previous molecular characterizations, of which 2056 (67.2%) were directly supported by other molecular methods, and 978 (32.0%) were consistent with but not directly supported by previous molecular characterizations. Results directly conflicting or inconsistent with previous methods, were obtained for 25 (0.8%) of the characteristics tested. Here we report the validation of the bead-based MLPA and demonstrate its potential to simultaneously identify a range of drug resistance markers, discriminate the species within the Mycobacterium tuberculosis complex, determine the genetic lineage and detect and identify the clinically most relevant non-tuberculous mycobacterial species. The detection of multiple genetic markers in clinically derived Mycobacterium tuberculosis strains with a multiplex assay could reduce the number of TB-dedicated screening methods needed for full characterization. Additionally, as a proportion of the marke

Published
2012
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26. Molecular patterns of multidrug resistance of Mycobacterium tuberculosisin Georgia

Author

Shubladze, N., Tadumadze, N., and Bablishvili, N.

Abstract

Tuberculosis (TB) infections caused by multidrug-resistant Mycobacterium tuberculosis(MDR MTB) remain a significant public health concern worldwide. Georgia has a high prevalence of MDR MTB. The genetic mechanisms underlying the emergence of MDR MTB strains in this region are poorly understood and need to be determined for developing better strategies for TB control. This study investigated the frequency of major drug resistance mutations across rpoB, katGand inhAloci of Georgian MDR MTB strains and explored differences between new and previously treated patients.

Published
2013
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27. Impact of gyrBand eisMutations in Improving Detection of Second-Line-Drug Resistance among Mycobacterium tuberculosisIsolates from Georgia

Author

Bablishvili, N., Tukvadze, N., Shashkina, E., Mathema, B., Gandhi, N. R., Blumberg, H. M., and Kempker, R. R.

Abstract

ABSTRACTThe country of Georgia has a high burden of multi- and extensively drug-resistant tuberculosis (XDR-TB). To evaluate whether mutations in gyrBand eisgenes increased the sensitivity of detection of phenotypic resistance to ofloxacin and kanamycin or capreomycin compared to use of the first-generation MTBDRslassay alone, which tests for mutations in gyrAand rrsgenes, a retrospective study of stored Mycobacterium tuberculosisisolates was performed. All isolates underwent DNA sequencing of resistance-determining regions. Among 112 M. tuberculosisisolates with DNA extraction data, targeted sequencing was successfully performed for each gene as follows: for gyrA, 98% sensitivity; for gyrB, 96%; for rrs, 93%; for the eisgene and its promoter, 93%. The specificity and hence the positive predictive value of gyrAand gyrBmutations for detecting ofloxacin resistance were 100%. The addition of gyrBmutations increased the sensitivity of phenotypic ofloxacin resistance detection by 13% (75% to 88%). All rrsresistance-conferring mutations were A1401G, and this mutation had low sensitivity (40% and 18%) and high specificity (95% and 100%) in predicting phenotypic capreomycin and kanamycin resistance, respectively. The eisC-14T mutation increased the sensitivity of phenotypic kanamycin resistance detection by 9% (18% to 27%) and was found solely in kanamycin phenotypic resistance isolates. Our data showed that the inclusion of eisC-14T and gyrBmutations in addition to rrsand gyrAmutations improves the sensitivity of detection of phenotypic ofloxacin and kanamycin resistance, respectively.

Published
2017
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28. Delayed diagnosis of tuberculosis in persons living with HIV in Eastern Europe: associated factors and effect on mortality-a multicentre prospective cohort study

Author

Kraef, Christian, Bentzon, Adrian, Panteleev, Alexander, Skrahina, Alena, Bolokadze, Natalie, Tetradov, Simona, Podlasin, Regina, Karpov, Igor, Borodulina, Elena, Denisova, Elena, Azina, Inga, Lundgren, Jens, Johansen, Isik Somuncu, Mocroft, Amanda, Podlekareva, Daria, Kirk, Ole, Vassilenko, A., Klimuk, D., Kondratenko, O., Zalutskaya, A., Bondarenko, V., Mitsura, V., Kozorez, E., Tumash, O., Suetnov, O., Paduto, D., Iljina, V., Kummik, T., Mshvidobadze, K., Lanchava, N., Goginashvili, L., Mikiashvili, L., Bablishvili, Nino, Rozentale, B., Zeltina, I., Janushkevich, I., Caplinskiene, I., Caplinskas, S., Kancauskiene, Z., Wiercinska-Drapalo, A., Thompson, M., Kozlowska, J., Grezesczuk, A., Bura, M., Knysz, B., Inglot, M., Garlicki, A., Loster, J., uiculescu, D.D., Rakhmanova, A., Panteleev, O., Yakovlev, A., Kozlov, A., Tyukalova, A., Vlasova, Y., rofimov, T.T., Kyselyova, G., Obel, N., Gerstoft, J., Kronborg, G., Payen, M.C., abeya, K.K., Necsoi, C., Dabis, F., Tsaranazy, A., Cazanave, C., Furrer, H., Sagette, M., Rickenbach, M., Sculier, D., Calmy, A., Cavassini, Matthias, Bruno, A., Bernasconi, E., Hoffmann, M., Vernazza, P., Fehr, J., Weber, R., Miller, R., Vora, N., Cooke, G., Mullaney, S., Wilkins, E., George, V., Collini, P., Dockrell, D., Post, F., Campbell, L., Brum, R., Mabonga, E., Saigal, P., Kegg, S., Ainsworth, J., Waters, A., Dhar, J., Ellis, K., Girardi, E., Rianda, A., Galati, V., Pinnetti, C., Tommasi, C., Lapadula, G., Di Biagio, A., Parisini, A., Carbonara, S., Angarano, G., Purgatorio, M., Matteelli, A., Apostoli, A., Miro, J.M., Manzardo, C., Ligero, C., Gonzalez, J., Martinez-Martinez, J.A., Sanchez, F., Knobel Freud, Hernando, Salvadó, M., Lopez-Colomes, J.L., Martínez-Lacasa, X., Cuchí, E., Falcó, Vicenç, Curran, Adrian, Tortola, M.T., Ocaña Rivera, Immaculada, Vidal, R., Sambeat, M.A., Pomar, Virginia, Coll, P., Pozamczer, D., Saumoy, M., Alcaide, Fernando, Caylà, Joan A, Moreno Camacho, Asunción, Millet, Joan-Pau, Orcau, Àngels, Fina, L., Romero, A., Roldan, L.L., Iribarren, J.A., Ibarguren, M., Moreno, S., González, A., Miralles, P., Aldámiz-Echevarría, T., Losso, M., Toibaro, J., Gambardella, L., Moreno Macias, L., Warley, E., Tavella, S., Garcia Messina, O., Gear, O., Laplume, H., Marson, C., Contarelia, J., Michaan, M., Scapellato, P., Bartoletti, B., Palmero, D., Elias, C., Cortes, C., Crabtree, B., Mosqueda Gomez, J.L., Villanueva, J.A., Gonzalez Hernandez, L.A., Badial, F., Kraef, C, Bentzon, A, Panteleev, A, Skrahina, A, Bolokadze, N, Tetradov, S, Podlasin, R, Karpov, I, Borodulina, E, Denisova, E, Azina, I, Lundgren, J, Johansen, I, Mocroft, A, Podlekareva, D, Kirk, O, Vassilenko, A, Klimuk, D, Kondratenko, O, Zalutskaya, A, Bondarenko, V, Mitsura, V, Kozorez, E, Tumash, O, Suetnov, O, Paduto, D, Iljina, V, Kummik, T, Mshvidobadze, K, Lanchava, N, Goginashvili, L, Mikiashvili, L, Bablishvili, N, Rozentale, B, Zeltina, I, Janushkevich, I, Caplinskiene, I, Caplinskas, S, Kancauskiene, Z, Wiercinska-Drapalo, A, Thompson, M, Kozlowska, J, Grezesczuk, A, Bura, M, Knysz, B, Inglot, M, Garlicki, A, Loster, J, Uiculescu, D, Rakhmanova, A, Panteleev, O, Yakovlev, A, Kozlov, A, Tyukalova, A, Vlasova, Y, Rofimov, T, Kyselyova, G, Obel, N, Gerstoft, J, Kronborg, G, Payen, M, Abeya, K, Necsoi, C, Dabis, F, Tsaranazy, A, Cazanave, C, Furrer, H, Sagette, M, Rickenbach, M, Sculier, D, Calmy, A, Cavassini, M, Bruno, A, Bernasconi, E, Hoffmann, M, Vernazza, P, Fehr, J, Weber, R, Miller, R, Vora, N, Cooke, G, Mullaney, S, Wilkins, E, George, V, Collini, P, Dockrell, D, Post, F, Campbell, L, Brum, R, Mabonga, E, Saigal, P, Kegg, S, Ainsworth, J, Waters, A, Dhar, J, Ellis, K, Girardi, E, Rianda, A, Galati, V, Pinnetti, C, Tommasi, C, Lapadula, G, Di Biagio, A, Parisini, A, Carbonara, S, Angarano, G, Purgatorio, M, Matteelli, A, Apostoli, A, Miro, J, Manzardo, C, Ligero, C, Gonzalez, J, Martinez-Martinez, J, Sanchez, F, Knobel, H, Salvado, M, Lopez-Colomes, J, Martinez-Lacasa, X, Cuchi, E, Falco, V, Curran, A, Tortola, M, Ocana, I, Vidal, R, Sambeat, M, Pomar, V, Coll, P, Pozamczer, D, Saumoy, M, Alcaide, F, Cayla, J, Moreno, A, Millet, J, Orcau, A, Fina, L, Romero, A, Roldan, L, Iribarren, J, Ibarguren, M, Moreno, S, Gonzalez, A, Miralles, P, Aldamiz-Echevarria, T, Losso, M, Toibaro, J, Gambardella, L, Moreno Macias, L, Warley, E, Tavella, S, Garcia Messina, O, Gear, O, Laplume, H, Marson, C, Contarelia, J, Michaan, M, Scapellato, P, Bartoletti, B, Palmero, D, Elias, C, Cortes, C, Crabtree, B, Mosqueda Gomez, J, Villanueva, J, Gonzalez Hernandez, L, and Badial, F

Subjects
medicine.medical_specialty, Tuberculosis, Delayed Diagnosis, Aged, Europe, Eastern, Humans, Middle Aged, Prospective Studies, HIV Infections, Tuberculosi, Epidemiology, Tuberculosis/diagnosis, HIV Infections/complications, Infectious and parasitic diseases, RC109-216, Eastern Europe, Eastern, Logistic regression, Europa de l'Est, Medical microbiology, Weight loss, Internal medicine, medicine, VIH (Virus), HIV Infection, Europe, Eastern/epidemiology, Prospective cohort study, Epidemiologia, business.industry, Proportional hazards model, Transmission (medicine), HIV (Viruses), Research, Hazard ratio, Delayed Diagnosi, medicine.disease, Europe, Prospective Studie, Infectious Diseases, medicine.symptom, business, Human
Abstract

Background Early diagnosis of tuberculosis (TB) is important to reduce transmission, morbidity and mortality in people living with HIV (PLWH). Methods PLWH with a diagnosis of TB were enrolled from HIV and TB clinics in Eastern Europe and followed until 24 months. Delayed diagnosis was defined as duration of TB symptoms (cough, weight-loss or fever) for ≥ 1 month before TB diagnosis. Risk factors for delayed TB diagnosis were assessed using multivariable logistic regression. The effect of delayed diagnosis on mortality was assessed using Kaplan–Meier estimates and Cox models. Findings 480/740 patients (64.9%; 95% CI 61.3–68.3%) experienced a delayed diagnosis. Age ≥ 50 years (vs. Conclusion Nearly two thirds of PLWH with TB in Eastern Europe had a delayed TB diagnosis, in particular those of older age, people who inject drugs, ART naïve, with disseminated disease, and presenting with weight loss. Patients with delayed TB diagnosis were subsequently at higher risk of death in unadjusted analysis. There is a need for optimisation of the current TB diagnostic cascade and HIV care in PLWH in Eastern Europe.

Published
2021

29. Management of MDR-TB in HIV co-infected patients in Eastern Europe: Results from the TB:HIV study

Author

A.M.W. Efsen, A. Schultze, R.F. Miller, A. Panteleev, A. Skrahin, D.N. Podlekareva, J.M. Miro, E. Girardi, H. Furrer, M.H. Losso, J. Toibaro, J.A. Caylà, A. Mocroft, J.D. Lundgren, F.A. Post, O. Kirk, I. Karpov, A. Vassilenko, A. Skrahina, D. Klimuk, O. Kondratenko, A. Zalutskaya, V. Bondarenko, V. Mitsura, E. Kozorez, O. Tumash, O. Suetnov, D. Paduto, V. Iljina, T. Kummik, N. Bolokadze, K. Mshvidobadze, N. Lanchava, L. Goginashvili, L. Mikiashvili, N. Bablishvili, B. Rozentale, I. Zeltina, I. Janushkevich, I. Caplinskiene, S. Caplinskas, Z. Kancauskiene, R. Podlasin, A. Wiercinska-Drapalo, M. Thompson, J. Kozlowska, A. Grezesczuk, M. Bura, B. Knysz, M. Inglot, A. Garlicki, J. Loster, S. Tetradov, D. Duiculescu, A. Rakhmanova, O. Panteleeva, A. Yakovlev, A. Kozlov, A. Tyukalova, Y. Vlasova, T. Trofimov, G. Kyselyova, A.B. Andersen, K. Thorsteinsson, M.C. Payen, K. Kabeya, C. Necsoi, F. Dabis, M. Bruyand, P. Morlat, A. Dupont, Y. Gerard, F. Bonnal, J. Ceccaldi, S. De Witte, E. Monlun, P. Lataste, I. Chossat, R. Miller, N. Vora, G. Cooke, S. Mullaney, E. Wilkins, V. George, P. Collini, D. Dockrell, F. Post, L. Campbell, R. Brum, E. Mabonga, P. Saigal, S. Kegg, J. Ainsworth, A. Waters, J. Dhar, L. Mashonganyika, A. Rianda, V. Galati, C. Pinnetti, C. Tommasi, G. Lapadula, A. Di Biagio, A. Parisini, S. Carbonara, G. Angarano, M. Purgatorio, A. Matteelli, A. Apostoli, L. Moreno Macias, E. Warley, S. Tavella, O. Garcia Messina, O. Gear, H. Laplume, C. Marson, J. Contarelia, M. Michaan, P. Scapellato, D.D. Alessandro, B. Bartoletti, D. Palmero, C. Elias, C. Cortes, B. Crabtree, J.L. Mosqueda Gomez, A. Villanueva, L.A. Gonzalez Hernandez, Universitat de Barcelona, Efsen, A, Schultze, A, Miller, R, Panteleev, A, Skrahin, A, Podlekareva, D, Miro, J, Girardi, E, Furrer, H, Losso, M, Toibaro, J, Cayla, J, Mocroft, A, Lundgren, J, Post, F, Kirk, O, Karpov, I, Vassilenko, A, Skrahina, A, Klimuk, D, Kondratenko, O, Zalutskaya, A, Bondarenko, V, Mitsura, V, Kozorez, E, Tumash, O, Suetnov, O, Paduto, D, Iljina, V, Kummik, T, Bolokadze, N, Mshvidobadze, K, Lanchava, N, Goginashvili, L, Mikiashvili, L, Bablishvili, N, Rozentale, B, Zeltina, I, Janushkevich, I, Caplinskiene, I, Caplinskas, S, Kancauskiene, Z, Podlasin, R, Wiercinska-Drapalo, A, Thompson, M, Kozlowska, J, Grezesczuk, A, Bura, M, Knysz, B, Inglot, M, Garlicki, A, Loster, J, Tetradov, S, Duiculescu, D, Rakhmanova, A, Panteleeva, O, Yakovlev, A, Kozlov, A, Tyukalova, A, Vlasova, Y, Trofimov, T, Kyselyova, G, Andersen, A, Thorsteinsson, K, Payen, M, Kabeya, K, Necsoi, C, Dabis, F, Bruyand, M, Morlat, P, Dupont, A, Gerard, Y, Bonnal, F, Ceccaldi, J, De Witte, S, Monlun, E, Lataste, P, Chossat, I, Vora, N, Cooke, G, Mullaney, S, Wilkins, E, George, V, Collini, P, Dockrell, D, Campbell, L, Brum, R, Mabonga, E, Saigal, P, Kegg, S, Ainsworth, J, Waters, A, Dhar, J, Mashonganyika, L, Rianda, A, Galati, V, Pinnetti, C, Tommasi, C, Lapadula, G, Di Biagio, A, Parisini, A, Carbonara, S, Angarano, G, Purgatorio, M, Matteelli, A, Apostoli, A, Macias, L, Warley, E, Tavella, S, Garcia Messina, O, Gear, O, Laplume, H, Marson, C, Contarelia, J, Michaan, M, Scapellato, P, Alessandro, D, Bartoletti, B, Palmero, D, Elias, C, Cortes, C, Crabtree, B, Mosqueda Gomez, J, Villanueva, A, and Gonzalez Hernandez, L

Subjects
Male, Pediatrics, Art initiation, Antitubercular Agents, Human immunodeficiency virus (HIV), HIV Infections, Hiv management, Eastern, medicine.disease_cause, Cohort Studies, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, Tuberculosis, Multidrug-Resistant, Health care, Medicine, Europe, Eastern, Prospective Studies, 030212 general & internal medicine, Viral suppression, Prospective cohort study, Coinfection, Disease Management, Multidrug-Resistant, 3. Good health, Europe, Infectious Diseases, Female, Eastern Europe, HIV, MDR-TB, Tuberculosis, Microbiology (medical), Viral load, HIV infections, Adult, medicine.medical_specialty, Anti-HIV Agents, Tuberculosi, Antiretroviral Therapy, Article, 03 medical and health sciences, Humans, Highly Active, business.industry, medicine.disease, 030228 respiratory system, Infeccions per VIH, business
Abstract

Summary Objectives Mortality among HIV patients with tuberculosis (TB) remains high in Eastern Europe (EE), but details of TB and HIV management remain scarce. Methods In this prospective study, we describe the TB treatment regimens of patients with multi-drug resistant (MDR) TB and use of antiretroviral therapy (ART). Results A total of 105 HIV-positive patients had MDR-TB (including 33 with extensive drug resistance) and 130 pan-susceptible TB. Adequate initial TB treatment was provided for 8% of patients with MDR-TB compared with 80% of those with pan-susceptible TB. By twelve months, an estimated 57.3% (95%CI 41.5–74.1) of MDR-TB patients had started adequate treatment. While 67% received ART, HIV-RNA suppression was demonstrated in only 23%. Conclusions Our results show that internationally recommended MDR-TB treatment regimens were infrequently used and that ART use and viral suppression was well below the target of 90%, reflecting the challenging patient population and the environment in which health care is provided. Urgent improvement of management of patients with TB/HIV in EE, in particular for those with MDR-TB, is needed and includes widespread access to rapid TB diagnostics, better access to and use of second-line TB drugs, timely ART initiation with viral load monitoring, and integration of TB/HIV care.

Published
2017

30. EFFICACY AND SAFETY OF SILVER NANOCOMPOSITES ON RIFAMPICIN-RESISTANT M. TUBERCULOSIS STRAINS.

Author

Kiria N, Avaliani T, Bablishvili N, Chichiveishvili N, Phichkhaia G, Sharvadze L, and Kiria N

Subjects
Animals, Humans, Microbial Sensitivity Tests, Drug Resistance, Bacterial drug effects, Tuberculosis, Multidrug-Resistant drug therapy, Tuberculosis, Multidrug-Resistant microbiology, Antitubercular Agents pharmacology, Antibiotics, Antitubercular pharmacology, Rifampin pharmacology, Silver chemistry, Silver pharmacology, Nanocomposites chemistry, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis growth & development, Metal Nanoparticles chemistry, Metal Nanoparticles therapeutic use
Abstract

Background: Control of rifampicin-resistant tuberculosis (RR-MTB) requires novel technologies for restoring the anti-TB efficacy of priority drugs. We sought to evaluate the ability of nanotechnology application in the recovery of the anti-tuberculosis efficacy of rifampicin., Methods: Nanocomposite- standard dose of rifampicin and 20 nm silver nanoparticles (AgNPs) suspension solution of 6 different concentrations: 0.25%; 0.5%; 1%; 2.5%; 5%; and 10%, were supplemented to 70 rifampicin-resistant mycobacterium tuberculosis (RR-MTB) isolates. The control arm consisted of 35 RR-MTB isolates and AgNPs suspension with identical concentrations. The inhibitory effect of nanocomposites was evaluated by MTB growth rate using the BACTECTM MGIT 960TM. The safety assessment of single-use AgNPs was conducted in experimental animals., Results: The suppression process of AgNPs on RR-MTB isolates started with 2,5% nanocomposite solution application and full suppression was achieved in 5% and 10% nanocomposite solutions. A standard dose of rifampicin and a 2.5% solution of AgNPs increased the minimal inhibitory effect on RR-MTB by 10% (total 80%) vs the isolated use of a 2.5% solution of AgNPs (70%). An experiment on animals revealed the complete safety of a single injection of ultra-high doses of AgNPs., Conclusion: The study showed the potentiating effect of AgNPs in overcoming the resistance of MTB to rifampicin providing a scientific basis for further research.

Published
2024

31. Linezolid Exposure Is Associated with Cytopenias in Patients Treated for Multidrug-Resistant Tuberculosis.

Author

Graciaa DS, Kipiani M, Magee MJ, Mikiashvili L, Barbakadze K, Bablishvili N, Auld SC, Alghamdi WA, Alshaer MH, Peloquin CA, Avaliani Z, Blumberg HM, and Kempker RR

Subjects
Humans, Incidence, Linezolid adverse effects, Prospective Studies, Antitubercular Agents adverse effects, Tuberculosis, Multidrug-Resistant drug therapy
Abstract

Although linezolid is effective for multidrug-resistant TB (MDR-TB) tuberculosis treatment, it is associated with cytopenias after 4 weeks of administration. Data on toxicities with long-term use of linezolid and drug pharmacodynamics in MDR-TB treatment are limited, and concerns about toxicity present barriers to wider implementation. This was a secondary analysis of a prospective cohort study of patients treated for MDR-TB in the country of Georgia from 2015 to 2017. Intensive blood sampling 4 to 6 weeks after treatment initiation with linezolid 600 mg daily was performed for pharmacokinetic (PK) analysis, including linezolid trough concentration ( C min ) and area under the curve from 0 to 24 hours (AUC 0-24 ). Linezolid exposure was defined using literature-reported thresholds. Cytopenias were defined using an NIH adverse event (AE) scale. Logistic regression was used to evaluate the relationship between linezolid exposure and cytopenias. Among 76 patients receiving linezolid in their baseline treatment regimen and who had PK data available, cytopenia AEs occurred in 30 (39.5%) for an incidence rate of 46 per 100 person-years. The median duration of linezolid therapy was 526 days. No patients required dose reduction or interruption due to cytopenias. Median linezolid C min was 0.235 mg/L (interquartile range [IQR], 0.069 to 0.529), and median AUC 0-24 was 89.6 mg·h/L (IQR, 69.2 to 116.2). Cytopenias were associated with linezolid PK parameters ( C min  > 2 mg/L and AUC 0-24  > 160 mg·h/L). Cytopenias occurred frequently with long-term use of linezolid 600 mg/day and were associated with PK parameters but did not result in the need for treatment interruption in the management of a cohort of patients with MDR-TB.

Published
2022
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32. Investigating resistance in clinical Mycobacterium tuberculosis complex isolates with genomic and phenotypic antimicrobial susceptibility testing: a multicentre observational study.

Author

Finci I, Albertini A, Merker M, Andres S, Bablishvili N, Barilar I, Cáceres T, Crudu V, Gotuzzo E, Hapeela N, Hoffmann H, Hoogland C, Kohl TA, Kranzer K, Mantsoki A, Maurer FP, Nicol MP, Noroc E, Plesnik S, Rodwell T, Ruhwald M, Savidge T, Salfinger M, Streicher E, Tukvadze N, Warren R, Zemanay W, Zurek A, Niemann S, and Denkinger CM

Subjects
Antitubercular Agents pharmacology, Genomics, Humans, Phenotype, Prospective Studies, Rifampin pharmacology, Mycobacterium tuberculosis genetics, Tuberculosis drug therapy, Tuberculosis, Multidrug-Resistant diagnosis
Abstract

Background: Whole-genome sequencing (WGS) of Mycobacterium tuberculosis complex has become an important tool in diagnosis and management of drug-resistant tuberculosis. However, data correlating resistance genotype with quantitative phenotypic antimicrobial susceptibility testing (AST) are scarce., Methods: In a prospective multicentre observational study, 900 clinical M tuberculosis complex isolates were collected from adults with drug-resistant tuberculosis in five high-endemic tuberculosis settings around the world (Georgia, Moldova, Peru, South Africa, and Viet Nam) between Dec 5, 2014, and Dec 12, 2017. Minimum inhibitory concentrations (MICs) and resulting binary phenotypic AST results for up to nine antituberculosis drugs were determined and correlated with resistance-conferring mutations identified by WGS., Findings: Considering WHO-endorsed critical concentrations as reference, WGS had high accuracy for prediction of resistance to isoniazid (sensitivity 98·8% [95% CI 98·5-99·0]; specificity 96·6% [95% CI 95·2-97·9]), levofloxacin (sensitivity 94·8% [93·3-97·6]; specificity 97·1% [96·7-97·6]), kanamycin (sensitivity 96·1% [95·4-96·8]; specificity 95·0% [94·4-95·7]), amikacin (sensitivity 97·2% [96·4-98·1]; specificity 98·6% [98·3-98·9]), and capreomycin (sensitivity 93·1% [90·0-96·3]; specificity 98·3% [98·0-98·7]). For rifampicin, pyrazinamide, and ethambutol, the specificity of resistance prediction was suboptimal (64·0% [61·0-67·1], 83·8% [81·0-86·5], and 40·1% [37·4-42·9], respectively). Specificity for rifampicin increased to 83·9% when borderline mutations with MICs overlapping with the critical concentration were excluded. Consequently, we highlighted mutations in M tuberculosis complex isolates that are often falsely identified as susceptible by phenotypic AST, and we identified potential novel resistance-conferring mutations., Interpretation: The combined analysis of mutations and quantitative phenotypes shows the potential of WGS to produce a refined interpretation of resistance, which is needed for individualised therapy, and eventually could allow differential drug dosing. However, variability of MIC data for some M tuberculosis complex isolates carrying identical mutations also reveals limitations of our understanding of the genotype and phenotype relationships (eg, including epistasis and strain genetic background)., Funding: Bill & Melinda Gates Foundation, German Centre for Infection Research, German Research Foundation, Excellence Cluster Precision Medicine of Inflammation (EXC 2167), and Leibniz ScienceCampus EvoLUNG., Competing Interests: Declaration of interests MM and SN report grants from the German Center for Infection Research, Excellenz Cluster Precision Medicine in Chronic Inflammation, and Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG). TR reports personal fees from FIND, grants from the US National Institute of Allergy and Infectious Diseases, and is a board member for Verus Diagnostics; and has a provisional patent (#63/048.989) and a pending patent (#14840432.0) for tuberculosis diagnostics. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Published
2022
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33. Genomic analyses of Mycobacterium tuberculosis from human lung resections reveal a high frequency of polyclonal infections.

Author

Moreno-Molina M, Shubladze N, Khurtsilava I, Avaliani Z, Bablishvili N, Torres-Puente M, Villamayor L, Gabrielian A, Rosenthal A, Vilaplana C, Gagneux S, Kempker RR, Vashakidze S, and Comas I

Subjects
Antitubercular Agents therapeutic use, Biopsy, Clone Cells, Cohort Studies, Genetic Variation, Georgia (Republic), Granuloma drug therapy, Granuloma microbiology, Granuloma surgery, Humans, Lung microbiology, Lung pathology, Lung surgery, Mycobacterium tuberculosis classification, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis pathogenicity, Reactive Oxygen Species metabolism, Sputum microbiology, Tuberculosis, Multidrug-Resistant drug therapy, Tuberculosis, Multidrug-Resistant microbiology, Tuberculosis, Multidrug-Resistant surgery, Tuberculosis, Pulmonary drug therapy, Tuberculosis, Pulmonary microbiology, Tuberculosis, Pulmonary surgery, Drug Resistance, Multiple, Bacterial genetics, Genome, Bacterial, Granuloma pathology, Mycobacterium tuberculosis genetics, Tuberculosis, Multidrug-Resistant pathology, Tuberculosis, Pulmonary pathology
Abstract

Polyclonal infections occur when at least two unrelated strains of the same pathogen are detected in an individual. This has been linked to worse clinical outcomes in tuberculosis, as undetected strains with different antibiotic resistance profiles can lead to treatment failure. Here, we examine the amount of polyclonal infections in sputum and surgical resections from patients with tuberculosis in the country of Georgia. For this purpose, we sequence and analyse the genomes of Mycobacterium tuberculosis isolated from the samples, acquired through an observational clinical study (NCT02715271). Access to the lung enhanced the detection of multiple strains (40% of surgery cases) as opposed to just using a sputum sample (0-5% in the general population). We show that polyclonal infections often involve genetically distant strains and can be associated with reversion of the patient's drug susceptibility profile over time. In addition, we find different patterns of genetic diversity within lesions and across patients, including mutational signatures known to be associated with oxidative damage; this suggests that reactive oxygen species may be acting as a selective pressure in the granuloma environment. Our results support the idea that the magnitude of polyclonal infections in high-burden tuberculosis settings is underestimated when only testing sputum samples.

Published
2021
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34. A comparison of linezolid lung tissue concentrations among patients with drug-resistant tuberculosis.

Author

Kempker RR, Heinrichs MT, Nikolaishvili K, Sabulua I, Bablishvili N, Gogishvili S, Avaliani Z, Little BP, Bernheim A, Derendorf H, Blumberg HM, Vashakidze S, and Peloquin CA

Subjects
Adult, Antitubercular Agents administration & dosage, Humans, Linezolid administration & dosage, Male, Mycobacterium tuberculosis drug effects, Antitubercular Agents pharmacokinetics, Extensively Drug-Resistant Tuberculosis drug therapy, Linezolid pharmacokinetics, Tuberculosis, Multidrug-Resistant drug therapy
Abstract

Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com

Published
2018
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35. Moxifloxacin target site concentrations in patients with pulmonary TB utilizing microdialysis: a clinical pharmacokinetic study.

Author

Heinrichs MT, Vashakidze S, Nikolaishvili K, Sabulua I, Tukvadze N, Bablishvili N, Gogishvili S, Little BP, Bernheim A, Guarner J, Peloquin CA, Blumberg HM, Derendorf H, and Kempker RR

Subjects
Adult, Female, Georgia (Republic), Humans, Lung chemistry, Male, Microdialysis, Middle Aged, Serum chemistry, Topoisomerase II Inhibitors, Young Adult, Antitubercular Agents administration & dosage, Antitubercular Agents pharmacokinetics, Moxifloxacin administration & dosage, Moxifloxacin pharmacokinetics, Tuberculosis, Multidrug-Resistant drug therapy, Tuberculosis, Pulmonary drug therapy
Abstract

Background: Moxifloxacin is a second-line anti-TB drug that is useful in the treatment of drug-resistant TB. However, little is known about its target site pharmacokinetics. Lower drug concentrations at the infection site (i.e. in severe lung lesions including cavitary lesions) may lead to development and amplification of drug resistance. Improved knowledge regarding tissue penetration of anti-TB drugs will help guide drug development and optimize drug dosing., Methods: Patients with culture-confirmed drug-resistant pulmonary TB scheduled to undergo adjunctive surgical lung resection were enrolled in Tbilisi, Georgia. Five serum samples per patient were collected at different timepoints including at the time of surgical resection (approximately at Tmax). Microdialysis was performed in the ex vivo tissue immediately after resection. Non-compartmental analysis was performed and a tissue/serum concentration ratio was calculated., Results: Among the seven patients enrolled, the median moxifloxacin dose given was 7.7 mg/kg, the median age was 25.2 years, 57% were male and the median creatinine clearance was 95.4 mL/min. Most patients (71%) had suboptimal steady-state serum Cmax (total drug) concentrations. The median free moxifloxacin serum concentration at time of surgical resection was 1.23 μg/mL (range = 0.12-1.80) and the median free lung tissue concentration was 3.37 μg/mL (range = 0.81-5.76). The median free-tissue/free-serum concentration ratio was 3.20 (range = 0.66-28.08)., Conclusions: Moxifloxacin showed excellent penetration into diseased lung tissue (including cavitary lesions) among patients with pulmonary TB. Moxifloxacin lung tissue concentrations were higher than those seen in serum. Our findings highlight the importance of moxifloxacin in the treatment of MDR-TB and potentially any patient with pulmonary TB and severe lung lesions., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2018
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36. Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective multicentre diagnostic accuracy study.

Author

Dorman SE, Schumacher SG, Alland D, Nabeta P, Armstrong DT, King B, Hall SL, Chakravorty S, Cirillo DM, Tukvadze N, Bablishvili N, Stevens W, Scott L, Rodrigues C, Kazi MI, Joloba M, Nakiyingi L, Nicol MP, Ghebrekristos Y, Anyango I, Murithi W, Dietze R, Lyrio Peres R, Skrahina A, Auchynka V, Chopra KK, Hanif M, Liu X, Yuan X, Boehme CC, Ellner JJ, and Denkinger CM

Subjects
Adult, Africa, Asia, Bacteriological Techniques methods, Brazil, Europe, Female, Humans, Male, Middle Aged, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis genetics, Prospective Studies, Sensitivity and Specificity, Sputum microbiology, Antibiotics, Antitubercular pharmacology, Drug Resistance, Bacterial, Molecular Diagnostic Techniques methods, Mycobacterium tuberculosis isolation & purification, Rifampin pharmacology, Tuberculosis, Multidrug-Resistant diagnosis, Tuberculosis, Pulmonary diagnosis
Abstract

Background: The Xpert MTB/RIF assay is an automated molecular test that has improved the detection of tuberculosis and rifampicin resistance, but its sensitivity is inadequate in patients with paucibacillary disease or HIV. Xpert MTB/RIF Ultra (Xpert Ultra) was developed to overcome this limitation. We compared the diagnostic performance of Xpert Ultra with that of Xpert for detection of tuberculosis and rifampicin resistance., Methods: In this prospective, multicentre, diagnostic accuracy study, we recruited adults with pulmonary tuberculosis symptoms presenting at primary health-care centres and hospitals in eight countries (South Africa, Uganda, Kenya, India, China, Georgia, Belarus, and Brazil). Participants were allocated to the case detection group if no drugs had been taken for tuberculosis in the past 6 months or to the multidrug-resistance risk group if drugs for tuberculosis had been taken in the past 6 months, but drug resistance was suspected. Demographic information, medical history, chest imaging results, and HIV test results were recorded at enrolment, and each participant gave at least three sputum specimen on 2 separate days. Xpert and Xpert Ultra diagnostic performance in the same sputum specimen was compared with culture tests and drug susceptibility testing as reference standards. The primary objectives were to estimate and compare the sensitivity of Xpert Ultra test with that of Xpert for detection of smear-negative tuberculosis and rifampicin resistance and to estimate and compare Xpert Ultra and Xpert specificities for detection of rifampicin resistance. Study participants in the case detection group were included in all analyses, whereas participants in the multidrug-resistance risk group were only included in analyses of rifampicin-resistance detection., Findings: Between Feb 18, and Dec 24, 2016, we enrolled 2368 participants for sputum sampling. 248 participants were excluded from the analysis, and 1753 participants were distributed to the case detection group (n=1439) and the multidrug-resistance risk group (n=314). Sensitivities of Xpert Ultra and Xpert were 63% and 46%, respectively, for the 137 participants with smear-negative and culture-positive sputum (difference of 17%, 95% CI 10 to 24); 90% and 77%, respectively, for the 115 HIV-positive participants with culture-positive sputum (13%, 6·4 to 21); and 88% and 83%, respectively, across all 462 participants with culture-positive sputum (5·4%, 3·3 to 8·0). Specificities of Xpert Ultra and Xpert for case detection were 96% and 98% (-2·7%, -3·9 to -1·7) overall, and 93% and 98% for patients with a history of tuberculosis. Xpert Ultra and Xpert performed similarly in detecting rifampicin resistance., Interpretation: For tuberculosis case detection, sensitivity of Xpert Ultra was superior to that of Xpert in patients with paucibacillary disease and in patients with HIV. However, this increase in sensitivity came at the expense of a decrease in specificity., Funding: Government of Netherlands, Government of Australia, Bill & Melinda Gates Foundation, Government of the UK, and the National Institute of Allergy and Infectious Diseases., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Published
2018
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37. Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis.

Author

Kempker RR, Heinrichs MT, Nikolaishvili K, Sabulua I, Bablishvili N, Gogishvili S, Avaliani Z, Tukvadze N, Little B, Bernheim A, Read TD, Guarner J, Derendorf H, Peloquin CA, Blumberg HM, and Vashakidze S

Subjects
Adolescent, Adult, Female, Humans, Isoniazid therapeutic use, Lung metabolism, Male, Middle Aged, Mycobacterium tuberculosis drug effects, Rifampin therapeutic use, Young Adult, Antitubercular Agents pharmacokinetics, Antitubercular Agents therapeutic use, Pyrazinamide pharmacokinetics, Pyrazinamide therapeutic use, Tuberculosis, Multidrug-Resistant drug therapy, Tuberculosis, Pulmonary drug therapy
Abstract

Improved knowledge regarding the tissue penetration of antituberculosis drugs may help optimize drug management. Patients with drug-resistant pulmonary tuberculosis undergoing adjunctive surgery were enrolled. Serial serum samples were collected, and microdialysis was performed using ex vivo lung tissue to measure pyrazinamide concentrations. Among 10 patients, the median pyrazinamide dose was 24.7 mg/kg of body weight. Imaging revealed predominant lung lesions as cavitary ( n = 6 patients), mass-like ( n = 3 patients), or consolidative ( n = 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of ≤5.5. Tissue samples from two patients were positive for Mycobacterium tuberculosis by culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60 μg/ml. The median lung tissue free pyrazinamide concentration was 20.96 μg/ml. The median tissue-to-serum pyrazinamide concentration ratio was 0.77 (range, 0.54 to 0.93). There was a significant inverse correlation between tissue pyrazinamide concentrations and the amounts of necrosis ( R = -0.66, P = 0.04) and acid-fast bacilli ( R = -0.75, P = 0.01) identified by histopathology. We found good penetration of pyrazinamide into lung tissue among patients with pulmonary tuberculosis with a variety of radiological lesion types. Our tissue pH results revealed that most lesions had a pH conducive to pyrazinamide activity. The tissue penetration of pyrazinamide highlights its importance in both drug-susceptible and drug-resistant antituberculosis treatment regimens., (Copyright © 2017 American Society for Microbiology.)

Published
2017
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38. pncA Gene Mutations Associated with Pyrazinamide Resistance in Drug-Resistant Tuberculosis, South Africa and Georgia.

Author

Allana S, Shashkina E, Mathema B, Bablishvili N, Tukvadze N, Shah NS, Kempker RR, Blumberg HM, Moodley P, Mlisana K, Brust JC, and Gandhi NR

Subjects
Amidohydrolases genetics, Extensively Drug-Resistant Tuberculosis microbiology, Georgia (Republic) epidemiology, Humans, Mutation, South Africa epidemiology, Amidohydrolases metabolism, Antitubercular Agents pharmacology, Drug Resistance, Multiple, Bacterial genetics, Extensively Drug-Resistant Tuberculosis epidemiology, Pyrazinamide pharmacology
Abstract

Although pyrazinamide is commonly used for tuberculosis treatment, drug-susceptibility testing is not routinely available. We found polymorphisms in the pncA gene for 70% of multidrug-resistant and 96% of extensively drug-resistant Mycobacterium tuberculosis isolates from South Africa and Georgia. Assessment of pyrazinamide susceptibility may be prudent before using it in regimens for drug-resistant tuberculosis.

Published
2017
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39. High-throughput mycobacterial interspersed repetitive-unit-variable-number tandem-repeat genotyping for Mycobacterium tuberculosis epidemiological studies.

Author

Gauthier M, Bidault F, Mosnier A, Bablishvili N, Tukvadze N, Somphavong S, Paboriboune P, Ocheretina O, Pape JW, Paranhos-Baccala G, and Berland JL

Subjects
Automation, Laboratory methods, High-Throughput Screening Assays, Humans, Molecular Epidemiology methods, Reproducibility of Results, Time Factors, Tuberculosis epidemiology, Genotyping Techniques, Minisatellite Repeats, Molecular Typing methods, Mycobacterium tuberculosis classification, Mycobacterium tuberculosis genetics, Tuberculosis microbiology
Abstract

The emergence of drug-resistant forms of tuberculosis (TB) represents a major public health concern. Understanding the transmission routes of the disease is a key factor for its control and for the implementation of efficient interventions. Mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) marker typing is a well-described method for lineage identification and transmission tracking. However, the conventional manual genotyping technique is cumbersome and time-consuming and entails many risks for errors, thus hindering its implementation and dissemination. We describe here a new approach using the QIAxcel system, an automated high-throughput capillary electrophoresis system that also carries out allele calling. This automated method was assessed on 1,824 amplicons from 82 TB isolates and tested with sets of markers of 15 or 24 loci. Overall allele-calling concordance between the methods from 140 to 1,317 bp was 98.9%. DNA concentrations and repeatability and reproducibility performances showed no biases in allele calling. Furthermore, turnaround time using this automated system was reduced by 81% compared to the conventional manual agarose gel method. In sum, this new automated method facilitates MIRU-VNTR genotyping and provides reliable results. Therefore, it is well suited for field genotyping. The implementation of this method will help to achieve accurate and cost-effective epidemiological studies, especially in countries with a high prevalence of TB, where the high number of strains complicates the surveillance of circulating lineages and requires efficient interventions to be carried out in an urgent manner., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Published
2015
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40. Cavitary penetration of levofloxacin among patients with multidrug-resistant tuberculosis.

Author

Kempker RR, Barth AB, Vashakidze S, Nikolaishvili K, Sabulua I, Tukvadze N, Bablishvili N, Gogishvili S, Singh RS, Guarner J, Derendorf H, Peloquin CA, and Blumberg HM

Subjects
Adolescent, Adult, Antitubercular Agents blood, Female, Humans, Levofloxacin blood, Male, Middle Aged, Young Adult, Antitubercular Agents pharmacokinetics, Antitubercular Agents therapeutic use, Levofloxacin pharmacokinetics, Levofloxacin therapeutic use, Tuberculosis, Multidrug-Resistant blood, Tuberculosis, Multidrug-Resistant drug therapy
Abstract

A better understanding of second-line drug (SLD) pharmacokinetics, including cavitary penetration, may help optimize SLD dosing. Patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) undergoing adjunctive surgery were enrolled in Tbilisi, Georgia. Serum was obtained at 0, 1, 4, and 8 h and at the time of cavitary removal to measure levofloxacin concentrations. After surgery, microdialysis was performed using the ex vivo cavity, and levofloxacin concentrations in the collected dialysate fluid were measured. Noncompartmental analysis was performed, and a cavitary-to-serum levofloxacin concentration ratio was calculated. Twelve patients received levofloxacin for a median of 373 days before surgery (median dose, 11.8 mg/kg). The median levofloxacin concentration in serum (Cmax) was 6.5 μg/ml, and it was <2 μg/ml in 3 (25%) patients. Among 11 patients with complete data, the median cavitary concentration of levofloxacin was 4.36 μg/ml (range, 0.46 to 8.82). The median cavitary/serum levofloxacin ratio was 1.33 (range, 0.63 to 2.36), and 7 patients (64%) had a ratio of >1. There was a significant correlation between serum and cavitary concentrations (r = 0.71; P = 0.01). Levofloxacin had excellent penetration into chronic cavitary TB lesions, and there was a good correlation between serum and cavitary concentrations. Optimizing serum concentrations will help ensure optimal cavitary concentrations of levofloxacin, which may enhance treatment outcomes., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Published
2015
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41. Optimizing multiplex SNP-based data analysis for genotyping of Mycobacterium tuberculosis isolates.

Author

Sengstake S, Bablishvili N, Schuitema A, Bzekalava N, Abadia E, de Beer J, Tadumadze N, Akhalaia M, Tuin K, Tukvadze N, Aspindzelashvili R, Bachiyska E, Panaiotov S, Sola C, van Soolingen D, Klatser P, Anthony R, and Bergval I

Subjects
DNA, Bacterial genetics, DNA, Bacterial metabolism, Drug Resistance, Microbial genetics, Genetic Linkage, Genotype, Humans, Mycobacterium tuberculosis isolation & purification, Nucleic Acid Amplification Techniques methods, Nucleic Acid Amplification Techniques standards, Tuberculosis microbiology, Tuberculosis pathology, Mycobacterium tuberculosis genetics, Polymorphism, Single Nucleotide
Abstract

Background: Multiplex ligation-dependent probe amplification (MLPA) is a powerful tool to identify genomic polymorphisms. We have previously developed a single nucleotide polymorphism (SNP) and large sequence polymorphisms (LSP)-based MLPA assay using a read out on a liquid bead array to screen for 47 genetic markers in the Mycobacterium tuberculosis genome. In our assay we obtain information regarding the Mycobacterium tuberculosis lineage and drug resistance simultaneously. Previously we called the presence or absence of a genotypic marker based on a threshold signal level. Here we present a more elaborate data analysis method to standardize and streamline the interpretation of data generated by MLPA. The new data analysis method also identifies intermediate signals in addition to classification of signals as positive and negative. Intermediate calls can be informative with respect to identifying the simultaneous presence of sensitive and resistant alleles or infection with multiple different Mycobacterium tuberculosis strains., Results: To validate our analysis method 100 DNA isolates of Mycobacterium tuberculosis extracted from cultured patient material collected at the National TB Reference Laboratory of the National Center for Tuberculosis and Lung Diseases in Tbilisi, Republic of Georgia were tested by MLPA. The data generated were interpreted blindly and then compared to results obtained by reference methods. MLPA profiles containing intermediate calls are flagged for expert review whereas the majority of profiles, not containing intermediate calls, were called automatically. No intermediate signals were identified in 74/100 isolates and in the remaining 26 isolates at least one genetic marker produced an intermediate signal., Conclusion: Based on excellent agreement with the reference methods we conclude that the new data analysis method performed well. The streamlined data processing and standardized data interpretation allows the comparison of the Mycobacterium tuberculosis MLPA results between different experiments. All together this will facilitate the implementation of the MLPA assay in different settings.

Published
2014
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42. Draft Genome Sequence of Mycobacterium tuberculosis Clinical Strain G-12-005.

Author

Berland JL, de Carvalho FM, de Almeida LG, Bablishvili N, Gauthier M, Paranhos-Baccalà G, and de Vasconcelos AT

Abstract

Infection caused by drug-resistant Mycobacterium tuberculosis is a growing concern, especially in eastern Europe. We report an annotated draft genome sequence of M. tuberculosis strain G-12-005 obtained from a patient in Georgia.

Published
2014
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43. Use of a molecular diagnostic test in AFB smear positive tuberculosis suspects greatly reduces time to detection of multidrug resistant tuberculosis.

Author

Tukvadze N, Kempker RR, Kalandadze I, Kurbatova E, Leonard MK, Apsindzelashvili R, Bablishvili N, Kipiani M, and Blumberg HM

Subjects
Antitubercular Agents pharmacology, Georgia, Humans, Isoniazid pharmacology, Mutation, Reproducibility of Results, Sputum microbiology, Tuberculosis, Multidrug-Resistant genetics, Molecular Diagnostic Techniques methods, Tuberculosis, Multidrug-Resistant diagnosis
Abstract

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.

Published
2012
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44. Combined species identification, genotyping, and drug resistance detection of Mycobacterium tuberculosis cultures by MLPA on a bead-based array.

Author

Bergval I, Sengstake S, Brankova N, Levterova V, Abadía E, Tadumaze N, Bablishvili N, Akhalaia M, Tuin K, Schuitema A, Panaiotov S, Bachiyska E, Kantardjiev T, de Zwaan R, Schürch A, van Soolingen D, van 't Hoog A, Cobelens F, Aspindzelashvili R, Sola C, Klatser P, and Anthony R

Subjects
Drug Resistance, Bacterial genetics, Genotype, Polymorphism, Single Nucleotide genetics, Multiplex Polymerase Chain Reaction methods, Mycobacterium tuberculosis genetics
Abstract

The population structure of Mycobacterium tuberculosis is typically clonal therefore genotypic lineages can be unequivocally identified by characteristic markers such as mutations or genomic deletions. In addition, drug resistance is mainly mediated by mutations. These issues make multiplexed detection of selected mutations potentially a very powerful tool to characterise Mycobacterium tuberculosis. We used Multiplex Ligation-dependent Probe Amplification (MLPA) to screen for dispersed mutations, which can be successfully applied to Mycobacterium tuberculosis as was previously shown. Here we selected 47 discriminative and informative markers and designed MLPA probes accordingly to allow analysis with a liquid bead array and robust reader (Luminex MAGPIX technology). To validate the bead-based MLPA, we screened a panel of 88 selected strains, previously characterised by other methods with the developed multiplex assay using automated positive and negative calling. In total 3059 characteristics were screened and 3034 (99.2%) were consistent with previous molecular characterizations, of which 2056 (67.2%) were directly supported by other molecular methods, and 978 (32.0%) were consistent with but not directly supported by previous molecular characterizations. Results directly conflicting or inconsistent with previous methods, were obtained for 25 (0.8%) of the characteristics tested. Here we report the validation of the bead-based MLPA and demonstrate its potential to simultaneously identify a range of drug resistance markers, discriminate the species within the Mycobacterium tuberculosis complex, determine the genetic lineage and detect and identify the clinically most relevant non-tuberculous mycobacterial species. The detection of multiple genetic markers in clinically derived Mycobacterium tuberculosis strains with a multiplex assay could reduce the number of TB-dedicated screening methods needed for full characterization. Additionally, as a proportion of the markers screened are specific to certain Mycobacterium tuberculosis lineages each profile can be checked for internal consistency. Strain characterization can allow selection of appropriate treatment and thereby improve treatment outcome and patient management.

Published
2012
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45. Bioregulator Vilon-induced reactivation of chromatin in cultured lymphocytes from old people.

Author

Lezhava T, Khavison V, Monaselidze J, Jokhadze T, Dvalishvili N, Bablishvili N, and Barbakadze S

Subjects
Adult, Aged, Aged, 80 and over, Calorimetry, Differential Scanning, Cells, Cultured, Gene Expression Regulation, Heterochromatin chemistry, Heterochromatin metabolism, Humans, Lymphocytes cytology, Nucleic Acid Conformation, Polymorphism, Genetic, Ribosomes genetics, Ribosomes metabolism, Aging physiology, Dipeptides pharmacology, Heterochromatin drug effects, Lymphocytes metabolism
Abstract

The effect of the synthetic peptide bioregulator Vilon on structural and facultative heterochromatin of cultured lymphocytes from old people has been studied. The data obtained indicate that Vilon (a) induces unrolling (deheterochromatinization) of total heterochromatin; (b) activates synthetic processes caused by the reactivation of ribosomal genes as a result of deheterochromatinization of nucleolus organizer regions; (c) releases the genes repressed due to the condensation of euchromatic regions forming facultative heterochromatin; (d) does not induce decondensation of pericentromeric structural heterochromatin. Our results indicate that Vilon causes progressive activation (deheterochromatinization) of the facultative heterochromatin with increased aging., (Copyright 2004 Kluwer Academic Publishers)

Published
2004
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