GenoType<sup>®</sup> MTBDR<i>sl</i> assay for resistance to second‐line anti‐tuberculosis drugs

Grant Theron; Jonny Peter; Marty Richardson; Rob Warren; Keertan Dheda; Karen R Steingart

doi:10.1002/14651858.CD010705.pub3

Prueba GenoType^® MTBDRsl para la resistencia a los fármacos antituberculosos de segunda línea

Declaraciones de intereses de los autores

Versión publicada: 08 septiembre 2016 Historial de versiones

https://doi.org/10.1002/14651858.CD010705.pub3

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Resumen

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Antecedentes

GenoType® MTBDRsl (MTBDRsl) es una prueba rápida basada en el ADN para la detección de mutaciones específicas asociadas con la resistencia a las fluoroquinolonas y a los fármacos inyectables de segunda línea (FISL) en el complejo Mycobacterium tuberculosis. La versión 2.0 de la MTBDRsl (comercializada en 2015) identifica las mutaciones detectadas por la versión 1.0, así como mutaciones adicionales. La prueba se puede realizar en un aislado de cultivo o en una muestra del paciente, lo que elimina los retrasos asociados con el cultivo. La versión 1.0 requiere una muestra con baciloscopia positiva, mientras que la versión 2.0 puede utilizar una muestra con baciloscopia positiva o negativa. Esta revisión actualizada se realizó como parte de un proceso de la Organización Mundial de la Salud para formular las guías actualizadas para el uso de la MTBDRsl.

Objetivos

Evaluar y comparar la exactitud diagnóstica de la MTBDRsl para: 1. la resistencia a fluoroquinolonas, 2. la resistencia a los FISL, y 3. la tuberculosis de alta resistencia a los fármacos, indirectamente en un aislado de M. tuberculosis obtenido de un cultivo o directamente de la muestra de un paciente. Los participantes fueron pacientes con tuberculosis resistente a la rifampicina o resistente a múltiples fármacos. La función de la MTBDRsl sería una prueba inicial que reemplaza a la prueba de susceptibilidad farmacológica (PSF) basada en cultivo, para detectar la farmacorresistencia de segunda línea.

Métodos de búsqueda

Se realizaron búsquedas en las siguientes bases de datos, sin restricciones de idioma, hasta el 21 septiembre de 2015: registro especializado del Grupo Cochrane de Enfermedades Infecciosas (Cochrane Infectious Diseases Group Specialized Register); MEDLINE; Embase OVID; Science Citation Index Expanded, Conference Proceedings Citation Index‐Science, y en BIOSIS Previews (las tres de Web of Science); LILACS; y SCOPUS; registros de ensayos en curso; y en ProQuest Dissertations & Theses A&I. Se revisaron las referencias de los estudios incluidos y se contactó con especialistas en el tema.

Criterios de selección

Se incluyeron estudios transversales y de casos y controles que determinaron la exactitud de la MTBDRsl contra un estándar de referencia definido (PSF basada en cultivo, secuenciación genética o ambas).

Obtención y análisis de los datos

Dos autores de la revisión de manera independiente extrajeron los datos y evaluaron la calidad con la herramienta Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) Los datos de las versiones 1.0 y 2.0 se resumieron por separado. Se calculó la sensibilidad y la especificidad de la MTBDRsl para la resistencia a las fluoroquinolonas, la resistencia a los FISL y la tuberculosis de alta resistencia a los fármacos, cuando la prueba se realizó indirecta o directamente (muestra con baciloscopia positiva para la versión 1.0, muestra con baciloscopia positiva o negativa para la versión 2.0). Se exploró la influencia sobre los cálculos de la exactitud de los fármacos individuales de una clase de fármaco y de diferentes estándares de referencia. La mayoría de los análisis se realizaron con un modelo de efectos aleatorios de dos variables, y la PSF basada en cultivo fue el estándar de referencia.

Resultados principales

Se excluyeron 27 estudios. Veintiséis estudios evaluaron la versión 1.0 y un estudio la versión 2.0. De 26 estudios que declararon el país de origen de la muestra, 15 estudios (58%) evaluaron pacientes de países de ingresos bajos o medianos. En general, se consideró que los estudios tuvieron una calidad metodológica alta. Sin embargo, sólo tres estudios (11%) tuvieron bajo riesgo de sesgo para el estándar de referencia; estos estudios utilizaron las concentraciones críticas recomendadas por la Organización Mundial de la Salud (OMS) para todos los fármacos en el estándar de referencia de la PSF basada en cultivo.

MTBDRsl versión 1.0

Resistencia a fluoroquinolonas: para las pruebas indirectas, la sensibilidad y la especificidad (intervalo de confianza [IC] del 95%) agrupadas de la MTBDRsl fueron 85,6% (79,2% a 90,4%) y 98,5% (95,7% a 99,5%), (19 estudios, 2223 participantes); para las pruebas directas (muestra con baciloscopia positiva), la sensibilidad y la especificidad agrupadas fueron 86,2% (74,6% a 93,0%) y 98,6% (96,9% a 99,4%), (nueve estudios, 1771 participantes, evidencia de calidad moderada ).

Resistencia a los FISL: para las pruebas indirectas, la sensibilidad y la especificidad agrupadas de la MTBDRsl fueron 76,5% (63,3% a 86,0%) y 99,1% (97,3% a 99,7%), (16 estudios, 1921 participantes); para las pruebas directas (muestra con baciloscopia positiva), la sensibilidad y la especificidad agrupadas fueron 87,0% (38,1% a 98,6%) y 99,5% (93,6% a 100,0%), (ocho estudios, 1639 participantes, evidencia de baja calidad).

Tuberculosis de alta resistencia a los fármacos: para las pruebas indirectas, la sensibilidad y la especificidad agrupadas de la MTBDR sl fueron 70,9% (42,9% a 88,8%) y 98,8% (96,1% a 99,6%), (ocho estudios, 880 participantes); para las pruebas directas (muestra con baciloscopia positiva), la sensibilidad y la especificidad agrupadas fueron 69,4% (38,8% a 89,0%) y 99,4% (95,0% a 99,3%), (seis estudios, 1420 participantes, evidencia de baja calidad).

Al igual que en la revisión Cochrane original, no se encontró evidencia de una diferencia significativa en la exactitud de la versión 1.0 de la MTBDRsl entre las pruebas indirectas y directas de resistencia a las fluoroquinolonas, la resistencia a los FISL y la tuberculosis de alta resistencia a los fármacos.

MTBDRsl versión 2.0

Resistencia a fluoroquinolonas: para las pruebas directas, la sensibilidad y la especificidad de la MTBDRsl fueron 97% (83% a 100%) y 98% (93% a 100%), muestra con baciloscopia positiva; y 80% (28% a 99%) y 100% (40% a 100%), muestra con baciloscopia negativa.

Resistencia a los FISL: para las pruebas directas, la sensibilidad y la especificidad de la MTBDRsl fueron 89% (72% a 98%) y 90% (84% a 95%), muestra con baciloscopia positiva; y 80% (28% a 99%) y 100% (40% a 100%), muestra con baciloscopia negativa.

Tuberculosis de alta resistencia a los fármacos: para las pruebas directas, la sensibilidad y la especificidad de la MTBDRsl fueron 79% (49% a 95%) y 97% (93% a 99%), muestra con baciloscopia positiva; y 50% (1% a 99%) y 100% (59% a 100%), muestra con baciloscopia negativa.

No hubo datos suficientes para calcular la sensibilidad y la especificidad resumida de la versión 2.0 (muestras con baciloscopia positiva y negativa) o para comparar la exactitud de las dos versiones.

Una limitación fue que, en su mayoría, los estudios incluidos no utilizaron de manera consistente las concentraciones recomendadas por la Organización Mundial de la Salud (OMS) para los fármacos en el estándar de referencia de la PSF basada en cultivo.

Conclusiones de los autores

En pacientes con tuberculosis resistente a la rifampicina o resistente a múltiples fármacos, la MTBDRsl realizada en un aislado de cultivo o en una muestra con baciloscopia positiva puede ser útil para la detección de la farmacorresistencia de segunda línea. La MTBDRsl (muestra con baciloscopia positiva) clasificó correctamente a alrededor de seis de cada siete pacientes como que presentaban resistencia a las fluoroquinolonas o a los FISL, aunque los cálculos de la sensibilidad para la resistencia a los FISL varió. En pocas ocasiones la prueba dio un resultado positivo en los pacientes sin farmacorresistencia. Sin embargo, cuando no se detecta farmacorresistencia de segunda línea (el resultado de la MTBDRsl es negativo), todavía puede utilizarse la PSF convencional para evaluar a los pacientes con respecto a la resistencia a las fluoroquinolonas o a los FISL.

Se recomienda que los trabajos futuros evalúen la versión 2.0 de la MTBDRsl, en particular en los muestras con baciloscopia negativa y en diferentes contextos para tomar en cuenta las diferentes mutaciones que causan resistencia, que pueden variar según la cepa. Los investigadores también deben considerar la posibilidad de incorporar las concentraciones críticas recomendadas por la OMS en sus estándares de referencia basados en cultivo.

Resumen en términos sencillos

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Prueba rápida GenoType® MTBDRsl para detectar la resistencia a los fármacos de segunda línea contra la TB

Antecedentes

Se dispone de diferentes fármacos para el tratamiento de la tuberculosis (TB), aunque la resistencia a estos fármacos es un problema creciente. Los pacientes con tuberculosis farmacorresistente requieren fármacos de segunda línea contra la TB que, comparados con los fármacos de primera línea, se deben tomar durante más tiempo y se pueden asociar con más efectos perjudiciales. La detección rápida de la farmacorresistencia de la TB es importante para mejorar la salud, reducir las muertes y reducir la propagación de la tuberculosis farmacorresistente.

Definiciones
La tuberculosis resistente a múltiples fármacos (TB‐RMF) es causada por bacterias de la TB que son resistentes a al menos la isoniazida y la rifampicina, los dos fármacos más potentes contra la TB.

La TB altamente resistente a los fármacos (TB‐ARF) es un tipo de TB‐RMF que es resistente a casi todos los fármacos contra la TB.

¿Qué prueba se evalúa mediante esta revisión?

GenoType^® MTBDRsl (MTBDRsl) es una prueba rápida para detectar la resistencia a los fármacos de segunda línea contra la TB. En pacientes con TB‐RMF, la MTBDRsl se utiliza para detectar la farmacorresistencia adicional. La prueba se puede realizar en bacterias de la TB que crecen en cultivos de la muestra de un paciente (pruebas indirectas) o en la muestra de un paciente (pruebas directas), lo que elimina los retrasos asociados con el cultivo. La versión 1.0 de la MTBDRsl requiere que una muestra tenga una baciloscopia positiva por microscopía, mientras que la versión 2.0 (comercializada en 2015) puede utilizar una muestra con baciloscopia positiva o negativa.

¿Cuáles son los objetivos de la revisión?

Se deseaba determinar cuán exacta es la MTBDRsl para detectar la farmacorresistencia; comparar las pruebas indirectas y directas; y comparar las dos versiones de la prueba.

¿Cuál es el grado de actualización de la revisión?

Se buscaron y utilizaron estudios publicados hasta el 21 de septiembre de 2015.

¿Cuáles son los principales resultados de la revisión?

Se encontraron 27 estudios; 26 estudios evaluaron la versión 1.0 de la MTBDRsl y un estudio evaluó la versión 2.0.

Fármacos del tipo de las fluoroquinolonas

La versión 1.0 de la MTBDRsl (muestra con baciloscopia positiva) detectó el 86% de los pacientes con resistencia a las fluoroquinolonas y en pocas ocasiones dio un resultado positivo en los pacientes sin resistencia (GRADE, evidencia de calidad moderada).

Fármacos inyectables de segunda línea

La versión 1.0 de la MTBDRsl (muestra con baciloscopia positiva) detectó el 87% de los pacientes con resistencia a los fármacos inyectables de segunda línea y en pocas ocasiones dio un resultado positivo en los pacientes sin resistencia (GRADE, evidencia de baja calidad).

TB‐ARF

La versión 1.0 de la MTBDRsl (muestra con baciloscopia positiva) detectó el 69% de los pacientes con TB‐ARF y en pocas ocasiones dio un resultado positivo en los pacientes sin resistencia (GRADE, evidencia de baja calidad).

Para la versión 1.0 de la MTBDRsl se encontraron resultados similares de las pruebas indirectas y directas (muestra con baciloscopia positiva).

Debido a que sólo se identificó un estudio que evaluó la versión 2.0 de la MTBDRsl, no fue posible asegurar la exactitud diagnóstica de la versión 2.0. Además, no fue posible comparar la exactitud de las dos versiones.

¿Cuál es la calidad metodológica de la evidencia?

Se utilizó la herramienta Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) para evaluar la calidad de los estudios. En general se consideró que los estudios incluidos fueron de alta calidad; sin embargo, hubo inquietudes acerca de cómo se aplicó el estándar de referencia (el parámetro de referencia contra el que se midió la MTBDRsl).

¿Cuáles son las conclusiones de los autores?

La MTBDRsl (muestra con baciloscopia positiva) identificó a la mayoría de los pacientes con farmacorresistencia de segunda línea. Cuando la prueba informa un resultado negativo, todavía se puede utilizar la prueba convencional para la farmacorresistencia.

Conclusiones de los autores

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Implicaciones para la práctica

En pacientes con tuberculosis resistente a la rifampicina o resistente a múltiples fármacos, la MTBDRsl realizada en un aislado de cultivo o en una muestra con baciloscopia positiva puede ser útil para la detección de la farmacorresistencia de segunda línea. La MTBDRsl realizada en una muestra con baciloscopia positiva clasificó correctamente a alrededor de seis de siete personas como presencia de resistencia a las fluoroquinolonas o a los FISL, aunque los cálculos de la sensibilidad para la resistencia a los FISL variaron. En pocas ocasiones la prueba dio un resultado positivo en los pacientes sin farmacorresistencia. Sin embargo, cuando no se detecta farmacorresistencia de segunda línea (el resultado de la MTBDRsl es negativo), todavía puede utilizarse la PSF convencional para evaluar a los pacientes con respecto a la resistencia a las fluoroquinolonas o a los FISL.

Una mejora de la versión 2.0 de la MTBDRsl en comparación con la versión 1.0 es que, según el fabricante, la prueba se puede realizar en una muestra con baciloscopia negativa con una exactitud diagnóstica alta, aunque no hubo datos suficientes para investigar este aspecto.

Implicaciones para la investigación

Los estudios futuros deben evaluar la versión 2.0 de la MTBDRsl, en particular en muestras con baciloscopia negativa y en diferentes contextos de laboratorio y poblaciones (por ejemplo, en pacientes con pruebas positivas para el VIH). La exactitud de la prueba se debe determinar y comparar con cepas de diferentes regiones geográficas, ya es probable que tengan diferentes frecuencias de mutaciones que causan resistencia fuera de los genes a los que se dirige la MTBDRsl (y, por lo tanto, es probable que la MTBDRsl tenga diferentes sensibilidades para cada clase de fármaco en estas cepas). Estos estudios de investigación futuros deben incluir como estándar de referencia la secuenciación dirigida a todas las mutaciones conocidas que determinan la resistencia, y no sólo a las detectables mediante la MTBDRsl. Las pruebas moleculares futuras para la resistencia a las FQ y los FISL deben tener más objetivos genéticos, aparte de gyrA, gyrB, eis y rrs. Se necesitan estudios para determinar la variabilidad interlector de la prueba. Aunque se reconoce que las concentraciones críticas recomendadas por la OMS para los fármacos individuales pueden cambiar con el transcurso del tiempo, los investigadores deben considerar la posibilidad de incorporar estas concentraciones críticas a sus estándares de referencia basados en cultivo. También se necesitan estudios para evaluar el efecto de la implementación de la MTBDRsl sobre el tiempo hasta el tratamiento, los resultados de salud de los pacientes y la coste‐efectividad.

Summary of findings

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Summary of findings 1. MTBDRsl for FQ resistance, direct testing on smear‐positive specimens

Participants: patients with rifampicin‐resistant or MDR‐TB Prior testing: patients who received MTBDRsl testing may have first received smear microscopy, Xpert® MTB/RIF or other nucleic acid amplification test, and culture to diagnose TB and Xpert® MTB/RIF, MTBDRplus version 2.0 or an alternative line‐probe assay to detect first‐line drug resistance Role: The role of MTBDRsl would be as the initial test, replacing culture‐based drug susceptibility testing, for detecting second‐line drug resistance Settings: intermediate or central level laboratories Index (new) test: MTBDRsl version 1.0.* The test was performed by direct testing on smear‐positive specimens Reference standard: culture‐based drug susceptibility testing Studies: mainly cross‐sectional studies Limitations: most included studies did not consistently use the World Health Organization (WHO)‐recommended concentrations for drugs in the culture‐based reference standard Pooled sensitivity (95% CI): 86.2% (74.6% to 93.0%) Pooled specificity (95% CI): 98.6% (96.9% to 99.4%)
Test result	Number of results per 1000 patients tested (95% CI)			Number of participants (studies)	Quality of the evidence (GRADE)
	Prevalence of 5%	Prevalence of 10%	Prevalence of 15%
True positives (patients correctly diagnosed with FQ resistance)	43 (37 to 47)	86 (75 to 93)	129 (112 to 140)	519 (9)	⊕⊕⊕⊝^1,2,3,4 moderate
False negatives (patients incorrectly classified as not having FQ resistance)	7 (3 to 13)	14 (7 to 25)	21 (10 to 38)
True negatives (patients correctly classified as not having FQ resistance)	937 (921 to 944)	887 (872 to 895)	838 (824 to 845)	1252 (9)	⊕⊕⊕⊕^1,2,3 high
False positives (patients incorrectly classified as having FQ resistance)	13 (6 to 29)	13 (5 to 28)	12 (5 to 26)
Abbreviations: CI: confidence interval; DST: drug susceptibility testing; FQ: fluoroquinolone; GRADE: Grading of Recommendations, Assessment, Development and Evaluation; SLID: second‐line injectable drug; TB: tuberculosis; XDR‐TB: extensively drug‐resistant TB. By indirect testing, MTBDRsl sensitivity and specificity (95% CI) were 85.6% (79.2% to 90.4%) and 98.5% (95.7% to 99.5%). *This systematic review mainly evaluated MTBDRsl version 1.0, which has recently been replaced with version 2.0. We considered the findings in this review to be applicable to the current version of the test. ¹Eight studies used a cross‐sectional study design and one study used a case‐control study design. ²We used QUADAS‐2 to assess risk of bias. All studies used consecutive sampling. In seven studies, the reader of the index test was blinded to results of the reference standard and in two studies information about blinding to the reference standard was not reported. Several studies used critical concentrations for the culture‐based DST reference standard that differed from the concentrations recommended by the WHO. This may have lowered specificity, but this was not observed. We did not downgrade. ³We considered indirectness (applicability) from the perspective of diagnostic accuracy and had low concern. We did not downgrade. ⁴For individual studies, sensitivity estimates ranged from 33% to 100%. One small study with the lowest sensitivity only included three FQ‐resistant patients. However, we could not explain the remaining heterogeneity by study quality or other factors. We downgraded one level for inconsistency.

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Summary of findings 2. MTBDRsl for SLID resistance, direct testing on smear‐positive specimens

Participants: patients with rifampicin‐resistant or MDR‐TB Prior testing: patients who received MTBDRsl testing may have first received smear microscopy, Xpert® MTB/RIF or other nucleic acid amplification test, and culture to diagnose TB and Xpert® MTB/RIF, MTBDRplus version 2.0 or an alternative line‐probe assay to detect first‐line drug resistance Role: The role of MTBDRsl would be as the initial test, replacing culture‐based drug susceptibility testing, for detecting second‐line drug resistance Settings: intermediate or central level laboratories Index (new) test: MTBDRsl version 1.0.* The test was performed by direct testing on smear‐positive specimens Reference standard: culture‐based drug susceptibility testing Studies: cross‐sectional studies Limitations: most included studies did not consistently use the World Health Organization (WHO)‐recommended concentrations for drugs in the culture‐based reference standard Pooled sensitivity (95% CI): 87.0% (38.1% to 98.6%) Pooled specificity (95% CI): 99.5% (93.6% to 100.0%)
Test result	Number of results per 1000 patients tested (95% CI)			Number of participants (studies)	Quality of the evidence (GRADE)
	Prevalence of 5%	Prevalence of 10%	Prevalence of 15%
True positives (patients correctly diagnosed with SLID resistance)	44 (19 to 49)	87 (38 to 99)	131 (57 to 148)	348 (8)	⊕⊕⊝⊝^1,2,3,4 low
False negatives (patients incorrectly classified as not having SLID resistance)	6 (1 to 31)	13 (1 to 62)	19 (2 to 93)
True negatives (patients correctly classified as not having SLID resistance)	945 (889 to 950)	896 (842 to 900)	846 (796 to 850)	8 (1291)	⊕⊕⊕⊝^1,2 moderate
False positives (patients incorrectly classified as having SLID resistance)	5 (0 to 61)	4 (0 to 58)	4 (0 to 54)
Abbreviations: CI: confidence interval; DST: drug susceptibility testing; FQ: fluoroquinolone; GRADE: Grading of Recommendations, Assessment, Development and Evaluation; SLID: second‐line injectable drug; TB: tuberculosis; XDR‐TB: extensively drug‐resistant TB. By indirect testing, MTBDRsl sensitivity and specificity (95% CI) were 76.5% (63.3% to 86.0%) and 99.1% (97.3% to 99.7%). This systematic review mainly evaluated MTBDRsl version 1.0, which has recently been replaced with version 2.0. We considered the findings in this review to be applicable to the current version of the test. ¹We used QUADAS‐2 to assess risk of bias. All studies used consecutive or random sampling. In six studies, the reader of the index test was blinded to results of the reference standard in two studies information about blinding to the reference standard was not reported. Fifty per cent of the studies used critical concentrations for the culture‐based DST reference standard that differed from the concentrations recommended by the WHO. We downgraded one level. ²We considered indirectness (applicability) from the perspective of diagnostic accuracy and had low concern. We did not downgrade. ³For individual studies, sensitivity estimates ranged from 9% to 100%. We thought heterogeneity could be explained in part by the use of different drugs, critical concentrations, and types of culture media in the reference standard and likely presence of eis* mutations in patients in Eastern Europe. We did not downgrade for inconsistency and considered this in the context of other factors, in particular imprecision. ⁴The wide CI around true positives and false negatives may lead to different decisions depending on which confidence limits are assumed. We downgraded one level.

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Summary of findings 3. MTBDRsl for XDR‐TB, direct testing on smear‐positive specimens

Participants: patients with rifampicin‐resistant or MDR‐TB Prior testing: patients who received MTBDRsl testing may have first received smear microscopy, Xpert® MTB/RIF or other nucleic acid amplification test, and culture to diagnose TB and Xpert® MTB/RIF, MTBDRplus version 2.0 or an alternative line‐probe assay to detect first‐line drug resistance Role: The role of MTBDRsl would be as the initial test, replacing culture‐based drug susceptibility testing, for detecting second‐line drug resistance Settings: intermediate or central level laboratories Index (new) test: MTBDRsl version 1.0.* The test was performed by direct testing on smear‐positive specimens Reference standard: culture‐based drug susceptibility testing Studies: cross‐sectional studies Limitations: most included studies did not consistently use the World Health Organization (WHO)‐recommended concentrations for drugs in the culture‐based reference standard Pooled sensitivity (95% CI): 69.4% (38.8% to 89.0%) Pooled specificity (95% CI): 99.4% (95.0% to 99.3%)
Test result	Number of results per 1000 patients tested (95% CI)			Number of participants (studies)	Quality of the evidence (GRADE)
	Prevalence of 1%	Prevalence of 5%	Prevalence of 10%
True positives (patients correctly diagnosed with XDR‐TB)	7 (4 to 9)	35 (19 to 45)	69 (39 to 89)	143 (6)	⊕⊕⊝⊝^1,2,3,4 low
False negatives (patients incorrectly classified as not having XDR‐TB)	3 (1 to 6)	15 (5 to 31)	31 (11 to 61)
True negatives (patients correctly classified as not having XDR‐TB)	980 (941 to 983)	941 (903 to 943)	891 (855 to 894)	1277 (6)	⊕⊕⊕⊝^1,2 moderate
False positives (patients incorrectly classified as having XDR‐TB)	10 (7 to 49)	9 (7 to 47)	9 (6 to 45)
Abbreviations: CI: confidence interval; DST: drug susceptibility testing; FQ: fluoroquinolone; GRADE: Grading of Recommendations, Assessment, Development and Evaluation; SLID: second‐line injectable drug; TB: tuberculosis; WHO: World Health Organization; XDR‐TB: extensively drug‐resistant TB. By indirect testing, MTBDRsl sensitivity and specificity (95% CI) were 70.9% (42.9% to 88.7%) and 98.8% (96.1% to 99.6%). This systematic review mainly evaluated MTBDRsl version 1.0, which has recently been replaced with version 2.0. We considered the findings in this review to be applicable to the current version of the test. ¹We used QUADAS‐2 to assess risk of bias. All studies used consecutive sampling. In four studies, the reader of the test was blinded to results of the reference standard and in two studies information about blinding was not reported. Most studies used critical concentrations for the phenotypic culture‐based DST reference standard that differed from the concentrations recommended by the WHO. We downgraded the evidence by one level. ²We considered indirectness (applicability) from the perspective of diagnostic accuracy and had low concern. We did not downgrade. ³For individual studies, sensitivity estimates ranged from 14% to 92%. We thought heterogeneity could be explained in part by the use of different drugs, critical concentrations, and types of culture media in the reference standard and likely presence of eis* mutations in patients in Eastern Europe. We did not downgrade for inconsistency and considered this in the context of other factors, in particular imprecision. ⁴The wide CI for true positives and false negatives may lead to different decisions depending on which confidence limits are assumed. We downgraded one level.

Antecedentes

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La tuberculosis (TB) es una enfermedad infecciosa transmitida por vía aérea causada por las bacterias Mycobacterium tuberculosis. En 2014, unas 9 600 000 personas desarrollaron TB y 1 500 000 murieron de TB; 1 100 000 pacientes tenían pruebas negativas para el virus de la inmunodeficiencia humana (VIH) y 400 000 pacientes tenían pruebas positivas para el virus (WHO 2015). Aunque la cantidad de muertes debidas a la TB ha disminuido en casi la mitad desde 1990, actualmente la TB es la causa más frecuente de muerte por enfermedad infecciosa en los adultos y sobrepasa al VIH/síndrome de inmunodeficiencia adquirida (SIDA), que arrebató 1 200 000 vidas. La TB es una enfermedad prevenible y tratable. La Organización Mundial de la Salud (OMS) calculó que, desde el año 2000, se han salvado 43 000 000 de vidas mediante el diagnóstico y el tratamiento efectivos (WHO 2015).

La TB afecta predominantemente a los pulmones (TB pulmonar), pero puede afectar a otras partes del cuerpo como el cerebro o la columna vertebral. La TB activa se confirma mediante la presencia de los bacilos de TB obtenidos en un cultivo. Los síntomas de la tuberculosis pulmonar incluyen tos persistente (durante al menos dos semanas), fiebre, sudores nocturnos, pérdida de peso, escalofríos, hemoptisis y fatiga. La TB sensible a los fármacos (también denominada TB farmacosusceptible) es el tipo más frecuente de TB y puede ser tratada de manera efectiva con un régimen estandarizado de fármacos antituberculosos de primera línea (WHO 2015). Sin embargo, los bacilos de la TB se pueden hacer farmacorresistentes, lo que significa que los fármacos antituberculosos de primera línea ya no pueden eliminarlos. La farmacorresistencia se desarrolla generalmente debido al uso inapropiado o incorrecto de los fármacos de primera línea, pero cada vez más, los casos nuevos son causados por la transmisión de persona a persona (Streicher 2011; Zhao 2012).

La aparición de la tuberculosis farmacorresistente amenaza con desestabilizar el control de la tuberculosis a nivel mundial. Hay dos definiciones estandarizadas de tuberculosis farmacorresistente: TB resistente a múltiples fármacos (TB‐RMF) y TB altamente farmacorresistente (TB‐AFR). La TB‐RMF es causada por el M. tuberculosis que, cuando se prueba microbiológicamente en el laboratorio, es resistente a la rifampicina y la isoniazida. Estos son dos de los fármacos antituberculosos más efectivos y más ampliamente utilizados, y forman parte del régimen de primera línea estandarizado para la TB sensible a los fármacos. Habitualmente los pacientes con TB‐RMF se tratan con fármacos pertenecientes a las clases de fármacos antituberculosos fluoroquinolonas (FQ) y con fármacos inyectables de segunda línea (FISL). Los fármacos FQ incluyen ofloxacina, levofloxacina, moxifloxacina y gatifloxacina, y los FISL incluyen amikacina y kanamicina (dos fármacos aminoglucósidos) y capreomicina (un fármaco péptido cíclico). La TB‐ARF es causada por M. tuberculosis resistentes a la isoniazida, la rifampicina, más cualquier FQ y al menos uno de los tres FISL. Por lo tanto, los pacientes con TB‐ARF son resistentes a los fármacos de primera línea y de segunda línea.

El tratamiento para la tuberculosis farmacorresistente requiere de más de 12 meses, y es tóxico y costoso. Una revisión sistemática calculó que sólo el 62% (intervalo de confianza [IC]del 95%: 58% al 67%) de los pacientes que iniciaron el tratamiento para la TB‐RMF fueron tratados con éxito (definido como curados o que completaron el tratamiento, Orenstein 2009). Alrededor del 10% de los pacientes con TB‐RMF tienen TB‐ARF, pero esta proporción puede ser tal alta como el 30% en partes de Europa oriental (WHO 2015). Las tasas de éxito del tratamiento de la TB‐ARF son deficientes (26%), con una mortalidad a los cinco años alta (73%) en ámbitos endémicos de VIH (Pietersen 2014; WHO 2015). En Sudáfrica, en 2011 el tratamiento de aproximadamente 8000 casos de tuberculosis farmacorresistente, que sólo comprendió el 2,2% de la carga total de la TB, consumió el 32% del presupuesto anual nacional del país para la TB, que era de USD 218 000 000 (Pooran 2013).

Las mejoras en el diagnóstico de la tuberculosis farmacorresistente también son importantes para reducir la transmisión. En Sudáfrica, se considera que el 80% de la TB‐RMF se propaga de persona a persona (Streicher 2011), y lo mismo es probablemente cierto para la TB‐RMF y la TB‐ARF en China (Zhao 2012). Los estudios con modelos han mostrado que, mediante la mejoría en la capacidad del diagnóstico rápido de la tuberculosis farmacorresistente, las tasas de curación de los pacientes pueden mejorar al iniciarse más temprano el tratamiento apropiado y efectivo de la TB (Basu 2007; Basu 2009; Dowdy 2008). Es importante señalar que este hecho puede reducir la infecciosidad en una a dos semanas (Menzies 1997). Sin embargo, el "período de infecciosidad" exacto para la tuberculosis farmacorresistente aún no está claro. Por lo tanto, existe una necesidad urgente de pruebas rápidas que permitan la detección temprana de la farmacorresistencia y la selección de los fármacos apropiados.

El uso de pruebas de susceptibilidad farmacológica (PSF) basadas en cultivo fenotípico convencional para la detección de la tuberculosis farmacorresistente depende del crecimiento de las bacterias de la TB, por lo que se asocia con considerables retrasos de tiempo (de dos a seis meses). Estos retrasos están exacerbados por los requisitos técnicos y de infraestructura de la prueba, la falta de métodos estándar para ciertos fármacos y la contaminación (que causa resultados poco claros que se deben repetir) (Richter 2009), así como por dificultades asociadas con los pacientes, como la pérdida durante el seguimiento. Una vez que se ha establecido un diagnóstico de TB‐RMF, habitualmente se utilizan PSF de segunda línea para diagnosticar la farmacorresistencia de segunda línea. En 2015, se informó sobre 300 000 casos de TB‐RMF (de 450 000 casos calculados); no obstante, sólo al 24% se le realizó una PSF de segunda línea (WHO 2015).

Las pruebas moleculares para detectar la farmacorresistencia, como la prueba GenoType® MTBDRsl (en lo adelante llamada MTBDRsl) han mostrado ser alentadoras para el diagnóstico de la TB farmacorresistente. Estas pruebas son rápidas (alrededor de cinco horas) y genotípicas, ya que detectan la presencia de mutaciones asociadas con la farmacorresistencia. La MTBDRsl pertenece a una categoría de pruebas genéticas moleculares llamadas pruebas con sondas en línea. La versión 1.0 de la MTBDRsl fue la primera prueba con sondas en línea comercial para la detección de la resistencia a los fármacos de segunda línea contra la TB y, desde inicios de 2016, ya no está disponible. La versión 2.0 de la MTBDRsl se comercializó en 2015. La versión 2.0 de la MTBDRsl detecta las mutaciones asociadas con la resistencia a las FQ y los FISL detectadas mediante la versión 1.0 de la MTBDRsl , así como mutaciones adicionales (que se describen a continuación). Se ha incluido un glosario de términos genéticos en el Apéndice 1. El borrador de esta revisión Cochrane actualizada informó al Guideline Development Group de la OMS que se reunió de febrero a marzo de 2016 para hacer las recomendaciones acerca del uso de esta prueba. La guía de políticas de la OMS, "Uso de las pruebas moleculares con sondas en línea para la detección de la resistencia a los fármacos antituberculosos de segunda línea", se publicó en mayo de 2016 (WHO 2016).

Enfermedad de interés diagnosticada

Se consideraron las siguientes condiciones objetivo.

Resistencia a las fluoroquinolonas (FQ).
Resistencia a los fármacos inyectables de segunda línea (FISL).
TB‐ARF.

Prueba/s índice

La prueba índice es la MTBDRsl en sus versiones 1.0 y 2.0 (Hain Life Sciences 2015; Tabla 1). La MTBDRsl detecta mutaciones específicas asociadas con la resistencia a las FQ (que incluyen ofloxacina, moxifloxacina, levofloxacina y gatifloxacina) y los FISL (que incluyen kanamicina, amikacina y capreomicina) en las especies del complejo M. tuberculosis. La versión 1.0 detecta mutaciones en la región que determina la resistencia a las quinolonas gyrA (codones 88, 90, 91, 94) y en rrs (codones 1401, 1402, 1484). La versión 2.0 detecta además mutaciones en la región que determina la resistencia a las quinolonas de gyrB (codones 538, 540) y la región del promotor eis (codones ‐37, ‐14, ‐12, ‐10, ‐2) (Hain Life Sciences 2015a). Debido a que las mutaciones en estas regiones pueden causar resistencia adicional a las FQ o a los FISL, respectivamente, la versión 2.0 de la MTBDRsl debe tener una mayor sensibilidad para la resistencia a estas clases de fármacos. Las mutaciones en algunas regiones (por ejemplo, la región del promotor eis) pueden causar más resistencia a un fármaco en una clase que en otros fármacos de dicha clase. Por ejemplo, la mutación eis C14T se asocia con resistencia a la kanamicina en las cepas de M. tuberculosis de Europa oriental (Gikalo 2012). La versión 1.0 de la MTBDRsl también detecta mutaciones en embB que pueden codificar la resistencia al etambutol. Como se trata de un fármaco de primera línea y se omitió de la versión 2.0 de la MTBDRsl , no se determinó la exactitud para la resistencia al etambutol.

Para las FQ, la presencia de mutaciones en cada uno de los genes investigados por la MTBDRsl tiene una concordancia alta pero imperfecta con la resistencia a todos los fármacos de esa clase. Por ejemplo, una mutación en el gen gyrA puede significar que una cepa es resistente a cada una de las FQ (por ejemplo, ofloxacina y moxifloxacina) (Sirgel 2012a). Lo mismo es válido para el gen rrs y los dos aminoglucósidos, kanamicina y amikacina (Sirgel 2012b). La evidencia con respecto al nivel de concordancia entre la resistencia a los dos aminoglucósidos y a la capreomicina que surge de las mutaciones en el gen rrs es mixta. La MTBDRsl informa de la presencia de mutaciones de estos genes (así como en gyrB y el promotor eispara la versión 2.0 de la MTBDRsl ) que se asocian con resistencia a una clase de fármacos. La presencia de mutación/es en estas regiones no implica necesariamente la resistencia a todos los fármacos de esa clase.

Para la versión 1.0 de la MTBDRsl , el fabricante recomendó que, si la muestra del paciente (generalmente esputo) tenía una baciloscopia positiva, la prueba se realice en la muestra (pruebas directas), y si la baciloscopia era negativa, que la prueba se realice en el aislado de cultivo que creció de la muestra del paciente (pruebas indirectas). El fabricante señala que la versión 2.0 de la MTBDRsl se puede realizar en una muestra con baciloscopia positiva o con baciloscopia negativa sin necesidad de cultivo.

El procedimiento de la prueba incluye los siguientes pasos: 1. descontaminación de la muestra; 2. aislamiento y amplificación del ADN; 3. detección de los productos de amplificación mediante hibridación inversa; y 4. visualización mediante una reacción colorimétrica de estreptavidina conjugada con fosfatasa alcalina. Las bandas observadas, cada una correspondiente con una sonda, se pueden utilizar para determinar el perfil de sensibilidad a los fármacos de la muestra analizada. La prueba se puede realizar en cinco horas.

La figura 1 muestra las tiras de la prueba con sondas en línea utilizadas para la versión 1.0 o la versión 2.0 de la MTBDRsl . Se incluye una banda para la detección del complejo M. tuberculosis (la banda "TUB"), así como dos controles internos (controles conjugado y de amplificación) y un control para cada lugar del gen (MTBDRsl versión 2.0: gyrA, gyrB, rrs, eis). Los dos controles internos más cada control del lugar del gen deben ser positivos; de no ser así la prueba no se puede evaluar para ese fármaco particular. Un resultado puede ser indeterminado para un lugar, pero válido para otro (según el fracaso del control para un lugar específico del gen). El fabricante proporciona una plantilla para ayudar a leer las tiras, en la que las combinaciones de las bandas se califican visualmente, se transcriben y se informan. En ámbitos de gran volumen es posible incorporar el GenoScan®, un lector automatizado, para interpretar automáticamente las combinaciones de bandas y dar una sugerencia de interpretación. Si el operador está de acuerdo con la interpretación, los resultados se cargan automáticamente, de manera que se reducen los posibles errores de transcripción.

Vía clínica

La figura 2 ilustra la vía clínica. Según el contexto, la PSF se le realiza a todos los pacientes con tuberculosis confirmada o a los pacientes en los que se sospecha clínicamente que tienen tuberculosis farmacorresistente (por ejemplo, si no se ha logrado la mejoría de los síntomas de los pacientes con el tratamiento de primera línea, o si todavía tienen bacilos de M. tuberculosis en el esputo después de un período prolongado de tratamiento). La PSF para la resistencia a los fármacos de segunda línea generalmente sólo se realiza si se confirma la resistencia a los fármacos de primera línea. Específicamente, un paciente con presunta tuberculosis farmacorresistente proporciona una muestra (generalmente esputo), que es examinada mediante baciloscopia. Si la baciloscopia es positiva, se puede utilizar la versión 1.0 o 2.0 de la MTBDRsl directamente en la muestra. Si la baciloscopia es negativa, no se debe utilizar la versión 1.0 de la MTBDRsl directamente en la muestra, sino en el aislado de cultivo. La versión 2.0 de la MTBDRsl se puede utilizar directamente en una muestra con baciloscopia negativa. Una prueba molecular para la farmacorresistencia de primera línea (por ejemplo, la prueba MTBDRplus) se puede utilizar antes de la prueba MTBDRsl si la resistencia a los fármacos de primera línea aún no se ha confirmado. La PSF fenotípica todavía se puede realizar en los aislados de cultivos positivos.

Prueba/s previa/s

A los pacientes a los que se les realizó la prueba MTBDRsl se les puede haber realizado primero una baciloscopia, la Xpert® MTB/RIF u otra prueba de amplificación de ácido nucleico y cultivo para diagnosticar la TB y la Xpert® MTB/RIF, la MTBDRplus, o una prueba alternativa con sondas en línea para detectar la farmacorresistencia de primera línea.

Función de la/s prueba/s índice

La función de la MTBDRsl sería la de prueba inicial y reemplazar a la PSF basada en cultivo para detectar la farmacorresistencia de segunda línea.

Prueba/s alternativa/s

Se conocen varias pruebas adicionales con sondas en línea comercializadas para la comprobación genotípica de la farmacorresistencia de segunda línea: TB Resistance Module Fluoroquinolones/Ethambutol y TB Resistance Module Kanamycin/Amikacin/Capreomycin/Streptomycin (Autoimmun Diagnostika GmbH (AID) Strassberg); MolecuTech REBA MTB‐FQ^®, MolecuTech REBA MTB‐KM^® y MolecuTech REBA MTB‐XDR^® (YD diagnostics, Seoul); y NiPro LiPA FQ (NiPro Co, Osaka) (Boyle 2015). Para una revisión integral de estas pruebas, el lector puede consultar el informe Tuberculosis Diagnostics Technology and Market Landscape (Boyle 2015).

Fundamento

Los fármacos de segunda línea contra la TB se utilizan para tratar a los pacientes con tuberculosis resistente a los fármacos de primera línea más efectivos y ampliamente utilizados. Para asegurar que a los pacientes se les administren lo más rápido posible los fármacos más apropiados y menos tóxicos, es fundamental conocer si un paciente presenta resistencia solamente a las FQ, a los FISL o a las FQ y los FISL (TB‐ARF), ya que este hecho guiará la selección de los fármacos. El método convencional para el diagnóstico de la farmacorresistencia (la PSF basada en cultivo) es susceptible a la contaminación y la pérdida de la viabilidad, lo que significa que en ocasiones las bacterias de la TB no pueden crecer nuevamente, por lo que no hay un aislado del cultivo disponible para la PSF. La PSF basada en cultivo también es lenta y puede demorar varios meses. El retraso resultante en el diagnóstico da lugar a morbilidad innecesaria, a mortalidad y al aumento de la transmisión, que es una causa importante de aparición de nuevos casos de TB. Se necesitan pruebas rápidas para mejorar el tiempo hasta el diagnóstico y las nuevas pruebas moleculares como la prueba MTBDRsl presentan una solución posiblemente alentadora.

Objetivos

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Evaluar y comparar la exactitud diagnóstica de la MTBDRsl para: 1. la resistencia a fluoroquinolonas, 2. la resistencia a los FISL, y 3. la tuberculosis de alta resistencia a los fármacos, como una prueba indirecta en un aislado de M. tuberculosis que crece en un cultivo o como una prueba directa en una muestra del paciente. Las poblaciones de interés fueron los pacientes con TB‐RMF o con tuberculosis resistente a la rifampicina, que se considera un sustituto de la TB‐RMF en ámbitos de alta carga, WHO 2011.

Objetivos secundarios

Se planificó investigar la heterogeneidad con relación al tipo de estándar de referencia (pruebas de susceptibilidad farmacológica [PSF] basadas en cultivo en comparación con la secuenciación, PSF basadas en cultivo y secuenciación y PSF basadas en el cultivo seguida de secuenciación en los resultados discrepantes) y la resistencia a los fármacos individuales de una clase de fármacos (por ejemplo, ofloxacina, moxifloxacina, levofloxacina y gatifloxacina de la clase de las FQ). También se preespecificó en el protocolo la investigación de la heterogeneidad con relación al estado del virus de la inmunodeficiencia humana (VIH), la condición de la muestra (fresca o congelada, volumen de la muestra), la población de pacientes (pacientes con sospecha de TB‐RMF o TB‐ARF), y si se utilizaron las concentraciones farmacológicas críticas recomendadas por la Organización Mundial de la Salud (OMS) para el estándar de referencia de la PSF basada en cultivo. Con posterioridad al protocolo publicado, se agregó la investigación de la heterogeneidad con relación al grado de la baciloscopia.

Métodos

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Criterios de inclusión de estudios para esta revisión

Tipos de estudios

Se incluyeron todos los estudios que determinaron la exactitud diagnóstica de la prueba índice en comparación con un estándar de referencia definido, incluidos los diseños de casos y controles. Sólo se incluyeron los estudios de los que fue posible extraer datos sobre los verdaderos positivos (VP), los falsos positivos (FP), los falsos negativos (FN) y los verdaderos negativos (VN). Se excluyeron los estudios no publicados informados solamente en resúmenes y actas de congresos.

Participantes

Se incluyeron pacientes de cualquier edad que presentaban tuberculosis o TB‐RMF resistente a la rifampicina o que pueden haber presentado resistencia a cualquiera de los fármacos de segunda línea contra la TB, independientemente de los antecedentes relacionados con la carga de la farmacorresistencia y la población de pacientes.

Pruebas índice

La prueba índice fue la MTBDRsl , versión 1.0 o versión 2.0.

Enfermedades de interés

Se consideraron las siguientes condiciones objetivo.

Resistencia a las fluoroquinolonas (FQ).
Resistencia a los fármacos inyectables de segunda línea (FISL).
TB‐ARF.

Estándares de referencia

Se incluyeron los estudios que utilizaron uno o más de los siguientes estándares de referencia.

Prueba de sensibilidad farmacológica (PSF) basada en cultivo: cultivo sólido o cultivo líquido.
Secuenciación de los genes gyrA o rrs (MTBDRsl versión 1.0) o de manera adicional las regiones del promotor gyrB y eis (MTBDRsl , versión 2.0).
Una estándar de referencia compuesto con dos componentes: PSF y secuenciación basada en cultivo de las mismas muestras. Si una muestra era resistente según la PSF basada en cultivo o tenía una mutación, la muestra se clasificó como presencia de la condición objetivo. Si la PSF basada en cultivo y la secuenciación indicaron sensibilidad, la muestra se clasificó como no presencia de la condición objetivo.
Dos estándares de referencia utilizados de manera secuencial: PSF basada en cultivo seguida de una prueba selectiva mediante secuenciación de las muestras en los resultados discrepantes. Los resultados discrepantes pueden ser prueba índice positiva/PSF basada en cultivo negativa, o prueba índice negativa/PSF basada en cultivo positiva.

Hay fortalezas y limitaciones relacionadas con cada uno de los estándares de referencia. La PSF basada en cultivo es el estándar de referencia aceptado, pero se considera imperfecta y depende del umbral de concentración de los fármacos utilizado para definir la resistencia. La secuenciación se considera más exacta que la PSF basada en cultivo; sin embargo, esto sólo es cierto si se dirige a todas las regiones conocidas que determinan la resistencia, que no se conocen completamente para las FQ y los FISL. Por lo tanto, la secuenciación dirigida puede pasar por alto mutaciones que causan farmacorresistencia.

Se realizaron análisis separados para los diferentes estándares de referencia, que se describen a continuación. En el análisis primario se utilizó la PSF basada en cultivo como el estándar de referencia. Se esperaba que todos o casi todos los estudios incluidos presentaran los resultados basados en este estándar de referencia.

Métodos de búsqueda para la identificación de los estudios

We attempted to identify all relevant studies regardless of language and publication status (published, unpublished, in press, and ongoing).

Búsquedas electrónicas

Vittoria Lutje (VL), the Information Specialist for the Cochrane Infectious Diseases Group (CIDG), performed literature searches up to 21 September 2015 without language restrictions. To identify all relevant studies, she searched the following databases using the search terms and strategy described in Appendix 2: CIDG Specialized Register; MEDLINE (PubMed, 1966 to 21 September 2015); Embase OVID (1980 to 21 September 2015); Science Citation Index Expanded (SCI‐EXPANDED, 1900 to 21 September 2015, Conference Proceedings Citation Index‐Science (CPCI‐S, 1990 to 21 September 2015), and BIOSIS Previews (1926 to 21 September 2015; all three from Web of Science); LILACS (http://lilacs.bvsalud.org/en/; 1982 to 21 September 2015); and SCOPUS (1995 to 21 September 2015). She also searched the ISRCTN registry (http://isrctn.com) and the search portal of the World Health Organization International Clinical Trials Registry Platform (ICTRP; http://apps.who.int/trialsearch/) to identify ongoing trials, and ProQuest Dissertations & Theses A&I to identify relevant dissertations (all websites accessed on 21 September 2015). We searched MEDION in the previous version of the review, Theron 2014, but this database was unavailable in September 2015.

Búsqueda de otros recursos

We reviewed reference lists of included articles and any relevant review articles identified through the above methods. We contacted researchers at FIND and other experts in the field of TB diagnostics for information on ongoing or unpublished studies.

Obtención y análisis de los datos

Selección de los estudios

Two review authors (GT and JP) independently scrutinized titles and abstracts identified by electronic literature searches to identify potentially eligible studies. We selected all citations identified as suitable during this screen for full‐text review. The same two review authors then independently reviewed full‐text papers for study eligibility using the predefined inclusion and exclusion criteria. For full‐text articles, we resolved any discrepancies by discussion with a third review author (KRS). We maintained a list of excluded studies and their reasons for exclusion, and recorded these details in the 'Characteristics of excluded studies' table and prepared a PRISMA diagram.

Extracción y manejo de los datos

We developed a standardized data extraction form and piloted the form with two of the included studies. Based upon the pilot, we finalized the form. Then two review authors (GT and JP) independently extracted data on the following characteristics and resolved any discrepancies by discussion.

Details of study: first author; publication year; country where testing was performed; specimen country origin; setting (primary care laboratory, hospital laboratory, reference laboratory); study design; manner of participant selection; number of participants enrolled; number of participants for whom results available; industry sponsorship.
Characteristics of participants: age; HIV status; smear status; history of TB; known MDR‐TB, pre‐XDR‐TB (defined as MDR‐TB and resistance to a FQ or SLID, but not to drugs from both classes), or XDR‐TB status.
Target conditions: resistance to FQ and SLID drug classes and XDR‐TB.
Resistances to individual drugs: ofloxacin, moxifloxacin, levofloxacin, gatifloxacin, amikacin, kanamycin, and capreomycin.
Reference standards: type; percentage of patients whose reference standard was 'uninterpretable' (for example, contaminated, sequencing failed).
Details of specimen: type (such as expectorated sputum, induced sputum or culture isolate); condition (fresh or frozen); definition of a positive smear; type of testing (direct testing or indirect testing); smear grade (negative, scanty, 1+, 2+, 3+).
Details of outcomes: the number of TP, FP, FN, and TN results; number of indeterminate assay results.
Intra‐reader and inter‐reader variability.
Time to treatment initiation: defined as the time from specimen collection until patient starts treatment.
Time to diagnosis: defined as the time from specimen collection until there is an available TB result in lab or clinic, if the assay was performed in a clinic.

We assigned country income status (high, middle or low) as classified by the World Bank List of Economies (World Bank 2015). We contacted authors of primary studies for missing data or clarifications. We assigned smear grade according to the WHO definition (WHO 2014). We entered all data into a database manager (Microsoft Excel 2014).

For one study that tested the same panel of TB isolates in multiple centres, we selected one centre that provided results in the middle range (neither the best nor the worst results) (Ignatyeva 2012). One study included extrapulmonary specimens, which we excluded from the analysis (Barnard 2012). Whenever possible, we extracted data that used a single patient as the unit of analysis (one MTBDRsl result per one specimen from one patient).

When culture‐based DST was performed using more than one drug from the FQs (ofloxacin, moxifloxacin, levofloxacin, or gatifloxacin) or SLIDs (amikacin, kanamycin or capreomycin), we extracted TP, FP, FN, and TN values for each drug and for each class overall. If the reference standard indicated resistance for at least one drug in that class, we classified the sample as resistant to that class of drugs. We did not require reference standard DST results for all drugs in a class in order to classify a sample as resistant or susceptible.

In the 2 x 2 tables of TP, FP, FN, and TN, we based the results of the index test on categorical assay results defined by the visual readout of the MTBDRsl strip.

Possible results for the GenoType® MTBDRsl assay (as defined by the product manual)

Sensitive to either FQs or SLIDs (referred to as 'aminoglycosides/cyclic peptides'), or both (conjugation and amplification bands present; Mycobacterium tuberculosis complex‐specific control (TUB) band present; gene locus band present; all wild type (wt) bands for each gene present; no mutation bands present). In the case of susceptibility to both drug classes, the test would indicate susceptibility for each, rather than having a single composite readout specifying XDR‐TB.
Resistant to either FQs or SLIDs, or both (conjugation and amplification bands present; TUB band present; gene locus band present; all, none or some wt bands for each gene present; all, none or some mutation bands present with similar intensity to amplification control). In the case of resistance to both drug classes, the test would indicate resistance for each, rather than having a composite readout.
Indeterminate (faint bands) or no result (no conjugation or amplification bands present, no locus band present for the gene of interest).
No TB (negative for MTB complex irrespective of locus control band).
No result (failure of any one of the control bands, as well as the TUB band).

No studies reported on the number of 'no TB' or 'no result' results obtained from MTBDRsl, therefore we only extracted the number and percentage of 'indeterminate' results.

Assignment of results to the fluoroquinolones, second‐line injectable drugs, or both categories

We were able to report accuracy estimates for individual drugs within the drug classes when that drug was used as part of the culture‐based DST reference standard. For determining resistance to the drug class, we used the following approach. For a culture‐based DST reference standard, one study might have used detection of ofloxacin resistance and another study, detection of moxifloxacin resistance to confirm an MTBDRsl FQ‐resistant result. In such a scenario, if culture‐based DST is positive for resistance to one of the drugs in the drug class and the MTBDRsl result is concordant, we classified the index test result as a true positive for resistance to the FQs. We adopted the same approach for the SLIDs.

For sequencing as a reference standard, if the index test reported resistance to FQs and the presence of mutations known to be associated with drug resistance to the FQs was confirmed in the same regions of the genome targeted by MTBDRsl, we recorded the test result as concordant and classified the index test as a true positive for resistance to the FQs. We adopted the same approach for the SLIDs.

Evaluación de la calidad metodológica

We appraised the quality of the included studies with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) tool (Whiting 2011; Appendix 3). QUADAS‐2 consists of four domains: patient selection, index test, reference standard, and flow and timing. We assessed all domains for risk of bias and the first three domains for concerns regarding applicability. We used signalling questions in each domain to form judgments about the risk of bias. One review author (GT) piloted the tool with two included studies and finalized the tool based on experience gained from the pilot testing. Three review authors (GT, JP, and KRS) then independently assessed the methodological quality of included studies with the finalized tool and finalized judgments by discussion.

Análisis estadístico y síntesis de los datos

We performed descriptive analyses for key variables (such as country income status) of the primary studies using Stata (Stata 2015), and displayed key study characteristics in the 'Characteristics of included studies' table.

We analysed data separately for MTBDRsl version 1.0 and version 2.0. We used the reference standard culture‐based DST in our primary analyses. We stratified these analyses first by target condition and second by type of MTBDRsl testing (indirect testing or direct testing). Within each stratum (for example, FQ resistance by indirect testing), we plotted estimates of the studies' observed sensitivities and specificities in forest plots with 95% confidence intervals (CIs) and in receiver operating characteristic (ROC) space using Review Manager (RevMan) (RevMan 2014). Where adequate data were available, we combined data using meta‐analysis. We performed most meta‐analyses by fitting the bivariate random‐effects model (Macaskill 2010; Reitsma 2005), using Stata with the metandi and xtmelogit commands (Stata 2015). In situations with few studies, we performed meta‐analysis where appropriate by reducing the bivariate model to two univariate random‐effects logistic regression models by assuming no correlation between sensitivity and specificity. When we observed little or no heterogeneity on forest plots and summary receiver operating characteristic (SROC) plots, we further simplified the models into fixed‐effect models by eliminating the random‐effects parameters for sensitivity or specificity, or both sensitivity and specificity (Takwoingi 2015).

We compared results from studies of direct testing with results from studies of indirect testing by adding a covariate for the type of testing to the model. We assessed the significance of the differences in sensitivity and specificity estimates between studies in which MTBDRsl was performed by direct testing or indirect testing by a likelihood ratio test comparing models with and without covariate terms. Where data were sufficient, we performed comparative analyses including only those studies that made direct comparisons between test evaluations with the same participants. Otherwise, we included all studies with available data. Comparative studies are preferred to non‐comparative studies when deriving evidence of diagnostic test accuracy (Takwoingi 2013).

Approach to uninterpretable (indeterminate) MTBDRsl results

We excluded indeterminate test results from the analyses for determination of sensitivity and specificity. We determined the percentage of indeterminate MTBDRsl results among the primary studies for each target condition and summarized these findings separately for indirect and direct testing when available, according to culture‐based reference standard.

Investigación de la heterogeneidad

Within each stratum (for example, SLID resistance, indirect testing), we investigated heterogeneity through visual examination of forest plots of sensitivity and specificity. Then, if sufficient studies were available, we explored the possible influence of the following prespecified categorical covariates: reference standard (culture, sequencing, culture and sequencing, culture followed by sequencing); resistance to the following drugs: ofloxacin, moxifloxacin, levofloxacin, gatifloxacin, amikacin, kanamycin, and capreomycin (we excluded resistance to ciprofloxacin because this drug is infrequently used in DST); and drug concentration used for culture‐based DST (WHO‐recommended critical concentration used or a different concentration used). In addition, for this updated review, we added an investigation of heterogeneity in relation to microscopy smear grade. We assessed the significance of the difference in test accuracy (for example, between studies using culture versus those using sequencing as the reference standard) by a likelihood ratio test comparing models with and without covariate terms.

We had planned to investigate the effect of HIV status, the condition of the specimen (fresh or frozen), sample volume, and population (patients thought to have MDR‐TB or XDR‐TB) on summary estimates of sensitivity and specificity in a meta‐regression analysis by adding covariate terms to the bivariate model. However, there were insufficient data for these additional analyses.

Análisis de sensibilidad

For our primary analyses using the culture‐based DST reference standard, we performed sensitivity analyses for QUADAS‐2 items to explore whether the accuracy estimates were robust with respect to the methodological quality of the studies. We included the following signalling questions.

Was a consecutive or random sample of patients/specimens enrolled?
Was a case‐control design avoided?
Were the index test results interpreted without knowledge of the results of the reference standard?
Was the test applied in the manner recommended by the manufacturer (index test domain, low concern about applicability)?

Evaluación del sesgo de notificación

We did not undertake a formal assessment of publication bias of data included in this review using methods such as funnel plots or regression tests because such techniques have been unhelpful for determining publication bias within diagnostic test accuracy studies (Macaskill 2010).

Other analyses

We had intended to summarize data on intra‐ and inter‐reader variability; however inter‐reader variability was the only information described in the included studies. We had also intended to summarize two patient outcomes, time‐to‐diagnosis, and time‐to‐treatment initiation; however time‐to‐diagnosis was the only outcome described in the included studies.

Assessment of the quality of evidence (certainty of the evidence)

We assessed the quality of evidence (also called certainty of the evidence or confidence in effect estimates) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Balshem 2011; GRADE 2013), and GRADEpro Guideline Development Tool (GDT) software (GRADEpro GDT 2015). In the context of a systematic review, the ratings of the certainty of the evidence reflect the extent of our confidence that the estimates of the effect (including test accuracy and associations) are correct. As recommended, we rated the quality of evidence as either high (not downgraded), moderate (downgraded by one level), low (downgraded by two levels), or very low (downgraded by more than two levels) for five domains: risk of bias, indirectness, inconsistency, imprecision, and publication bias. For each outcome, the quality of evidence started as high when there were high quality observational studies (cross‐sectional or cohort studies) that enrolled participants with diagnostic uncertainty. If we found a reason for downgrading, we used our judgement to classify the reason as either serious (downgraded by one level) or very serious (downgraded by two levels).

Three review authors (GT, JP, and KRS) discussed judgments and applied GRADE in the following way.

Risk of bias: we used QUADAS‐2 to assess risk of bias.
Indirectness: we considered indirectness from the perspective of test accuracy. We used QUADAS‐2 for concerns of applicability and looked for important differences between the populations studied (for example, in the spectrum of disease), the setting, and the review questions.
Inconsistency: GRADE recommends downgrading for unexplained inconsistency in sensitivity and specificity estimates. We carried out prespecified analyses to investigate potential sources of heterogeneity and did not downgrade the quality of the evidence when we felt we could explain inconsistency in the accuracy estimates.
Imprecision: we considered a precise estimate to be one that would allow a clinically meaningful decision. We considered the width of the CI, and asked ourselves, “Would we make a different decision if the lower or upper boundary of the CI represented the truth?” In addition, we worked out projected ranges for TP, FN, TN, and FP for a given TB prevalence and made judgements on imprecision from these calculations.
Publication bias: we rated publication bias as undetected (not serious) because of the comprehensiveness of the literature search and extensive outreach to TB researchers to identify studies.

Resultados

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Resultados de la búsqueda

We identified 27 unique studies that met the inclusion criteria of this review. All studies but two (Fan 2011, written in Chinese and Chikamatsu 2012, written in Japanese) were written in English. For MTBDRsl version 1.0, we included 26 studies: 21 studies from Theron 2014, the original Cochrane review (Ajbani 2012; Barnard 2012; Brossier 2010a; Chikamatsu 2012; Fan 2011; Ferro 2013; Hillemann 2009; Huang 2011; Ignatyeva 2012; Jin 2013; Kiet 2010; Kontsevaya 2011; Kontsevaya 2013; Lacoma 2012; Lopez‐Roa 2012; Miotto 2012; Said 2012; Surcouf 2011; Tukvadze 2014; van Ingen 2010; Zivanovic 2012) and five new studies (Catanzaro 2015; Kambli 2015a; Kambli 2015b; Simons 2015; Tomasicchio 2016). For MTBDRsl version 2.0, we included one study (Tagliani 2015). Figure 3 shows the flow of studies in the review. We recorded the excluded studies and the reasons for their exclusion in the 'Characteristics of excluded studies' table.

Calidad metodológica de los estudios incluidos

Figure 4 and Figure 5 show risk of bias and applicability concerns for each of the 27 included studies. In the patient selection domain, we judged that 17 studies (63%) had low risk of bias (Ajbani 2012; Barnard 2012; Catanzaro 2015; Ferro 2013; Huang 2011 Jin 2013; Kambli 2015a; Kambli 2015b; Kontsevaya 2011; Kontsevaya 2013; Lacoma 2012; Said 2012; Simons 2015; Surcouf 2011; Tagliani 2015; Tukvadze 2014; Zivanovic 2012). We judged that one study (4%) had unclear risk of bias because the manner of patient selection was unclear (Chikamatsu 2012). We judged that nine studies had high risk of bias for the following reasons.

There was a case‐control design (four studies: Brossier 2010a; Hillemann 2009; Ignatyeva 2012; Kiet 2010).
There was a cross‐sectional design for samples used in direct testing and case‐control design for samples used in indirect testing (two studies: Miotto 2012; Tomasicchio 2016).
Enrolment was by convenience (three studies: Fan 2011; Lopez‐Roa 2012; van Ingen 2010).

Regarding applicability (patient characteristics and setting), we judged that 21 studies (78%) had low concern and six studies had high concern (Brossier 2010a; Hillemann 2009; Ignatyeva 2012; Kiet 2010; Miotto 2012; van Ingen 2010). In the index test domain, we judged that 18 studies (67%) had low risk of bias (Ajbani 2012; Barnard 2012; Hillemann 2009; Huang 2011; Ignatyeva 2012; Jin 2013; Kambli 2015a; Kambli 2015b; Kontsevaya 2011; Kontsevaya 2013; Lacoma 2012; Miotto 2012; Said 2012; Simons 2015; Tagliani 2015; Tomasicchio 2016; van Ingen 2010; Zivanovic 2012); seven (26%) studies had unclear risk of bias because information about blinding was not reported (Brossier 2010a; Catanzaro 2015; Fan 2011; Ferro 2013; Lopez‐Roa 2012; Surcouf 2011; Tukvadze 2014); and two studies had high risk of bias because the index test results were not interpreted without knowledge of the reference standard results (Chikamatsu 2012; Kiet 2010). Regarding applicability of the index test, we judged that 24 studies (89%) had low concern, one study (4%) had high concern (Catanzaro 2015), and two studies had unclear concern (Brossier 2010a; Tukvadze 2014).

In the reference standard domain, we judged that only three studies (11%) had low risk of bias (Kambli 2015b; Lopez‐Roa 2012; Tomasicchio 2016) because these studies used the WHO‐recommended critical concentration for each drug included in the culture‐based drug susceptibility testing (DST) reference standard; 18 studies (67%) had unclear risk of bias (Ajbani 2012; Barnard 2012; Catanzaro 2015; Hillemann 2009; Huang 2011; Ignatyeva 2012; Fan 2011; Ferro 2013; Kambli 2015a; Kontsevaya 2011; Kontsevaya 2013; Miotto 2012; Said 2012; Simons 2015; Surcouf 2011; Tagliani 2015; Tukvadze 2014; Zivanovic 2012), because these studies used the World Health Organization (WHO)‐recommended critical concentration for some, but not all of the drugs included in the culture‐based DST reference standard; and six studies had high risk of bias (Brossier 2010a; Chikamatsu 2012; Jin 2013; Kiet 2010; Lacoma 2012; van Ingen 2010) because these studies did not use WHO‐recommended critical concentrations for any of the drugs included in the culture‐based DST reference standard. Regarding applicability of the reference standard, we judged that all studies had low concern. In the flow and timing domain, we judged that 26 studies (96%) had low risk of bias and one study had unclear risk of bias because we could not account for all patients in the analyses (Ferro 2013).

We noted industry involvement in eight studies (30%) and this included the following.

Donation of MTBDRsl (five studies: Ferro 2013; Hillemann 2009; Miotto 2012; Surcouf 2011; Tagliani 2015).
Preferred pricing of MTBDRsl (one study: Barnard 2012).
Financial support for non‐test related study costs (one study: Said 2012).
Involvement in the design, analysis or manuscript production (one study: Ajbani 2012).

Hallazgos

We presented key characteristics of the 27 included studies in the 'Characteristics of included studies' table. Of 26 studies reporting specimen country origin, 15 studies (58%) evaluated patients from low‐ or middle‐income countries. The median sample size (interquartile range) was 95 (44 to 176).

MTBDRsl version 1.0

Table 2 (indirect testing) and Table 3 (direct testing) show the number of studies that evaluated MTBDRsl version 1.0, according to the reference standard and target condition. We did not identify any studies that evaluated the accuracy of MTBDRsl for gatifloxacin resistance.

I. Fluoroquinolone resistance detection

A. Estimates of the diagnostic accuracy of MTBDRsl using culture‐based DST as a reference standard

1. Indirect testing

Nineteen studies (2223 participants, 869 (39.1%) confirmed cases of fluoroquinolone (FQ)‐resistant TB) evaluated MTBDRsl by indirect testing for detection of FQ resistance (Figure 6). Sensitivity estimates ranged from 57% to 100% and specificity estimates ranged from 77% to 100%. The pooled sensitivity and specificity (95% CI) were 85.6% (79.2% to 90.4%) and 98.5% (95.7% to 99.5%) (Table 4).

2. Direct testing

Nine studies (1771 participants, 519 (29.3%) confirmed cases of FQ‐resistant TB) evaluated MTBDRsl by direct testing for detection of FQ resistance, (Figure 6). Sensitivity estimates ranged from 33% to 100% and specificity estimates ranged from 91% to 100%. The pooled sensitivity and specificity (95% CI) were 86.2% (74.6% to 93.0%) and 98.6% (96.9% to 99.4%) (Table 4).

3. Comparison of indirect versus direct testing

(a) Diagnostic accuracy

Based on analysis of all data, there was no evidence of a statistically significant difference in MTBDRsl version 1.0 accuracy for FQ resistance between indirect and direct testing (smear‐positive specimen) when using culture‐based DST as a reference standard (P values for differences in sensitivity and specificity of 0.932 and 0.333, respectively) (Table 4). Direct within‐study comparisons were not possible because no studies performed MTBDRsl testing on specimens and isolates from the same patients.

(b) Indeterminate rates

MTBDRsl version 1.0: for indirect testing for culture‐confirmed resistance to FQs, of 14 studies that reported indeterminate MTBDRsl results, eight of 2065 results (0.4%) were indeterminate (seven culture‐DST resistant and one culture‐DST sensitive). For direct testing on a smear‐positive specimen, of nine studies that reported indeterminate MTBDRsl results, 147 of 2059 results (7.1%) were indeterminate (68 culture‐DST resistant, 73 susceptible, and six whose culture phenotypic status was unknown). The indeterminate rates for direct testing for each smear‐grade (smear‐negative, scanty, 1+, 2+, 3+) were 61/190 (32.1%), 28/133 (21.1%), 35/272 (12.9%), 19/211 (9.0%), and 44/388 (11%), respectively.

B. Investigations of heterogeneity

1. Indirect testing

(a) Individual drugs within the drug class

We present accuracy estimates for MTBDRsl by indirect testing for detection of resistance to ofloxacin, moxifloxacin, and levofloxacin in Table 5 and Appendix 4.

For detection of ofloxacin resistance by indirect testing, sensitivity estimates ranged from 70% to 100% and specificity estimates ranged from 91% to 100%. The pooled sensitivity and specificity (95% CI) were 85.2% (78.5% to 90.1%) and 98.5% (95.6% to 99.5%), (13 studies, 1927 participants).

For detection of moxifloxacin resistance by indirect testing, sensitivity estimates ranged from 57% to 100% and specificity estimates from 77% to 100%. The pooled sensitivity and specificity (95% CI) were 94.0% (82.2% to 98.1%) and 96.6% (85.2% to 99.3%), (six studies, 419 participants).

We identified two studies for detection of levofloxacin resistance by indirect testing. Sensitivity and specificity estimates (95% CI) were 80% (56% to 94%) and 96% (80% to 100%) for Chikamatsu 2012, and 100% (96% to 100%) and 100% (88% to 100%) for Kambli 2015b. We did not determine summary estimates because there were only two studies and the sensitivity was variable.

(b) Drug concentration used in culture‐based DST

Appendix 5 shows ofloxacin, levofloxacin, and moxifloxacin drug concentrations used in culture‐based DST in relation to the WHO‐recommended critical concentrations.

Ofloxacin: eight studies used the WHO‐recommended critical concentration of ofloxacin (Fan 2011; Huang 2011; Ignatyeva 2012; Kambli 2015a; Lopez‐Roa 2012; Miotto 2012; Said 2012; Tomasicchio 2016), whereas two did not (Brossier 2010a; Kiet 2010). Two studies used two different types of culture medium but only used the WHO‐recommended critical concentration of ofloxacin for one type of culture medium (Hillemann 2009; Zivanovic 2012). Jin 2013 used a non‐WHO recommended concentration for one type of culture medium and no recommended concentration existed for the other culture type. There was no evidence of a statistically significant difference in MTBDRsl version 1.0 accuracy for ofloxacin resistance between studies that did or did not use the WHO‐recommended critical concentration (P values for differences in sensitivity and specificity of 0.960 and 0.904, respectively).

Moxifloxacin: Ferro 2013 used the WHO‐recommended critical concentration for low‐level moxifloxacin resistance whereas Lacoma 2012 used the concentration recommended for high‐level resistance. Four studies did not use the recommended critical concentration of moxifloxacin (Fan 2011; Kambli 2015a; Simons 2015; van Ingen 2010).

Levofloxacin: one study used the WHO‐recommended critical concentration (Kambli 2015b), and one study (Chikamatsu 2012) used a culture media type for which a recommended concentration does not exist.

Comparisons between accuracy estimates for moxifloxacin and levofloxacin according to critical concentration were not possible given the small number of studies.

(c) Type of reference standard

We present MTBDRsl accuracy estimates for detection of FQ resistance against different reference standards in Table 6 and Appendix 6.

Reference standard is sequencing

Using sequencing, MTBDRsl version 1.0 sensitivity estimates ranged from 85% to 100% and specificity estimates ranged from 92% to 100%. Based on comparative studies, the pooled sensitivity and specificity (95% CI) were 99.3% (81.2% to 100.0%) and 99.3% (90.8% to 100.0%), (six studies, 873 participants). There was evidence of a significantly higher sensitivity using sequencing as the reference standard compared with culture‐based DST (P value < 0.001), but not specificity (P value of 0.735).

Reference standard is culture‐based DST and sequencing (i.e. both investigations performed on all isolates)

Using culture and sequencing, MTBDRsl version 1.0 sensitivity estimates ranged from 74% to 91% and specificity estimates ranged from 99% to 100%. Based on comparative studies, the pooled sensitivity and specificity (95% CI) were 82.0% (77.7% to 85.6%) and 99.8% (98.5% to 100.0%), (seven studies, 1211 participants). There was no evidence of a statistically significant difference using both culture‐based DST and sequencing as the reference standard compared with culture‐based DST (P values for differences in sensitivity and specificity of 0.664 and 0.070, respectively).

Reference standard is culture‐based DST followed by sequencing of discrepant index test‐culture‐based DST results

Using sequencing of discrepant results, MTBDRsl version 1.0 sensitivity estimates ranged from 73% to 100% and specificity estimates ranged from 94% to 100%. The pooled sensitivity and specificity (95% CI) were 83.7% (74.2% to 90.8%) and 99.7% (98.4% to 100.0%), (three studies, 427 participants). We did not perform within study comparisons between accuracy estimates using this reference standard and culture‐based DST given the small number of studies in the former group.

2. Direct testing

(a) Individual drugs within the drug class

We present accuracy estimates for MTBDRsl version 1.0 by direct testing for detection of resistance to ofloxacin and moxifloxacin in Table 5 and Appendix 7. We did not identify any studies that performed direct testing for detection for levofloxacin resistance.

For detection of ofloxacin resistance by direct testing, MTBDRsl version 1.0 sensitivity estimates ranged from 79% to 100% and specificity estimates ranged from 98% to 100%, (seven studies, 1667 participants). The pooled sensitivity and specificity (95% CI) were 90.9% (84.7% to 94.7%) and 98.9% (97.8% to 99.4%). Based on all data, there was no evidence of a statistically significant difference between indirect and direct testing for ofloxacin resistance (P values for differences in sensitivity and specificity of 0.180 and 0.161, respectively).

For detection of moxifloxacin resistance by direct testing, Catanzaro 2015 reported MTBDRsl version 1.0 sensitivity of 96% and specificity of 99% and Ajbani 2012 reported a sensitivity of 92% and specificity of 98%. The pooled sensitivity and specificity (95% CI) were 95.0% (92.1% to 96.9%) and 99.0% (95% CI 97.5% to 99.6%), (two studies, 821 participants). Based on all data, there was no evidence of a statistically significant difference between indirect and direct testing for moxifloxacin resistance (P values for differences in sensitivity and specificity of 0.820 and 0.365, respectively).

(b) Drug concentration used in culture‐based DST

Appendix 5 shows ofloxacin and moxifloxacin drug concentrations used in culture‐based DST in relation to the WHO‐recommended critical concentrations.

Ofloxacin: five studies used the WHO‐recommended critical concentration of ofloxacin (Ajbani 2012; Barnard 2012: Catanzaro 2015; Miotto 2012; Tomasicchio 2016), whereas one study did not (Tukvadze 2014). Hillemann 2009, which used two types of culture medium, used the recommended concentration for one culture type and a non‐recommended concentration for the other.

Moxifloxacin: neither study used the WHO‐recommended critical concentration of moxifloxacin (Ajbani 2012; Catanzaro 2015).

Comparisons between accuracy estimates according to whether or not WHO‐recommended critical drug concentrations were used for culture‐based reference testing were not possible given the small number of studies.

(c) Stratification by smear grade

There were limited data on MTBDRsl version 1.0 accuracy for individual FQ drugs by smear grade. Figure 10 presents the forest plots for ofloxacin resistance by smear grade.

(d) Type of reference standard

Reference standard is sequencing

No studies performed direct MTBDRsl version 1.0 testing and used sequencing as a reference standard.

Reference standard is culture‐based DST and sequencing (i.e. both investigations performed on all isolates)

No studies performed direct MTBDRsl version 1.0 testing and used both culture‐based DST and sequencing (performed on all isolates) as a reference standard.

Reference standard is culture‐based DST followed by sequencing of discrepant index test‐culture‐based DST results

Two studies (685 participants) reported MTBDRsl version 1.0 sensitivity and specificity when performed directly for the detection of resistance to FQs, with culture‐based DST and sequencing performed only on discrepant results as a reference standard. The reported sensitivity and specificity (95% CI) were 91% (84% to 96%) and 98% (92% and 100%) for Ajbani 2012, and 96% (88% to 100%) and 99% (98% to 100%) for Barnard 2012.

II. Second‐line injectable drug resistance detection

A. Estimates of the diagnostic accuracy of MTBDRsl using culture‐based DST as a reference standard

1. Indirect testing

Sixteen studies (1921 participants, 575 (29.9%) confirmed cases of second‐line injectable drug (SLID)‐resistant TB) evaluated MTBDRsl version 1.0 by indirect testing for detection of SLID resistance (Figure 11). Sensitivity estimates ranged from 25% to 100% and specificity estimates ranged from 86% to 100%. The pooled sensitivity and specificity (95% CI) were 76.5% (63.3% to 86.0%) and 99.1% (97.3% to 99.7%) (Table 4).

2. Direct testing

Eight studies (1639 participants, 348 (21.2%) confirmed cases of FQ‐resistant TB) evaluated MTBDRsl version 1.0 by direct testing for detection of SLID resistance (Figure 11). For individual studies, sensitivity estimates ranged from 9% to 100% and specificity estimates ranged from 58% to 100%. The pooled sensitivity and specificity (95% CI) were 87.0% (38.1% to 98.6%) and 99.5% (93.6% to 100.0%) (Table 4).

3. Comparison of indirect versus direct testing

(a) Diagnostic accuracy

Based on analysis of all data, there was no evidence of a statistically significant difference in MTBDRsl version 1.0 accuracy for SLID resistance between indirect and direct testing when using culture‐based DST as a reference standard (P values for differences in sensitivity or specificity of 0.547 and 0.664, respectively) (Table 4). Direct within‐study comparisons were not possible because no studies performed MTBDRsl testing on specimens and isolates from the same patients.

(b) Indeterminate rates

For indirect testing for culture‐confirmed resistance to SLIDs, of 10 studies that reported indeterminate MTBDRsl version 1.0 results, seven (0.5%) of 1316 results were indeterminate (two culture‐DST resistant and five culture‐DST sensitive). For direct testing on a smear‐positive specimen, of four studies that reported indeterminate MTBDRsl results, 219 (13.5%) of 1627 results were indeterminate (34 were culture‐DST resistant, 165 were culture‐DST susceptible, and 20 whose culture phenotypic status was unknown). The indeterminate rates for direct testing for each smear‐grade (smear‐negative, scanty, 1+, 2+, 3+) were 76/180 (42.2%), 35/91 (38.5%), 47/213 (22.1%), 29/200 (14.5%), and 70/364 (19.2%), respectively.

B. Investigations of heterogeneity

1. Indirect testing

(a) Individual drugs within the drug class

We present accuracy estimates for MTBDRsl version 1.0 by indirect testing for detection of resistance to amikacin, kanamycin, and capreomycin in Table 5 and Figure 12.

For detection of amikacin resistance by indirect testing, MTBDRsl version 1.0 sensitivity estimates ranged from 75% to 100% and specificity estimates ranged from 95% to 100%. The pooled sensitivity and specificity (95% CI) were 84.9% (79.2% to 89.1%) and 99.1% (97.6% to 99.6%), (11 studies, 1301 participants).

For detection of kanamycin resistance by indirect testing, MTBDRsl version 1.0 sensitivity estimates ranged from 25% to 100% and specificity estimates ranged from 86% to 100%. The pooled sensitivity and specificity (95% CI) were 66.9% (44.1% to 83.8%) and 98.6% (96.1% to 99.5%), (nine studies, 1342 participants).

For detection of capreomycin resistance by indirect testing), MTBDRsl version 1.0 sensitivity estimates ranged from 21% to 100% and specificity estimates from 86% to 100%. The pooled sensitivity and specificity (95% CI) were 79.5% (58.3% to 91.4%) and 95.8% (93.4% to 97.3%), (10 studies, 1406 participants).

(b) Drug concentration used in culture‐based DST

Appendix 5 shows amikacin, kanamycin, and capreomycin drug concentrations used in culture‐based DST in relation to the WHO‐recommended critical concentrations.

Amikacin: five studies used the WHO‐recommended critical concentration of amikacin (Fan 2011; Ignatyeva 2012; Miotto 2012; Lopez‐Roa 2012; Tomasicchio 2016), whereas three did not (Brossier 2010a; Ferro 2013; van Ingen 2010). Hillemann 2009 and Zivanovic 2012, which each used two types of culture media, used the WHO‐recommended concentration for one culture type and a non‐recommended concentration for the other type. Huang 2011 also used two types of culture media and used the WHO‐recommended concentration for one culture type and for the other culture type, no recommended concentration exists. Between studies that used and did not use the WHO‐recommended critical concentration for amikacin, there was evidence of a statistically significant difference in specificity (P value < 0.001), but not sensitivity (P value = 0.063).

Kanamycin: two studies used the WHO‐recommended critical concentration of kanamycin (Ferro 2013; Huang 2011 for both types of culture media), whereas seven did not (Brossier 2010a; Ignatyeva 2012; Jin 2013; Kiet 2010; Lacoma 2012; Miotto 2012; Said 2012).

Capreomycin: four studies used the WHO‐recommended critical concentration of capreomycin (Hillemann 2009 for both culture types; Ignatyeva 2012; Miotto 2012; Zivanovic 2012 for both culture types), and three did not (Brossier 2010a; Said 2012; van Ingen 2010). Huang 2011 used two types of culture media and used the WHO‐recommended concentration for one culture type and for the other culture type, no recommended concentration exists. Lacoma 2012 used a culture type for which no recommended concentration exists and Jin 2013 did not report the critical concentration used. There was no evidence of a statistically significant difference in MTBDRsl version 1.0 accuracy for capreomycin resistance between studies that used and did not use the WHO‐recommended critical concentration (P values for differences in sensitivity and specificity of 0.161 and 0.625, respectively).

Comparisons between accuracy estimates for kanamycin according to critical concentration were not possible given the small number of studies.

(c) Type of reference standard

We present MTBDRsl version 1.0 accuracy estimates for detection of SLID resistance against different reference standards in Table 6 and Appendix 8.

Reference standard is sequencing

Using sequencing, MTBDRsl version 1.0 sensitivity estimates ranged from 62% to 100% and specificity estimates ranged from 96% to 100%, (seven studies, 962 participants). We restricted the meta‐analysis to comparative studies (six studies, 873 participants). The pooled sensitivity and specificity (95% CI) were 97.0% (77.0% to 99.7%) and 99.5% (94.5% to 100.0%). There was evidence of a significantly higher sensitivity using sequencing as the reference standard compared with culture‐based DST (P value of 0.034), but not specificity (P value of 0.456).

Reference standard is culture‐based DST and sequencing (i.e. both investigations performed on all isolates)

Using culture and sequencing, MTBDRsl version 1.0 sensitivity estimates ranged from 30% to 85% and specificity estimates ranged from 99% to 100%, (seven studies, 1491 participants). We restricted the meta‐analysis to comparative studies (six studies, 1159 participants). The pooled sensitivity and specificity (95% CI) were 61.3% (45.8% to 74.8%) and 99.9% (99.0% to 100.0%). There was no evidence of a statistically significant difference in accuracy using culture and sequencing as the reference standard compared with culture‐based DST (P values for differences in sensitivity and specificity of 0.458 and 0.203, respectively).

Reference standard is culture‐based DST followed by sequencing of discrepant index test‐culture‐based DST results

Using sequencing of discrepant results, MTBDRsl version 1.0 sensitivity estimates ranged from 34% to 100% and specificity estimates ranged from 95% to 100%, (three studies, 619 participants). We did not determine summary estimates because there were only three studies and the sensitivity was variable.

2. Direct testing

(a) Individual drugs within the drug class

We present MTBDRsl accuracy estimates for detection of resistance to amikacin, kanamycin, and capreomycin by direct testing against a phenotypic culture‐based reference standard in Figure 14.

For detection of amikacin resistance by direct testing, MTBDRsl version 1.0 sensitivity estimates ranged from 64% to 100% and specificity estimates ranged from 88% to 100%. The pooled sensitivity and specificity (95% CI) were 91.9% (71.5% to 98.1%) and 99.9% (95.2% to 100.0%), (six studies, 1491 participants). Based on all data, there was no evidence of a statistically significant difference in accuracy between indirect and direct testing for amikacin resistance (P values for differences in sensitivity of specificity 0.338 and 0.213, respectively).

For detection of kanamycin resistance by direct testing, MTBDRsl version 1.0 sensitivity estimates ranged from 9% to 100% and specificity estimates ranged from 90% to 100%. The pooled sensitivity and specificity (95% CI) were 78.7% (11.9% to 99.0%) and 99.7% (95% CI 93.8% to 100.0%), (five studies, 1020 participants). Based on all data, there was no evidence of a statistically significant difference in accuracy between indirect and direct testing for kanamycin resistance (P values for differences in sensitivity of specificity 0.836 and 0.445, respectively).

For detection of capreomycin resistance by direct testing, MTBDRsl version 1.0 sensitivity estimates ranged from 57% to 100% and specificity estimates ranged from 88% to 100%. The pooled sensitivity and specificity (95% CI) were 76.6% (61.1% to 87.3%) and 98.2% (92.5% to 99.6%), (five studies, 1027 participants). Based on all data, there was no evidence of a statistically significant difference in accuracy between indirect and direct testing for capreomycin resistance (P values for differences in sensitivity and specificity of 0.841 and 0.353, respectively).

(b) Drug concentration used in culture‐based

Amikacin: all six studies in this category used the WHO‐recommended critical concentration (Ajbani 2012; Barnard 2012; Catanzaro 2015; Kontsevaya 2013; Miotto 2012; Tomasicchio 2016).

Kanamycin: three studies used the WHO‐recommended critical concentration for kanamycin (Ajbani 2012; Catanzaro 2015; Tukvadze 2014), whereas two did not (Kontsevaya 2013; Miotto 2012).

Capreomycin: all five studies used the WHO‐recommended critical concentration (Ajbani 2012; Catanzaro 2015; Kontsevaya 2013; Miotto 2012; Tukvadze 2014).

Comparisons between accuracy estimates according to whether or not WHO‐recommended critical drug concentrations were used for culture‐based reference testing were not possible.

(c) Stratification by smear grade

There were limited data on MTBDRsl version 1.0 accuracy for individual SLID drugs by smear grade. Figure 15 presents the forest plots for amikacin resistance by smear grade.

(d) Type of reference standard

Reference standard is sequencing

No studies performed direct MTBDRsl version 1.0 testing and used sequencing as a reference standard.

Reference standard is culture‐based DST and sequencing (i.e. both investigations performed on all isolates)

No studies performed direct MTBDRsl version 1.0 testing and used both culture‐based DST and sequencing (performed on all isolates) as a reference standard.

Reference standard is culture‐based DST followed by sequencing of discrepant index test culture‐based DST results

We identified two studies, both of which reported perfect sensitivity and specificity (95% CI): 100% (85% to 100%) and 100% (97% to 100%) for Ajbani 2012, and 100% (92% to 100%) and 100% (98% to 100%) for Barnard 2012, respectively.

III. XDR‐TB detection

A. Estimates of the diagnostic accuracy of MTBDRsl using culture‐based DST as a reference standard

1. Indirect testing

Eight studies (880 participants, 173 (19.7%) confirmed cases of XDR‐TB) evaluated MTBDRsl version 1.0 by indirect testing for detection of XDR‐TB, (Figure 16). Sensitivity estimates ranged from 20% to 100% and specificity estimates ranged from 96% to 100%. The pooled sensitivity and specificity (95% CI) were 70.9% (42.9% to 88.8%) and 98.8% (96.1% to 99.6%).

2. Direct testing

Six studies (1420 participants, 143 (10.1%) confirmed cases of XDR‐TB) evaluated MTBDRsl version 1.0 by direct testing for detection of XDR‐TB, (Figure 16). Sensitivity estimates ranged from 14% to 92% and specificity estimates ranged from 82% to 100%. The pooled sensitivity and specificity (95% CI ) were 69.4% (38.8% to 89.0%) and 99.4% (95.0% to 99.3%).

3. Comparison of indirect versus direct testing

(a) Diagnostic accuracy

Based on analysis of all data, there was no evidence of a statistically significant difference in MTBDRsl version 1.0 accuracy for XDR‐TB between indirect and direct testing when using culture‐based DST as a reference standard (P values for differences in sensitivity and specificity of 0.916 and 0.387, respectively) (Table 4). Direct within‐study comparisons were not possible because no studies performed MTBDRsl version 1.0 testing on specimens and isolates from the same patients.

(b) Indeterminate rates

For indirect testing for XDR‐TB, of the six studies that reported version 1.0 results, one (0.2%) of 554 was indeterminate (one culture DST sensitive). For direct testing on a smear‐positive specimen, of seven studies that reported indeterminate MTBDRsl results, 224 (13.5%) of 1665 results were indeterminate (27 culture‐DST resistant, 186 culture‐DST susceptible, and 11 of unknown phenotypic culture status). The indeterminate rates for direct testing for each smear‐grade (smear‐negative, scanty, 1+, 2+, 3+) were 81/183 (44.2%), 39/186 (21.0%), 53/225 (23.5%), 33/301 (11.0%), and 82/177 (46.3%).

B. Investigations of heterogeneity

1. Indirect testing

(a) Drugs used in the culture‐based DST

One of the eight studies that performed indirect testing for XDR‐TB and used culture‐based DST as a reference standard used ofloxacin and kanamycin (Kiet 2010). Two studies used ofloxacin, amikacin, and capreomycin (Hillemann 2009; Zivanovic 2012). One study used ofloxacin, amikacin, and kanamycin (Miotto 2012). One study used levofloxacin, amikacin, kanamycin, and capreomycin (Chikamatsu 2012). One study used ofloxacin, amikacin, kanamycin, and capreomycin (Ignatyeva 2012). One study used ofloxacin, kanamycin, and capreomycin (Jin 2013). One study used moxifloxacin, amikacin, and ofloxacin (van Ingen 2010).

As all but two studies used a different combination of drugs, we did not compare test performance according to drugs used in the culture‐based DST.

(b) Drug concentration used in culture‐based DST

Ofloxacin: two studies in this category used the WHO‐recommended critical concentration for ofloxacin (Ignatyeva 2012; Miotto 2012), and two did not (Jin 2013; Kiet 2010). Two studies used two different types of culture but only used the WHO‐recommended critical concentration of ofloxacin for one type of culture (Hillemann 2009; Zivanovic 2012).

Moxifloxacin: van Ingen 2010 used moxifloxacin but did not use the WHO‐recommended critical concentration.

Levofloxacin: for the study that used levofloxacin (Chikamatsu 2012), the WHO does not recommend a critical concentration for the type of culture used (Ogawa culture).

Amikacin: for the six studies that used amikacin, two used the WHO‐recommended critical concentration (Ignatyeva 2012; Miotto 2012), one did not report the concentration used (Chikamatsu 2012), and one used a type of culture‐based testing (Middlebrook 7H10 media) for which the WHO did not specify a recommended critical concentration (van Ingen 2010). Two studies used two types of culture medium, one of which was done at a recommended concentration and the other not (Hillemann 2009;Zivanovic 2012).

Kanamycin: of the five studies that used kanamycin, four did not use the WHO‐recommended critical concentration (Ignatyeva 2012; Jin 2013; Kiet 2010; Miotto 2012), and one did not report the concentration used (Chikamatsu 2012).

Capreomycin: of the seven studies that used capreomycin, four used the WHO‐recommended critical concentration (Hillemann 2009 for both culture types; Ignatyeva 2012; Miotto 2012; Zivanovic 2012 for both culture types), whereas one study did not (van Ingen 2010); and two studies did not report the concentration used (Chikamatsu 2012; Jin 2013).

We did not compare MTBDRsl version 1.0 accuracy according to drug concentrations used in the culture‐based DST because there were few studies that used the same drugs and the same critical concentrations.

(c) Type of reference standard

We present MTBDRsl version 1.0 accuracy estimates for detection of XDR‐TB against different reference standards in Table 6 and Figure 17.

Reference standard is sequencing

For individual studies (four studies, 630 participants), MTBDRsl version 1.0 sensitivity estimates in all four studies were 100% and specificity estimates ranged from 95% to 100%. We restricted the meta‐analysis to comparative studies (three studies, 541 participants). Using a fixed‐effect model, the pooled sensitivity and specificity (95% CI) were 100% (94.6% to 100.0%) and 97.9% (96.3% to 98.8%).

Reference standard is culture‐based DST and sequencing (i.e. both investigations performed on all isolates)

We identified two studies with 435 participants. MTBDRsl version 1.0 sensitivity and specificity estimates (95% CI) were 56% (45% to 67%) and 99% (96% to 100%) for Jin 2013, and 71% (44% to 90%) and 99% (95% to 100%) for Miotto 2012. We did not perform a meta‐analysis.

Reference standard is culture‐based DST followed by sequencing of discrepant index test‐culture‐based DST results

No studies performed indirect MTBDRsl version 1.0 testing for XDR‐TB and used culture‐based DST and sequencing for discrepant results as a reference standard.

2. Direct testing

(a) Drugs used in the culture‐based DST

Two of the six studies that performed direct testing for XDR‐TB and used culture‐based DST as a reference standard used ofloxacin and amikacin (Barnard 2012; Tomasicchio 2016). Two studies used ofloxacin, moxifloxacin, amikacin, kanamycin, and capreomycin (Catanzaro 2015; Kontsevaya 2013). One study used ofloxacin, amikacin, kanamycin, and capreomycin (Miotto 2012). One study used ofloxacin, kanamycin, and capreomycin (Tukvadze 2014).

As all but two studies used a different combination of drugs, we did not compare test performance according to drugs used in the culture‐based DST.

(b) Drug concentration used in culture‐based DST

Ofloxacin: five studies in this category used the WHO‐recommended critical concentration for ofloxacin (Barnard 2012; Catanzaro 2015; Kontsevaya 2013; Miotto 2012; Tomasicchio 2016), whereas one did not (Tukvadze 2014).

Moxifloxacin: neither study used the WHO‐recommended critical concentration for moxifloxacin (Catanzaro 2015; Kontsevaya 2013).

Amikacin: four studies in this category used the WHO‐recommended critical concentration for amikacin (Catanzaro 2015; Kontsevaya 2013; Miotto 2012; Tomasicchio 2016), whereas on study did not (Barnard 2012).

Kanamycin: two studies used the WHO‐recommended critical concentration for kanamycin (Catanzaro 2015; Tukvadze 2014), whereas two studies did not (Kontsevaya 2013; Miotto 2012).

Capreomycin: all four studies in this category used the WHO‐recommended critical concentration for capreomycin (Catanzaro 2015; Kontsevaya 2013; Miotto 2012; Tukvadze 2014).

We did not compare test accuracy according to drug concentrations used in the culture‐based DST because there were few studies using the same drugs and the same critical concentrations.

(c) Type of reference standard

Reference standard is sequencing

No studies performed direct MTBDRsl version 1.0 testing for XDR‐TB and used sequencing as a reference standard.

Reference standard is culture‐based DST and sequencing (i.e. both investigations performed on all isolates)

No studies performed direct MTBDRsl version 1.0 testing and used both culture‐based DST and sequencing (performed on all isolates) as a reference standard.

Reference standard is culture‐based DST followed by sequencing of discrepant index test‐culture‐based DST results

We identified two studies that used culture‐based DST and performed sequencing only on discrepant results (Barnard 2012; Miotto 2012). These studies both reported sensitivities of 92% and specificities of 100%.

Sensitivity analyses

We have presented the MTBDRsl version 1.0 sensitivity analyses (using culture‐based DST as the reference standard) for the FQs (Table 7) and the SLIDs (Table 8). The sensitivity analyses made no difference to any of the findings.

MTBDRsl version 2.0

I. Fluoroquinolone resistance detection

A. Estimates of the diagnostic accuracy of MTBDRsl using culture‐based DST as a reference standard

1. Indirect testing

By indirect testing, MTBDRsl version 2.0 sensitivity and specificity (95% CI) were 84% (73% to 91%) and 100% (98% to 100%) (Tagliani 2015; Figure 18).

2. Direct testing

By direct testing, MTBDRsl version 2.0 sensitivity and specificity (95% CI) were 97% (83% to 100%) and 98% (93% to 100%) on a smear‐positive specimen and 80% (28% to 99%) and 100% (40% to 100%) on a smear‐negative specimen (Tagliani 2015; Figure 19).

3. Drug concentration used in culture‐based DST

Ofloxacin: Tagliani 2015 used the WHO‐recommended critical concentration.

Moxifloxacin: Tagliani 2015 used the WHO‐recommended critical concentration for low‐level moxifloxacin resistance.

Levofloxacin: Tagliani 2015 used the WHO‐recommended critical concentration.

4. Indeterminate rates

For both indirect and direct testing for culture‐confirmed resistance to FQs, Tagliani 2015 reported zero indeterminate results.

II. SLID resistance detection

A. Estimates of the diagnostic accuracy of MTBDRsl using culture‐based DST as a reference standard

1. Indirect testing

For MTBDRsl version 2.0 performed by indirect testing, sensitivity and specificity (95% CI) were 86% (80% to 91%) and 90% (81% to 96%) (Figure 18; Tagliani 2015).

2. Direct testing

By direct testing, sensitivity and specificity (95% CI) were 89% (72% to 98%) and 90% (84% to 95%) on a smear‐positive specimen and 80% (28% to 99%) and 100% (40% to 100%) on a smear‐negative specimen (Figure 19; Tagliani 2015).

3. Drug concentration used in culture‐based DST

Amikacin: Tagliani 2015 used the WHO‐recommended critical concentration of amikacin.

Kanamycin: Tagliani 2015 used the WHO‐recommended critical concentration of kanamycin.

Capreomycin: Tagliani 2015 used the WHO‐recommended critical concentration of capreomycin.

4. Indeterminate rates

For both indirect and direct testing for culture‐confirmed resistance to SLIDs, Tagliani 2015 reported zero indeterminate results.

III. XDR‐TB detection

A. Estimates of the diagnostic accuracy of MTBDRsl using culture‐based DST as a reference standard

1. Indirect testing

For MTBDRsl version 2.0 performed by indirect testing, sensitivity and specificity (95% CI) were 80% (66% to 91%) and 96% (82% to 98%) (Figure 18; Tagliani 2015).

2. Direct testing

By direct testing, sensitivity and specificity (95% CI) were 79% (49% to 95%) and 97% (93% to 99%) on a smear‐positive specimen and 50% (1% to 99%) and 100% (59% to 100%) on a smear‐negative specimen (Figure 19; Tagliani 2015).

3. Indeterminate rates

Tagliani 2015 reported zero indeterminate results for both indirect and direct testing for XDR‐TB.

Comparison of the accuracy of version 1.0 and 2.0

As we identified only one study that evaluated MTBDRsl version 2.0, we could not compare the accuracy of MTBDRsl version 1.0 and 2.0.

Other analyses

We did not identify any reports on intra‐reader variability. One study described inter‐reader variability and reported high concordance > 95% (Ignatyeva 2012).

Regarding patient outcomes, only four studies described the effect of MTBDRsl on time‐to‐diagnosis. Lopez‐Roa 2012 reported the test to have a time‐to‐diagnosis of eight hours, compared to DST using the agar proportion method (21 days) or the MGIT 960 method (eight days). Said 2012 stated that MTBDRsl had a median time‐to‐diagnosis of two days, compared to 11 days for the agar proportion method. Tukvadze 2014 noted a median time‐to‐diagnosis using MTBDRsl of 10 days, versus 70 to 104 days for culture‐based DST. Barnard 2012 reported MTBDRsl to have a median turn‐around‐time of one day (after the diagnosis of first‐line resistance), whereas the median turn‐around‐time for phenotypic culture‐based DST was 31 days.

Discusión

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Esta revisión sistemática actualizada resume la bibliografía más reciente, incluye 27 estudios e integra seis estudios nuevos: cinco estudios nuevos para la versión 1.0 de la MTBDRsl identificados desde la revisión Cochrane original (Theron 2014), y un estudio para la versión 2.0 de la MTBDRsl. Para la versión 1.0 de la MTBDRsl, los resultados de esta revisión actualizada son compatibles con los informados en la versión anterior de la revisión. La sensibilidad y especificidad promedio de la versión 1.0 de la MTBDRsl para la detección de la resistencia a las fluoroquinolonas (FQ) y los fármacos inyectables de segunda línea (FISL) y para la tuberculosis de alta resistencia a los fármacos (TB‐ARF) se presentan en las tablas "Resumen de resultados" (Resumen de resultados, tabla 1; Resumen de resultados, tabla 2; Resumen de resultados, tabla 3)y Tabla 4, Tabla 5, y Tabla 6.

Se encontró que, cuando se comparó la exactitud de la versión 1.0 de la MTBDRsl sobre la base de si la prueba se realizó directa o indirectamente, la sensibilidad fue similar para la resistencia a las FQ y a los FISL. Cuando se utilizó de manera indirecta en un aislado de cultivo, la MTBDRsl tuvo una sensibilidad agrupada mayor para la detección de la resistencia a las FQ (85,6%) que para la detección de la resistencia a los FISL (76,5%). Cuando se utilizó de manera directa en una muestra con baciloscopia positiva, la MTBDRsl tuvo una sensibilidad agrupada similar para la resistencia a las FQ (86,2%) y la resistencia a los FISL (87,0%); sin embargo, la sensibilidad agrupada para la resistencia a los FISL fue imprecisa (intervalo de confianza [IC] del 95%: 38,1% a 98,8%). Cuando se analizó la resistencia a los FISL para los fármacos individuales, la sensibilidad agrupada (pruebas directas) fue mayor para la amikacina (92%). Para la detección de la TB‐ARF, la sensibilidad agrupada de la MTBDRsl fue 70,9% con las pruebas indirectas y 69,4% con las pruebas directas. Para la detección de la resistencia a las FQ y los FISL y la TB‐ARF mediante pruebas indirectas o directas, la especificidad agrupada de la MTBDRsl fue alta (> 98%).

Se comparó la exactitud de la versión 1.0 de la MTBDRsl con diferentes estándares de referencia que incluyeron las pruebas de sensibilidad farmacológica (PSF) basada en cultivo (el estándar de referencia tradicional) o la secuenciación. Se examinó la exactitud de la versión 1.0 de la MTBDRsl en relación con cada tipo de estándar de referencia solo o en combinación (en que a todas las muestras se les realizó PSF basada en cultivo y secuenciación). Cuando se utilizó de manera indirecta en un aislado de cultivo para la detección de la resistencia a las FQ, la versión 1.0 de la MTBDRsl tuvo una sensibilidad agrupada mayor contra la secuenciación que contra la PSF basada en cultivo (99,3% versus 82,4%). Lo anterior indica que la MTBDRsl es sensible para detectar la resistencia a las FQ causada por las mutaciones en gyrA (el único gen objetivo de la MTBDRsl para la detección de la resistencia a las FQ). Sin embargo, contra la PSF basada en cultivo, la sensibilidad de la MTBDRsl para la resistencia a las FQ sólo fue del 82,4%; lo que indica que menos de uno de cada cinco casos puede ser causado por mutaciones fuera de gyrA, como el gyrB, un gen que no es objetivo de la versión 1.0 de la MTBDRsl. Una explicación alternativa es que la proporción de bacilos que hospedan la mutación está por debajo del umbral de detección de la MTBDRsl, pero no por debajo del umbral de detección de la prueba fenotípica.

De manera similar, se encontró una sensibilidad agrupada mayor para la resistencia a los FISL cuando se evaluó la versión 1.0 de la MTBDRsl contra la secuenciación, en lugar de la PSF basada en cultivo (97,0% versus 74,6%). En este caso, la secuenciación y la MTBDRsl sólo se dirigen al gen rrs para la resistencia a los FISL. Este enfoque puede pasar por alto las mutaciones fuera de esta región que causan resistencia a los FISL. Mediante la PSF basada en cultivo (sensibilidad 74,6%), al parecer alrededor de uno de cada cuatro casos de TB resistente a los FISL puede ser causado por mutaciones fuera de rrs. La prevalencia de estas mutaciones no rrs, que pueden ocurrir en regiones como tlyA, eis y gidB (Georghiou 2012), parece ser sumamente pronunciada para la kanamicina debido a la reducción de la sensibilidad (66,9%) de la MTBDRsl para la resistencia a este fármaco, en comparación con los otros FISL (sensibilidad 84,9% y 79,5% para amikacina y capreomicina, respectivamente, MTBDRsl realizada indirectamente contra PSF basada en cultivo). Es probable que la sensibilidad de la MTBDRsl para la resistencia a los FISL, y en particular para la resistencia a la kanamicina, varíe según los antecedentes genéticos de las cepas de M. tuberculosis, ya que algunas pueden tener una mayor frecuencia de mutaciones que causan resistencia fuera de rrs y diferentes niveles de resistencia cruzada de los FISL. A igual que en el caso de las FQ, los bacilos que hospedan mutaciones pueden estar por debajo del límite de detección de la MTBDRsl.

Se conocen dos revisiones sistemáticas de la MTBDRsl (Feng 2013; WHO 2013). Feng 2013 (11 estudios publicados) determinó la sensibilidad y la especificidad de la MTBDRsl para la resistencia a los fármacos antituberculosos de segunda línea mediante un metanálisis con un modelo de efectos fijos, en lugar de ajustarse al modelo de efectos aleatorios de dos variables actualmente recomendado. Los cálculos de la exactitud para la resistencia a la kanamicina y la resistencia a la capreomicina fueron significativamente menores que los encontrados en la presente revisión. Al igual que en la presente revisión, WHO 2013 (11 estudios publicados y siete no publicados) utilizó un metanálisis con un modelo de efectos aleatorios y llegó a estimaciones resumen similares. La revisión incluyó estudios adicionales no incluidos en estas revisiones anteriores. Se mantienen las preguntas clave relacionadas con la exactitud de la prueba y las posibles fuentes de heterogeneidad, incluido el riesgo de sesgo, el tipo de prueba (pruebas indirectas versus pruebas directas) y el estándar de referencia (por ejemplo, PSF basada en cultivo versus secuenciación genética). En la presente revisión se abordaron varias de estas preguntas. Aunque se planificó investigar si la exactitud observada de la prueba varió entre los estudios según el estado de infección por VIH, la condición de la muestra (congelada versus fresca), el tipo de muestra (muestra por esputo inducido o extrapulmonar), la concentración de los fármacos utilizada en la PSF basada en cultivo (estudios que utilizaron las concentraciones recomendadas por la Organización Mundial de la Salud [OMS] versus los que no lo hicieron) o la población (pacientes con sospecha de presentar TB‐RMF o TB‐ARF), desafortunadamente no hubo datos suficientes para realizar estos análisis adicionales para cada condición proyectada. Tampoco fue posible examinar las fuentes de heterogeneidad para la detección de la TB‐ARF debido a que no hubo datos suficientes. Asimismo, hubo datos limitados para investigar la influencia del grado de la baciloscopia en los cálculos de la exactitud.

Resumen de los resultados principales

Los resultados principales se describen en las tablas "Resumen de resultados".

Cuando se realizó indirectamente en un aislado de cultivo, la versión 1.0 de la MTBDRsl para la resistencia a las FQ tuvo una sensibilidad del 85,6% en comparación con el 86,2% cuando se realizó directamente en una muestra con baciloscopia positiva; la especificidad de las pruebas indirectas (98,5%) y de las pruebas directas (98,6%) fueron altas.
Cuando se realizó indirectamente, la versión 1.0 de la MTBDRsl para la resistencia a los FISL tuvo una sensibilidad del 76,5% en comparación con el 87,0% cuando se realizó directamente en una muestra con baciloscopia positiva; la especificidad de las pruebas indirectas (99,1%) y de las pruebas directas (99,5%) fueron altas.
Cuando se realizó indirectamente, la versión 1.0 de la MTBDRsl para la TB‐ARF tuvo una sensibilidad del 70,9% en comparación con el 69,4% cuando se realizó directamente en una muestra con baciloscopia positiva; la especificidad de las pruebas indirectas (98,8%) y de las pruebas directas (98,0%) fueron altas.
Para la versión 1.0 de la MTBDRsl 1.0, no se encontró evidencia de una diferencia estadísticamente significativa en la exactitud entre las pruebas indirectas y directas en una muestra con baciloscopia positiva para la resistencia a las FQ, la resistencia a los FISL o la TB‐ARF.
Tampoco hubo datos suficientes para calcular la exactitud diagnóstica resumida de la versión 2.0 de la MTBDRsl (muestras con baciloscopia positiva o con baciloscopia negativa), ni para comparar la exactitud de las dos versiones.

Aplicación del metanálisis a una cohorte hipotética

En las tablas "Resumen de resultados", se han resumido los resultados de la revisión para la versión 1.0 de la MTBDRsl al aplicar los resultados a una cohorte hipotética de 1000 individuos con tuberculosis resistente a la rifampicina o TB‐RMF que se piensa presentan resistencia a una FQ, un FISL o ambos (Resumen de resultados, tabla 1; Resumen de resultados, tabla 2; Resumen de resultados, tabla 3). Se presentan varios escenarios, según la prevalencia de tuberculosis farmacorresistente indicada por la OMS del 5%, el 10% y el 15% para las FQ y la resistencia a los FISL, y del 1%, el 5% y el 10% para la TB‐ARF. Se seleccionaron estos umbrales sobre la base de los resultados de la vigilancia global de la resistencia de segunda línea entre los pacientes con tuberculosis resistente a la rifampicina o la TB‐RMF de 75 países (WHO 2015). Las consecuencias de los resultados falsos positivos (FP) son la posible ansiedad de los pacientes, la morbilidad de las pruebas adicionales, los posibles retrasos en la evaluación diagnóstica adicional y el tratamiento prolongado e innecesario con fármacos que pueden tener una actividad bactericida inferior que los regímenes de segunda línea, y que a menudo tienen graves efectos secundarios. Las consecuencias de los resultados falsos negativos (FN) son un mayor riesgo de morbilidad y mortalidad en los pacientes, y el riesgo continuo de transmisión de la tuberculosis farmacorresistente en la comunidad.

Versión 1.0 de la MTBDRsl, prueba directa (muestra con baciloscopia positiva) para la resistencia a las fluoroquinolonas

Mediante la prueba directa (baciloscopia positiva), se detectó un 86% de pacientes con resistencia a la FQ y la misma rara vez proporcionó un resultado positivo en los pacientes sin resistencia. En una población de 1000 pacientes, en la que 150 presentan resistencia a la FQ, la MTBDRsl identificará correctamente a 129 pacientes con resistencia a la FQ y omitirá a 21 pacientes En esta misma población de 1000 pacientes, en la que 850 pacientes no presentan resistencia a la FQ, la prueba clasificará correctamente a 838 pacientes sin resistencia a la FQ y clasificará de forma errónea a 12 pacientes con resistencia.

Versión 1.0 de la MTBDRsl, prueba directa (muestra con baciloscopia positiva) para la resistencia a los FISL

Mediante la prueba indirecta (baciloscopia positiva), se detectó un 87% de pacientes con resistencia a los FISL y rara vez llevó a un resultado positivo en los pacientes sin resistencia. En una población de 1000 pacientes, en la que 150 presentan resistencia a los FISL, la MTBDRsl identificará correctamente a 131 pacientes con resistencia a los FISL y omitirá a 19 pacientes En esta misma población de 1000 pacientes, en la que 850 no presentan resistencia a los FISL, la prueba clasificará correctamente a 846 pacientes sin resistencia a los FISL y clasificará de forma errónea a cuatro pacientes con resistencia.

Versión 1.0 de la MTBDRsl, prueba directa (muestra con baciloscopia positiva) para la TB‐ARF

Mediante la prueba indirecta (baciloscopia positiva), se detectó un 69% de pacientes con TB‐ARF y la misma rara vez llevó a un resultado positivo en los pacientes sin resistencia. En una población de 1000 pacientes, en la que 100 presentan TB‐ARF, la MTBDRsl identificará correctamente a 69 pacientes con TB‐ARF y omitirá a 31. En esta misma población de 1000 pacientes, en la que 900 no presentan TB‐ARF, la prueba clasificará correctamente a 891 pacientes sin resistencia a los FISL y clasificará de forma errónea a nueve pacientes con resistencia.

Fortalezas y limitaciones de la revisión

Los resultados de esta revisión se basan en un proceso estricto y cuidadoso de búsquedas bibliográficas, inclusión de los estudios y extracción de los datos. La fortaleza de esta revisión radica en que permite una evaluación de diferentes métodos de prueba (indirecta versus directa) y diferentes estándares de referencia.

Completitud de la evidencia

Este es un conjunto de datos razonablemente completo. Se incluyó cualquier estudio no publicado en inglés del cual fue posible obtener datos sobre la exactitud. Sin embargo, se reconoce que es posible que, a pesar de la búsqueda exhaustiva, se hayan pasado por alto algunos estudios.

Exactitud de los estándares de referencia utilizados

Para el análisis primario se utilizó la PSF basada en cultivo. Esta prueba fue el estándar de referencia señalado con mayor frecuencia en los estudios incluidos. Aunque se considera el mejor estándar de referencia para la tuberculosis farmacorresistente, la PSF basada en cultivo no es 100% exacta para la detección de la farmacorresistencia, en particular en lo que se refiere a la detección de la farmacorresistencia de segunda línea. También se determinó la exactitud de la MTBDRsl cuando se utilizó la secuenciación (secuenciación de genes de los lugares que se conoce se asocian con farmacorresistencia), así como la secuenciación y la PSF basada en cultivo, como estándar de referencia. Muchos expertos en TB consideran que la secuenciación es el mejor estándar de referencia disponible, siempre que abarque todas las posibles regiones implicadas en la resistencia. Además, se determinó la exactitud de la MTBDRsl contra un cuarto estándar de referencia, en el que la secuenciación sólo se realizó como parte de un análisis cuando los resultados de la PSF basada en cultivo y la MTBDRsl fueron discrepantes. Sin embargo, en la mayoría de los casos no fue posible realizar los cálculos resumen debido al número pequeño de estudios y, por lo tanto, no fue posible comparar los cálculos de la exactitud de la MTBDRsl cuando se utilizó este estándar de referencia con los que se obtuvieron con la PSF basada en cultivo, la secuenciación o ambas, como estándar de referencia. En general, la exactitud de la MTBDRsl fue mayor cuando se midió contra un estándar de referencia que incluyó la evaluación genética. Sin embargo, dicha evaluación genética sólo se limitó a los genes objetivo de la MTBDRsl y no detectó mutaciones fuera de estos genes que podrían causar farmacorresistencia fenotípica.

Calidad y calidad del informe de los estudios incluidos

Se consideró que más del 50% de los estudios tuvieron bajo riesgo de sesgo para los dominios selección de los pacientes, prueba índice y flujo y momento. Se consideró que sólo tres estudios (11%) tuvieron bajo riesgo de sesgo para el dominio del estándar de referencia porque estos estudios utilizaron las concentraciones críticas recomendadas por la OMS para cada fármaco en el estándar de referencia PSF basada en cultivo, mientras que el otro estudio no lo hizo. Con respecto a la aplicabilidad, hubo pocas inquietudes para todos los dominios de QUADAS 2. En general, los estudios se informaron bastante bien, aunque se le envió correspondencia a casi todos los autores de los estudios en busca de datos adicionales e información faltante. Sin embargo, los datos de la exactitud para los fármacos individuales y los grados de la baciloscopia no se informaron de manera adecuada y el cegamiento no se informó en una pequeña parte de los estudios. Se recomienda con fuerza que los estudios futuros sigan las recomendaciones de la declaración Standards for Reporting Diagnostic Accuracy (STARD) para mejorar la calidad de la información (Bossuyt 2015).

Interpretabilidad de los análisis de subgrupos

Se investigaron las posibles fuentes de heterogeneidad en los diferentes estándares de referencia utilizados y los fármacos individuales en las clases de fármacos FQ y FISL. Se realizaron pruebas estadísticas y se proporcionó el valor de p cuando fue apropiado. Cuando los datos fueron suficientes, los cálculos de la exactitud se derivaron de estudios comparativos de la exactitud de la prueba en los que se utilizó el mismo conjunto de estudios para cada evaluación de la prueba. Cuando los datos de los estudios comparativos de la exactitud fueron limitados se utilizaron todos los datos relevantes. Para algunos subgrupos (por ejemplo, pacientes que viven con el VIH), no hubo datos suficientes para realizar el análisis.

Completitud y relevancia de la revisión

Actualmente hay varias pruebas comercialmente disponibles además de la MTBDRsl para la detección de la resistencia más allá de la TB‐RMF. Estas pruebas incluyen TB Resistance Module Fluoroquinolones/Ethambutol y TB Resistance Module Kanamycin/Amikacin/Capreomycin/Streptomycin (Autoimmun Diagnostika GmbH (AID) Strassberg); MolecuTech REBA MTB‐FQ^®, MolecuTech REBA MTB‐KM^® y MolecuTech REBA MTB‐XDR^® (YD diagnostics, Seoul); y NiPro LiPA FQ (NiPro Co, Osaka). La presente revisión es el análisis más completo de la exactitud diagnóstica de la prueba MTBDRsl hasta la fecha.

Datos no publicados

No se incluyeron datos no publicados.

Aplicabilidad de los hallazgos a la pregunta de la revisión

Hubo pocas inquietudes acerca de la aplicabilidad de los estudios incluidos con respecto a la pregunta de la revisión, evaluada mediante QUADAS‐2. La revisión evaluó principalmente la versión 1.0 de la MTBDRsl, que ha sido reemplazada recientemente por la versión 2.0. Se consideró que, al agregar las nuevas sondas dirigidas a más mutaciones causantes de resistencia, sería de esperar que la sensibilidad de la versión 2.0 de la MTBDRsl sería la misma o mayor que la de la versión 1.0 de la MTBDRsl, y que la especificidad permanecería igual o disminuiría ligeramente debido a una pequeña probabilidad de que al menos una de las sondas se pudiera asociar con una identificación errónea (y dar lugar a un aumento de los resultados falsos positivos). Por lo tanto, los resultados de esta revisión se deben considerar aplicables a la prueba. Sin embargo, es importante señalar que esta revisión evaluó la sensibilidad y la especificidad en contextos de investigación. Aunque las características de los pacientes y los contextos coincidieron con la pregunta de la revisión en la mayoría de los casos, debido a que los estudios se realizaron en condiciones de investigación, es posible que la exactitud de la MTBDRsl sea inferior en ámbitos de la práctica habitual.

Figure 1

Comparison of version 1.0 and version 2.0 of the GenoType® MTBDRsl test (adapted from Hain Life Sciences 2015).

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Figure 2

Clinical pathway. A patient to be evaluated for drug‐resistant tuberculosis (TB) provides a specimen (usually sputum), which is examined by smear microscopy. If smear‐positive, MTBDRsl version 1.0 or version 2.0 can be performed directly on the specimen. If smear‐negative, MTBDRsl version 1.0should not be performed directly on the specimen, but rather on the culture isolate. Version 2.0 may be performed directly on a smear‐negative specimen. A molecular test for first‐line drug resistance (for example, the MTBDRplus assay) may be performed prior to testing with MTBDRsl if resistance to the first‐line drugs is yet to be confirmed. Phenotypic (culture‐based) drug susceptibility testing (DST) may still be performed on culture‐positive isolates.

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Figure 3

Study flow diagram for searches run from January 2014 to 21 September 2015.

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Figure 4

Risk of bias and applicability concerns graph: review authors' judgements about each domain presented as percentages across included studies.

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Figure 5

Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study.

For direct testing of smear‐positive specimens, Miotto 2012 and Tomasicchio 2016 had low risk of bias in the patient selection domain.

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Figure 6

Forest plots of MTBDRsl sensitivity and specificity for fluoroquinolone (FQ) resistance, the test performed indirectly or directly against culture‐based drug susceptibility (DST) as a reference standard. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Values between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). The individual studies are ordered by decreasing sensitivity.

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Figure 7

Forest plots of MTBDRsl sensitivity and specificity for ofloxacin resistance by smear grade, using culture‐based drug susceptibility testing (DST) as a reference standard. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). The individual studies are ordered by decreasing sensitivity.

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Figure 8

Forest plots of MTBDRsl sensitivity and specificity for SLID resistance, the test performed indirectly or directly against culture‐based drug susceptibility testing (DST) as a reference standard. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Values between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). The individual studies are ordered by decreasing sensitivity.

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Figure 9

Forest plots of MTBDRsl sensitivity and specificity for the detection of resistance to amikacin, kanamycin, and capreomycin, the test performed indirectly against culture‐based drug susceptibility testing (DST) as a reference standard. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Values between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). The individual studies are ordered by decreasing sensitivity.

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Figure 10

Forest plots of MTBDRsl sensitivity and specificity for resistance to amikacin, kanamycin, and capreomycin, the test performed directly against culture‐based drug susceptibility testing (DST) as a reference standard. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). The individual studies are ordered by decreasing sensitivity.

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Figure 11

Forest plots of MTBDRsl sensitivity and specificity for detection of amikacin resistance by smear grade, using culture‐based drug susceptibility testing (DST) as a reference standard. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). The individual studies are ordered by decreasing sensitivity.

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Figure 12

Forest plots of MTBDRsl sensitivity and specificity for the detection of XDR‐TB, the test performed indirectly and directly against culture‐based drug susceptibility testing (DST) as a reference standard. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). The individual studies are ordered by decreasing sensitivity.

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Figure 13

Forest plots of MTBDRsl sensitivity and specificity for extensively drug‐resistant tuberculosis (XDR‐TB), the test performed indirectly against three different reference standards. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Values between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). The individual studies are ordered by decreasing sensitivity.

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Figure 14

Forest plots of MTBDRsl version 2.0 sensitivity and specificity for the detection of resistance to the fluoroquinolones (FQs) and second‐line injectable drugs (SLIDs) and extensively drug‐resistant tuberculosis (XDR‐TB), the test performed indirectly and directly against culture‐based drug susceptibility testing (DST) as a reference standard. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line).

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Figure 15

Forest plots of MTBDRsl version 2.0 sensitivity and specificity for the detection of resistance to the fluoroquinolones (FQs) and second‐line injectable drugs (SLIDs) and extensively drug‐resistant tuberculosis (XDR‐TB), the test performed directly on smear‐positive and smear‐negative specimens against culture‐based drug susceptibility testing (DST) as a reference standard. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line).

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Figure 16

Forest plots of MTBDRsl sensitivity and specificity for ofloxacin, moxifloxacin, and levofloxacin resistance, the test performed indirectly against culture‐based drug susceptibility testing (DST) as a reference standard. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Values between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). The individual studies are ordered by decreasing sensitivity.

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Figure 17

Forest plots of MTBDRsl sensitivity and specificity for fluoroquinolone (FQ) resistance, the test performed indirectly against different reference standards. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Values between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). The individual studies are ordered by decreasing sensitivity.

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Figure 18

Forest plots of MTBDRsl sensitivity and specificity for ofloxacin, moxifloxacin, and levofloxacin resistance, the test performed directly against culture‐based drug susceptibility testing (DST) as a reference standard. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Values between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). The individual studies are ordered by decreasing sensitivity.

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Figure 19

Forest plots of MTBDRsl sensitivity and specificity for second‐line injectable drug (SLID) resistance, the test performed indirectly against three different reference standards. TP = true positive; FP = false positive; FN = false negative; TN = true negative. Values between brackets are the 95% confidence intervals (CIs) of sensitivity and specificity. The figure shows the estimated sensitivity and specificity of the study (blue square) and its 95% CI (black horizontal line). The individual studies are ordered by decreasing sensitivity.

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Test 1

Indirect, FQ, culture.

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Test 2

Indirect, ofloxacin, culture.

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Test 3

Indirect, moxifloxacin, culture.

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Test 4

Indirect, levofloxacin, culture.

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Test 5

Indirect, ofloxacin, WHO critical concentration used.

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Test 6

Indirect, ofloxacin, WHO critical concentration not used.

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Test 7

Indirect, SLID, culture.

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Test 8

Indirect, amikacin, culture.

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Test 9

Indirect, kanamycin, culture.

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Test 10

Indirect, capreomycin, culture.

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Test 11

Indirect, amikacin, WHO critical concentration used.

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Test 12

Indirect, capreomycin, WHO critical concentration used.

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Test 13

Indirect, amikacin, WHO critical concentration not used.

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Test 14

Indirect, capreomycin, WHO critical concentration not used.

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Test 15

Indirect, XDR, culture.

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Test 16

Indirect, FQ, sequencing.

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Test 17

Indirect, SLID, sequencing.

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Test 18

Indirect, XDR, sequencing.

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Test 19

Indirect, FQ, sequencing and culture.

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Test 20

Indirect, SLID, sequencing and culture.

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Test 21

Indirect, XDR, sequencing and culture.

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Test 22

Indirect, FQ, culture followed by sequencing of discrepants.

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Test 23

Indirect, SLID, culture followed by sequencing of discrepants.

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Test 24

Direct, FQ, culture.

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Test 25

Direct, ofloxacin, culture.

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Test 26

Direct, moxifloxacin, culture.

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Test 27

Ofloxacin, smear positive.

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Test 28

Ofloxacin, smear negative.

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Test 29

Ofloxacin, smear grade = scanty.

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Test 30

Ofloxacin, smear grade = 1+.

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Test 31

Ofloxacin, smear grade ≥ 2+.

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Test 32

Moxifloxacin, smear positive.

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Test 33

Moxifloxacin, smear negative.

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Test 34

Moxifloxacin, smear grade = scanty.

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Test 35

Moxifloxacin, smear grade = 1+.

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Test 36

Moxifloxacin, smear grade ≥ 2+.

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Test 37

Direct, SLID, culture.

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Test 38

Direct, amikacin, culture.

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Test 39

Direct, kanamycin, culture.

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Test 40

Direct, capreomycin, culture.

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Test 41

Amikacin, smear positive.

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Test 42

Amikacin, smear negative.

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Test 43

Amikacin, smear grade = scanty.

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Test 44

Amikacin, smear grade= 1+.

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Test 45

Amikacin, smear grade ≥ 2+.

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Test 46

Kananycin, smear positive.

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Test 47

Kanamycin, smear negative.

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Test 48

Kanamycin, smear grade = scanty.

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Test 49

Kanamycin, smear grade = +1.

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Test 50

Kanamycin, smear grade ≥ 2+.

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Test 51

Capreomycin, smear positive.

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Test 52

Capreomycin, smear negative.

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Test 53

Capreomycin, smear grade = 1+.

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Test 54

Capreomycin, smear grade = scanty.

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Test 55

Capreomycin, smear grade ≥ 2+.

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Test 56

Direct, XDR, culture.

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Test 57

Direct, FQ, culture followed by sequencing of discrepants.

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Test 58

Direct, SLID, culture followed by sequencing of discrepants.

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Test 59

Direct, XDR, culture followed by sequencing of discrepants.

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Test 60

V2, Indirect, FQ, culture.

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Test 61

V2, Direct, FQ, smear positive.

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Test 62

V2, Direct, FQ, smear negative.

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Test 63

V2, Indirect, ofloxacin, culture.

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Test 64

V2, Indirect, moxifloxacin, culture.

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Test 65

V2, Indirect, SLID, culture.

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Test 66

V2, Direct, SLID, smear positive.

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Test 67

V2, Direct, SLID, smear negative.

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Test 68

V2, Indirect, amikacin, culture.

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Test 69

V2, Indirect, kanamycin, culture.

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Test 70

V2, Indirect, capreomycin, culture.

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Test 71

V2, Ofloxacin, smear positive.

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Test 72

V2, Ofloxacin, smear negative.

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Test 73

V2, Ofloxacin, smear grade = scanty.

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Test 74

V2, Ofloxacin, smear grade = 1+.

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Test 75

V2, Ofloxacin, smear grade ≥ 2+.

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Test 76

V2, Moxifloxacin, smear positive.

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Test 77

V2, Moxifloxacin, smear grade ≥ 2+.

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Test 78

V2, Levofloxacin, smear positive.

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Test 79

V2, Levofloxacin, smear grade = scanty.

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Test 80

V2, Levofloxacin, smear grade = 1+.

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Test 81

V2, Levofloxacin, smear grade ≥ 2+.

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Test 82

V2, Amikacin, smear positive.

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Test 83

V2, Amikacin, smear negative.

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Test 84

V2, Amikacin, smear grade = scanty.

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Test 85

V2, Amikacin, smear grade = 1+.

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Test 86

V2, Amikacin, smear grade ≥ 2+.

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Test 87

V2, Kanamycin, smear positive.

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Test 88

V2, Kanamycin, smear negative.

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Test 89

V2, Kanamycin, smear grade = scanty.

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Test 90

V2, Kanamycin, smear grade = 1+.

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Test 91

V2, Kanamycin, smear grade ≥ 2+.

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Test 92

V2, Capreomycin, smear positive.

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Test 93

V2, Capreomycin, smear negative.

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Test 94

V2, Capreomycin, smear grade = scanty.

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Test 95

V2, Capreomycin, smear grade = 1+.

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Test 96

V2, Capreomycin, smear grade ≥ 2+.

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Test 97

V2, Indirect, XDR, culture.

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Test 98

V2, Direct, XDR, smear positive.

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Test 99

V2, Direct, XDR, smear negative.

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Summary of findings 1. MTBDRsl for FQ resistance, direct testing on smear‐positive specimens

Participants: patients with rifampicin‐resistant or MDR‐TB Prior testing: patients who received MTBDRsl testing may have first received smear microscopy, Xpert® MTB/RIF or other nucleic acid amplification test, and culture to diagnose TB and Xpert® MTB/RIF, MTBDRplus version 2.0 or an alternative line‐probe assay to detect first‐line drug resistance Role: The role of MTBDRsl would be as the initial test, replacing culture‐based drug susceptibility testing, for detecting second‐line drug resistance Settings: intermediate or central level laboratories Index (new) test: MTBDRsl version 1.0.* The test was performed by direct testing on smear‐positive specimens Reference standard: culture‐based drug susceptibility testing Studies: mainly cross‐sectional studies Limitations: most included studies did not consistently use the World Health Organization (WHO)‐recommended concentrations for drugs in the culture‐based reference standard Pooled sensitivity (95% CI): 86.2% (74.6% to 93.0%) Pooled specificity (95% CI): 98.6% (96.9% to 99.4%)
Test result	Number of results per 1000 patients tested (95% CI)			Number of participants (studies)	Quality of the evidence (GRADE)
	Prevalence of 5%	Prevalence of 10%	Prevalence of 15%
True positives (patients correctly diagnosed with FQ resistance)	43 (37 to 47)	86 (75 to 93)	129 (112 to 140)	519 (9)	⊕⊕⊕⊝^1,2,3,4 moderate
False negatives (patients incorrectly classified as not having FQ resistance)	7 (3 to 13)	14 (7 to 25)	21 (10 to 38)
True negatives (patients correctly classified as not having FQ resistance)	937 (921 to 944)	887 (872 to 895)	838 (824 to 845)	1252 (9)	⊕⊕⊕⊕^1,2,3 high
False positives (patients incorrectly classified as having FQ resistance)	13 (6 to 29)	13 (5 to 28)	12 (5 to 26)
Abbreviations: CI: confidence interval; DST: drug susceptibility testing; FQ: fluoroquinolone; GRADE: Grading of Recommendations, Assessment, Development and Evaluation; SLID: second‐line injectable drug; TB: tuberculosis; XDR‐TB: extensively drug‐resistant TB. By indirect testing, MTBDRsl sensitivity and specificity (95% CI) were 85.6% (79.2% to 90.4%) and 98.5% (95.7% to 99.5%). *This systematic review mainly evaluated MTBDRsl version 1.0, which has recently been replaced with version 2.0. We considered the findings in this review to be applicable to the current version of the test. ¹Eight studies used a cross‐sectional study design and one study used a case‐control study design. ²We used QUADAS‐2 to assess risk of bias. All studies used consecutive sampling. In seven studies, the reader of the index test was blinded to results of the reference standard and in two studies information about blinding to the reference standard was not reported. Several studies used critical concentrations for the culture‐based DST reference standard that differed from the concentrations recommended by the WHO. This may have lowered specificity, but this was not observed. We did not downgrade. ³We considered indirectness (applicability) from the perspective of diagnostic accuracy and had low concern. We did not downgrade. ⁴For individual studies, sensitivity estimates ranged from 33% to 100%. One small study with the lowest sensitivity only included three FQ‐resistant patients. However, we could not explain the remaining heterogeneity by study quality or other factors. We downgraded one level for inconsistency.

Summary of findings 1. MTBDRsl for FQ resistance, direct testing on smear‐positive specimens

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Summary of findings 2. MTBDRsl for SLID resistance, direct testing on smear‐positive specimens

Participants: patients with rifampicin‐resistant or MDR‐TB Prior testing: patients who received MTBDRsl testing may have first received smear microscopy, Xpert® MTB/RIF or other nucleic acid amplification test, and culture to diagnose TB and Xpert® MTB/RIF, MTBDRplus version 2.0 or an alternative line‐probe assay to detect first‐line drug resistance Role: The role of MTBDRsl would be as the initial test, replacing culture‐based drug susceptibility testing, for detecting second‐line drug resistance Settings: intermediate or central level laboratories Index (new) test: MTBDRsl version 1.0.* The test was performed by direct testing on smear‐positive specimens Reference standard: culture‐based drug susceptibility testing Studies: cross‐sectional studies Limitations: most included studies did not consistently use the World Health Organization (WHO)‐recommended concentrations for drugs in the culture‐based reference standard Pooled sensitivity (95% CI): 87.0% (38.1% to 98.6%) Pooled specificity (95% CI): 99.5% (93.6% to 100.0%)
Test result	Number of results per 1000 patients tested (95% CI)			Number of participants (studies)	Quality of the evidence (GRADE)
	Prevalence of 5%	Prevalence of 10%	Prevalence of 15%
True positives (patients correctly diagnosed with SLID resistance)	44 (19 to 49)	87 (38 to 99)	131 (57 to 148)	348 (8)	⊕⊕⊝⊝^1,2,3,4 low
False negatives (patients incorrectly classified as not having SLID resistance)	6 (1 to 31)	13 (1 to 62)	19 (2 to 93)
True negatives (patients correctly classified as not having SLID resistance)	945 (889 to 950)	896 (842 to 900)	846 (796 to 850)	8 (1291)	⊕⊕⊕⊝^1,2 moderate
False positives (patients incorrectly classified as having SLID resistance)	5 (0 to 61)	4 (0 to 58)	4 (0 to 54)
Abbreviations: CI: confidence interval; DST: drug susceptibility testing; FQ: fluoroquinolone; GRADE: Grading of Recommendations, Assessment, Development and Evaluation; SLID: second‐line injectable drug; TB: tuberculosis; XDR‐TB: extensively drug‐resistant TB. By indirect testing, MTBDRsl sensitivity and specificity (95% CI) were 76.5% (63.3% to 86.0%) and 99.1% (97.3% to 99.7%). This systematic review mainly evaluated MTBDRsl version 1.0, which has recently been replaced with version 2.0. We considered the findings in this review to be applicable to the current version of the test. ¹We used QUADAS‐2 to assess risk of bias. All studies used consecutive or random sampling. In six studies, the reader of the index test was blinded to results of the reference standard in two studies information about blinding to the reference standard was not reported. Fifty per cent of the studies used critical concentrations for the culture‐based DST reference standard that differed from the concentrations recommended by the WHO. We downgraded one level. ²We considered indirectness (applicability) from the perspective of diagnostic accuracy and had low concern. We did not downgrade. ³For individual studies, sensitivity estimates ranged from 9% to 100%. We thought heterogeneity could be explained in part by the use of different drugs, critical concentrations, and types of culture media in the reference standard and likely presence of eis* mutations in patients in Eastern Europe. We did not downgrade for inconsistency and considered this in the context of other factors, in particular imprecision. ⁴The wide CI around true positives and false negatives may lead to different decisions depending on which confidence limits are assumed. We downgraded one level.

Summary of findings 2. MTBDRsl for SLID resistance, direct testing on smear‐positive specimens

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Summary of findings 3. MTBDRsl for XDR‐TB, direct testing on smear‐positive specimens

Participants: patients with rifampicin‐resistant or MDR‐TB Prior testing: patients who received MTBDRsl testing may have first received smear microscopy, Xpert® MTB/RIF or other nucleic acid amplification test, and culture to diagnose TB and Xpert® MTB/RIF, MTBDRplus version 2.0 or an alternative line‐probe assay to detect first‐line drug resistance Role: The role of MTBDRsl would be as the initial test, replacing culture‐based drug susceptibility testing, for detecting second‐line drug resistance Settings: intermediate or central level laboratories Index (new) test: MTBDRsl version 1.0.* The test was performed by direct testing on smear‐positive specimens Reference standard: culture‐based drug susceptibility testing Studies: cross‐sectional studies Limitations: most included studies did not consistently use the World Health Organization (WHO)‐recommended concentrations for drugs in the culture‐based reference standard Pooled sensitivity (95% CI): 69.4% (38.8% to 89.0%) Pooled specificity (95% CI): 99.4% (95.0% to 99.3%)
Test result	Number of results per 1000 patients tested (95% CI)			Number of participants (studies)	Quality of the evidence (GRADE)
	Prevalence of 1%	Prevalence of 5%	Prevalence of 10%
True positives (patients correctly diagnosed with XDR‐TB)	7 (4 to 9)	35 (19 to 45)	69 (39 to 89)	143 (6)	⊕⊕⊝⊝^1,2,3,4 low
False negatives (patients incorrectly classified as not having XDR‐TB)	3 (1 to 6)	15 (5 to 31)	31 (11 to 61)
True negatives (patients correctly classified as not having XDR‐TB)	980 (941 to 983)	941 (903 to 943)	891 (855 to 894)	1277 (6)	⊕⊕⊕⊝^1,2 moderate
False positives (patients incorrectly classified as having XDR‐TB)	10 (7 to 49)	9 (7 to 47)	9 (6 to 45)
Abbreviations: CI: confidence interval; DST: drug susceptibility testing; FQ: fluoroquinolone; GRADE: Grading of Recommendations, Assessment, Development and Evaluation; SLID: second‐line injectable drug; TB: tuberculosis; WHO: World Health Organization; XDR‐TB: extensively drug‐resistant TB. By indirect testing, MTBDRsl sensitivity and specificity (95% CI) were 70.9% (42.9% to 88.7%) and 98.8% (96.1% to 99.6%). This systematic review mainly evaluated MTBDRsl version 1.0, which has recently been replaced with version 2.0. We considered the findings in this review to be applicable to the current version of the test. ¹We used QUADAS‐2 to assess risk of bias. All studies used consecutive sampling. In four studies, the reader of the test was blinded to results of the reference standard and in two studies information about blinding was not reported. Most studies used critical concentrations for the phenotypic culture‐based DST reference standard that differed from the concentrations recommended by the WHO. We downgraded the evidence by one level. ²We considered indirectness (applicability) from the perspective of diagnostic accuracy and had low concern. We did not downgrade. ³For individual studies, sensitivity estimates ranged from 14% to 92%. We thought heterogeneity could be explained in part by the use of different drugs, critical concentrations, and types of culture media in the reference standard and likely presence of eis* mutations in patients in Eastern Europe. We did not downgrade for inconsistency and considered this in the context of other factors, in particular imprecision. ⁴The wide CI for true positives and false negatives may lead to different decisions depending on which confidence limits are assumed. We downgraded one level.

Summary of findings 3. MTBDRsl for XDR‐TB, direct testing on smear‐positive specimens

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Table 1. Characteristics of MTBDRsl versions 1.0 and 2.0

Detection	*Version 1.0: M. tuberculosis* complex and resistances to FQs, SLIDs, and ethambutol**	*Version 2.0: M. tuberculosis* complex and resistances to FQs and SLIDs**
Samples	Smear‐positive specimens and culture isolates	Smear‐positive and smear‐negative specimens and culture isolates
FQ resistance	Mutations in resistance determining region of the gyrA gene	Mutations in resistance determining regions of the gyrA and gyrB genes
SLID resistance	Mutations in resistance determining region of the rrs gene	Mutations in resistance determining region rrs gene and the eis promoter region
Ethambutol resistance	Mutations in the embB gene	Not included
Abbreviations: FQ: fluoroquinolone; SLID: second‐line injectable drug. MTBDRsl reports on the presence of mutations within genes (gyrA and rrs for version 1.0 and, in addition, gyrB and the eis promoter for version 2.0), which are associated with resistance to a class of drugs. The presence of mutation(s) in these regions does not necessarily imply resistance to all the drugs within that class. Although specific mutations within these regions may be associated with different levels of resistance to each drug within these classes, the extent of this poorly understood

Table 1. Characteristics of MTBDRsl versions 1.0 and 2.0

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Table 2. Map of review showing the number of studies evaluating MTBDRsl version 1.0 by indirect testing, according to the reference standard and target condition

Target condition, drug resistance to...	Reference standard
Target condition, drug resistance to...	Culture, n/N (%)	Sequencing, n/N (%)	Sequencing and culture, n/N (%)	Culture followed by sequencing of discrepant results, n/N (%)
FQs	19/19 (100)¹	7/19 (37)	7/19 (37)	3/19 (16)
Ofloxacin	13/19 (68)	0	0	0
Moxifloxacin	6/19 (32)	0	0	0
Levofloxacin	2/19 (11)	0	0	0
SLIDs	16/16 (100)¹	7/16 (44)	7/16 (44)	3/16 (19)
Amikacin	11/16 (69)	0	0	0
Kanamycin	9/16 (56)	0	0	0
Capreomycin	10/16 (63)	0	0	0
XDR‐TB	8/8 (100)	3/8 (38)	2/8 (25)	0
Abbreviations: FQ: fluoroquinolone; SLID: second‐line injectable drug; TB: tuberculosis; XDR‐TB: extensively drug‐resistant TB. ¹A total of 19, 16, and 8 studies were included that evaluated MTBDRsl for FQ resistance, SLID resistance, and XDR‐TB, respectively, against culture‐based DST. These form the denominators to generate percentages of studies that included a particular additional reference standard.

Table 2. Map of review showing the number of studies evaluating MTBDRsl version 1.0 by indirect testing, according to the reference standard and target condition

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Table 3. Map of review showing the number of studies evaluating MTBDRsl version 1.0 by direct testing, according to the reference standard and target condition

Target condition, drug resistance to...	Reference standard
Target condition, drug resistance to...	Culture, n/N (%)	Sequencing, n/N (%)	Sequencing and culture, n/N (%)	Culture followed by sequencing of discrepant results, n/N (%)
FQs	9/9 (100)¹	0	0	2/9 (22)
Ofloxacin	7/9 (78)	0	0	2/9 (11)
Moxifloxacin	2/9 (22)	0	0	0
Levofloxacin	0	0	0	0
Gatifloxacin	0	0	0	0
SLIDs	8/8 (100)¹	0	0	2/8 (25)
Amikacin	6/8 (75)	0	0	1/8 (13)
Kanamycin	5/8 (63)	0	0	0
Capreomycin	5/8 (63)	0	0	0
XDR‐TB	6/6 (100)	0	0	2/6 (33)
Abbreviations: FQ: fluoroquinolone; SLID: second‐line injectable drug; TB: tuberculosis; XDR‐TB: extensively drug‐resistant TB. ¹We included a total of 9, 8, and 6 studies that evaluated MTBDRsl for detection of FQ resistance, SLID resistance, and XDR‐TB, respectively, against culture‐based DST. These form the denominators to generate percentages of studies that included a particular additional reference standard.

Table 3. Map of review showing the number of studies evaluating MTBDRsl version 1.0 by direct testing, according to the reference standard and target condition

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Table 4. Accuracy of MTBDRsl version 1.0 for resistance to FQs and SLIDs and XDR‐TB, by type of testing, culture‐based DST reference standard

Pooled sensitivity (95% CI)	Pooled specificity (95% CI)	Pooled sensitivity (95% CI)	Pooled specificity (95% CI)	Pooled sensitivity P value¹	Pooled specificity P value¹
FQs, indirect testing (19 studies, 2223 participants)		FQs, direct testing (9 studies, 1771 participants)		0.932	0.333
85.6% (79.2 to 90.4)	98.5% (95.7 to 99.5)	86.2% (74.6 to 93.0)	98.6% (96.9 to 99.4)
SLIDs, indirect testing (16 studies, 1921 participants)		SLIDs, direct testing (8 studies, 1639 participants)		0.547	0.664
76.5% (63.3 to 86.0)	99.1% (97.3 to 99.7)	87.0% (38.1 to 98.6)	99.5% (93.6 to 100.0)
XDR‐TB, indirect testing (8 studies, 880 participants)		XDR‐TB, direct testing (6 studies, 1420 participants)		0.888	0.855
70.9% (42.9 to 88.7)	98.8% (96.1 to 99.6)	69.4% (38.8 to 89.0)	99.4% (95.0 to 99.3)
Abbreviations: CI: confidence interval; DST: drug susceptibility testing; FQ: fluoroquinolone; SLID: second‐line injectable drug; TB: tuberculosis; XDR‐TB: extensively drug‐resistant TB. The accuracy estimates were derived from non‐comparative studies of test accuracy in which different sets of studies were used. For example, for FQ resistance, the set of studies used for indirect testing differed from that used for direct testing. ¹Likelihood ratio test for evidence of a significant difference between accuracy estimates.

Table 4. Accuracy of MTBDRsl version 1.0 for resistance to FQs and SLIDs and XDR‐TB, by type of testing, culture‐based DST reference standard

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Table 5. Accuracy of MTBDRsl version 1.0 for resistance to select FQ and SLID drugs, culture‐based DST reference standard

Pooled sensitivity (95% CI)	Pooled specificity (95% CI)	Pooled sensitivity (95% CI)	Pooled specificity (95% CI)	Pooled sensitivity P value¹	Pooled specificity P value¹
Ofloxacin, indirect testing (13 studies, 1927 participants)		Ofloxacin, direct testing (7 studies, 1667 participants)		0.180	0.161
85.2% (78.5 to 90.1)	98.5% (95.6 to 99.5)	90.9% (84.7 to 94.7)	98.9% (97.8 to 99.4)
Moxifloxacin, indirect testing (6 studies, 419 participants)		Moxifloxacin, direct testing (2 studies, 821 participants)		0.820	0.365
94.0% (82.2 to 98.1)	96.6% (85.2 to 99.3)	95.0% (92.1 to 96.9)	99.0% (97.5 to 99.6)
Levofloxacin, indirect testing² (2 studies, 169 participants)		Levofloxacin, direct testing (0 studies, 0 participants)		Not applicable	Not applicable
Not applicable	Not applicable	Not applicable	Not applicable
Amikacin, indirect testing (11 studies, 1301 participants)		Amikacin, direct testing (6 studies, 1491 participants)		0.338	0.213
84.9% (79.2 to 89.1)	99.1% (97.6 to 99.6)	91.9% (71.5 to 98.1)	99.9% (95.2 to 100.0)
Kanamycin, indirect testing (9 studies, 1342 participants)		Kanamycin, direct testing (5 studies, 1020 participants		0.836	0.445
66.9% (44.1 to 83.8)	98.6% (96.1 to 99.5)	78.7% (11.9 to 99.0)	99.7% (93.8 to 100.0)
Capreomycin, indirect testing (10 studies, 1406 participants		Capreomycin, direct testing (5 studies, 1027 participants)		0.841	0.353
79.5% (58.3 to 91.4)	95.8% (93.4 to 97.3)	76.6% (61.1 to 87.3)	98.2% (92.5 to 99.6)
Abbreviations: CI: confidence interval; DST: drug susceptibility testing; FQ: fluoroquinolones; SLID: second‐line injectable drug. We derived the accuracy estimates from non‐comparative studies of test accuracy in which different sets of studies were used. For example, for ofloxacin resistance, the set of studies used for indirect testing differed from that used for direct testing. ¹Likelihood ratio test for evidence of a significant difference between accuracy estimates. ²Sensitivity and specificity (95% confidence intervals (CIs)) were 80% (56 to 94) and 96% (80 to 100) for Chikamatsu 2012 and 100% (96 to 100) and 100% (88 to 100) for Kambli 2015b. We did not perform a meta‐analysis.

Table 5. Accuracy of MTBDRsl version 1.0 for resistance to select FQ and SLID drugs, culture‐based DST reference standard

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Table 6. Accuracy of MTBDRsl version 1.0 by indirect testing for FQ and SLID resistance and XDR‐TB, by reference standard

Pooled sensitivity (95% CI)	Pooled specificity (95% CI)	Pooled sensitivity (95% CI)	Pooled specificity (95% CI)	Pooled sensitivity P value¹	Pooled specificity P value¹
FQ, culture (6 studies, 873 participants)		FQ, sequencing (6 studies, 873 participants)		< 0.001	0.735
82.4% (77.6 to 86.3)	98.8% (94.3 to 99.8)	99.3% (81.2 to 100.0)	99.3% (90.8 to 100)
FQ, culture (7 studies, 1211 participants)		FQ, sequencing and culture (7 studies, 1211 participants)		0.664	0.070
81.8% (77.2 to 85.7)	99.0% (95.0 to 99.8)	82.0% (77.7 to 85.6)	99.8% (98.5 to 100)
SLIDs, culture (6 studies, 873 participants)		SLIDs sequencing (6 studies, 873 participants)		0.034	0.456
74.6% (66.2 to 81.5)	99.9% (71.8 to 100.0)	97.0% (77.0 to 99.7)	99.5% (94.5 to 100.0)
SLIDs, culture (6 studies, 1159 participants)		SLIDs, sequencing and culture (6 studies, 1159 participants)		0.458	0.203
70.5% (52.0 to 84.1)	99.8% (93.8 to 100.0)	61.3% (45.8 to 74.8%)	99.9% (99.0 to 100.0)
XDR‐TB, culture (8 studies, 880 participants)		XDR‐TB, sequencing² (4 studies, 630 participants)		Could not determine	Could not determine
70.9% (42.9 to 88.8)	98.8% (96.1 to 99.6)	100% (94.6 to 100.0)	97.9% (96.3 to 98.8)
Abbreviations: CI: confidence interval; FQ: fluoroquinolones; SLID: second‐line injectable drug; TB: tuberculosis; XDR‐TB: extensively drug‐resistant TB. For detection of FQ and SLID resistance, the accuracy estimates were derived from comparative studies of test accuracy in which the same set of studies was used. For example, for FQ resistance, the set of studies using culture‐based drug susceptibility testing (DST) as a reference standard was the same as that using sequencing as a reference standard. For detection of XDR‐TB, the accuracy estimates were derived from non‐comparative studies of test accuracy in which different sets of studies were used. ¹Likelihood ratio test for evidence of a significant difference between accuracy estimates. ²Accuracy estimates were obtained with fixed‐effect model.

Table 6. Accuracy of MTBDRsl version 1.0 by indirect testing for FQ and SLID resistance and XDR‐TB, by reference standard

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Table 7. Sensitivity analyses MTBDRsl version 1.0, fluoroquinolone resistance

Culture, indirect testing			Culture, direct testing			Pooled sensitivity P value¹	Pooled specificity P value¹
Number of studies (participants)	Pooled sensitivity (95% CI)	Pooled specificity (95% CI)	Number of studies (participants)	Pooled sensitivity (95% CI)	Pooled specificity (95% CI)	Pooled sensitivity P value¹	Pooled specificity P value¹
All studies of fluoroquinolones
19 studies (2223)	85.6% (79.2 to 90.4)	98.5% (95.7 to 99.5)	9 studies (1771)	86.2% (74.6 to 93.0)	98.6% (96.9 to 99.4)	0.932	0.333
Was a consecutive or random sample of patients/specimens enrolled? Yes
14 studies (1979)	84.1% (75.7 to 90.0)	99.0% (94.8 to 99.8)	9 studies (1771)	86.2% (75.2 to 92.8)	98.9% (97.7 to 99.5)	0.725	0.506
Was a case‐control design avoided? Yes
13 studies (1389)	88.9 (79.4 to 94.3)	98.5% (93.4 to 99.7)	8 studies (1721)	85.6% (72.4 to 93.1)	98.5% (96.9 to 99.3)	0.613	0.417
Were the index test results interpreted without knowledge of the results of the reference standard? Yes
12 studies (1796)	86.1% (75.9 to 92.5)	99.3% (94.4 to 99.9)	7 studies (982)	83.8% (68.5 to 92.5)	98.1% (96.4 to 99.0)	0.768	0.946
Was the test applied in the manner recommended by the manufacturer? Yes
18 studies (2171)	85.6% (78.6 to 90.6)	98.6% (95.6 to 99.6)	7 studies (982)	83.8% (68.5 to 92.5)	98.1% (96.4 to 99.0)	0.736	0.652
Abbreviations: CI: confidence interval. We derived the accuracy estimates from non‐comparative studies of test accuracy in which different sets of studies were used. ¹Likelihood ratio test for evidence of a significant difference between accuracy estimates.

Table 7. Sensitivity analyses MTBDRsl version 1.0, fluoroquinolone resistance

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Table 8. Sensitivity analyses MTBDRsl version 1.0, second‐line injectable drug resistance

Culture, indirect testing			Culture, direct testing			Pooled sensitivity P value¹	Pooled specificity P value¹
Number of studies (participants)	Pooled sensitivity (95% CI)	Pooled specificity (95% CI)	Number of studies (participants)	Pooled sensitivity (95% CI)	Pooled specificity (95% CI)	Pooled sensitivity P value¹	Pooled specificity P value¹
All studies of second‐line injectable drugs
16 studies (1921)	76.5% (63.3 to 86.0)	99.1% (97.3 to 99.7)	8 studies (1639)	87.0% (38.1 to 98.6)	99.5% (93.6 to 100.0)	0.547	0.664
Was a consecutive or random sample of patients/specimens enrolled? Yes
11 studies (1869)	77.3% (58.9 to 89.0)	99.2% (96.4 to 99.8)	8 studies (1639)	87.0% (38.1 to 98.6)	99.5% (93.6 to 100.0)	0.896	0.873
Was a case‐control design avoided? Yes
10 studies (1088)	80.2% (57.1 to 92.4)	98.6% (95.3 to 99.6)	8 studies (1639)	87.0% (38.1 to 98.6)	99.5% (93.6 to 100.0)	0.822	0.889
Were the index test results interpreted without knowledge of the results of the reference standard? Yes
10 studies (1513)	75.4% (57.0 to 87.7)	99.0% (96.0 to 99.7)	6 studies (902)	96.1% (40.0 to 99.9)	99.2% (82.3 to 100.0)	0.471	0.573
Was the test applied in the manner recommended by the manufacturer? Yes
15 studies (1869)	77.2% (62.6 to 87.2)	99.0% (97.1 to 99.7)	6 studies (902)	96.1% (40.0 to 99.9)	99.2% (82.3 to 100.0)	0.228	0.926
Abbreviations: CI: confidence interval. We derived the accuracy estimates from non‐comparative studies of test accuracy in which different sets of studies were used. ¹Likelihood ratio test for evidence of a significant difference between accuracy estimates.

Table 8. Sensitivity analyses MTBDRsl version 1.0, second‐line injectable drug resistance

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Table Tests. Data tables by test

Test	No. of studies	No. of participants
1 Indirect, FQ, culture Show forest plot	19	2223

2 Indirect, ofloxacin, culture Show forest plot	13	1927

3 Indirect, moxifloxacin, culture Show forest plot	6	419

4 Indirect, levofloxacin, culture Show forest plot	2	169

5 Indirect, ofloxacin, WHO critical concentration used Show forest plot	8	1427

6 Indirect, ofloxacin, WHO critical concentration not used Show forest plot	4	481

7 Indirect, SLID, culture Show forest plot	16	1921

8 Indirect, amikacin, culture Show forest plot	11	1301

9 Indirect, kanamycin, culture Show forest plot	9	1342

10 Indirect, capreomycin, culture Show forest plot	10	1406

11 Indirect, amikacin, WHO critical concentration used Show forest plot	4	706

12 Indirect, capreomycin, WHO critical concentration used Show forest plot	4	473

13 Indirect, amikacin, WHO critical concentration not used Show forest plot	7	595

14 Indirect, capreomycin, WHO critical concentration not used Show forest plot	6	933

15 Indirect, XDR, culture Show forest plot	8	880

16 Indirect, FQ, sequencing Show forest plot	7	974

17 Indirect, SLID, sequencing Show forest plot	7	962

18 Indirect, XDR, sequencing Show forest plot	4	630

19 Indirect, FQ, sequencing and culture Show forest plot	7	1211

20 Indirect, SLID, sequencing and culture Show forest plot	7	1491

21 Indirect, XDR, sequencing and culture Show forest plot	2	435

22 Indirect, FQ, culture followed by sequencing of discrepants Show forest plot	3	427

23 Indirect, SLID, culture followed by sequencing of discrepants Show forest plot	3	619

24 Direct, FQ, culture Show forest plot	9	1771

25 Direct, ofloxacin, culture Show forest plot	7	1667

26 Direct, moxifloxacin, culture Show forest plot	2	821

27 Ofloxacin, smear positive Show forest plot	4	963

28 Ofloxacin, smear negative Show forest plot	2	120

29 Ofloxacin, smear grade = scanty Show forest plot	2	65

30 Ofloxacin, smear grade = 1+ Show forest plot	4	241

31 Ofloxacin, smear grade ≥ 2+ Show forest plot	4	647

32 Moxifloxacin, smear positive Show forest plot	2	821

33 Moxifloxacin, smear negative Show forest plot	1	91

34 Moxifloxacin, smear grade = scanty Show forest plot	1	51

35 Moxifloxacin, smear grade = 1+ Show forest plot	2	197

36 Moxifloxacin, smear grade ≥ 2+ Show forest plot	2	593

37 Direct, SLID, culture Show forest plot	8	1639

38 Direct, amikacin, culture Show forest plot	6	1491

39 Direct, kanamycin, culture Show forest plot	5	1020

40 Direct, capreomycin, culture Show forest plot	5	1027

41 Amikacin, smear positive Show forest plot	4	809

42 Amikacin, smear negative Show forest plot	2	104

43 Amikacin, smear grade = scanty Show forest plot	3	57

44 Amikacin, smear grade= 1+ Show forest plot	4	222

45 Amikacin, smear grade ≥ 2+ Show forest plot	4	602

46 Kananycin, smear positive Show forest plot	3	806

47 Kanamycin, smear negative Show forest plot	1	73

48 Kanamycin, smear grade = scanty Show forest plot	2	43

49 Kanamycin, smear grade = +1 Show forest plot	3	193

50 Kanamycin, smear grade ≥ 2+ Show forest plot	3	564

51 Capreomycin, smear positive Show forest plot	3	806

52 Capreomycin, smear negative Show forest plot	1	73

53 Capreomycin, smear grade = 1+ Show forest plot	3	193

54 Capreomycin, smear grade = scanty Show forest plot	2	43

55 Capreomycin, smear grade ≥ 2+ Show forest plot	3	564

56 Direct, XDR, culture Show forest plot	6	1420

57 Direct, FQ, culture followed by sequencing of discrepants Show forest plot	2	685

58 Direct, SLID, culture followed by sequencing of discrepants Show forest plot	2	666

59 Direct, XDR, culture followed by sequencing of discrepants Show forest plot	2	570

60 V2, Indirect, FQ, culture Show forest plot	1	228

61 V2, Direct, FQ, smear positive Show forest plot	1	155

62 V2, Direct, FQ, smear negative Show forest plot	1	9

63 V2, Indirect, ofloxacin, culture Show forest plot	1	226

64 V2, Indirect, moxifloxacin, culture Show forest plot	1	97

65 V2, Indirect, SLID, culture Show forest plot	1	228

66 V2, Direct, SLID, smear positive Show forest plot	1	164

67 V2, Direct, SLID, smear negative Show forest plot	1	9

68 V2, Indirect, amikacin, culture Show forest plot	1	226

69 V2, Indirect, kanamycin, culture Show forest plot	1	224

70 V2, Indirect, capreomycin, culture Show forest plot	1	218

71 V2, Ofloxacin, smear positive Show forest plot	1	153

72 V2, Ofloxacin, smear negative Show forest plot	1	9

73 V2, Ofloxacin, smear grade = scanty Show forest plot	1	38

74 V2, Ofloxacin, smear grade = 1+ Show forest plot	1	56

75 V2, Ofloxacin, smear grade ≥ 2+ Show forest plot	1	49

76 V2, Moxifloxacin, smear positive Show forest plot	1	22

77 V2, Moxifloxacin, smear grade ≥ 2+ Show forest plot	1	8

78 V2, Levofloxacin, smear positive Show forest plot	1	53

79 V2, Levofloxacin, smear grade = scanty Show forest plot	1	25

80 V2, Levofloxacin, smear grade = 1+ Show forest plot	1	22

81 V2, Levofloxacin, smear grade ≥ 2+ Show forest plot	1	6

82 V2, Amikacin, smear positive Show forest plot	1	155

83 V2, Amikacin, smear negative Show forest plot	1	9

84 V2, Amikacin, smear grade = scanty Show forest plot	1	40

85 V2, Amikacin, smear grade = 1+ Show forest plot	1	57

86 V2, Amikacin, smear grade ≥ 2+ Show forest plot	1	49

87 V2, Kanamycin, smear positive Show forest plot	1	155

88 V2, Kanamycin, smear negative Show forest plot	1	7

89 V2, Kanamycin, smear grade = scanty Show forest plot	1	37

90 V2, Kanamycin, smear grade = 1+ Show forest plot	1	55

91 V2, Kanamycin, smear grade ≥ 2+ Show forest plot	1	45

92 V2, Capreomycin, smear positive Show forest plot	1	164

93 V2, Capreomycin, smear negative Show forest plot	1	9

94 V2, Capreomycin, smear grade = scanty Show forest plot	1	40

95 V2, Capreomycin, smear grade = 1+ Show forest plot	1	57

96 V2, Capreomycin, smear grade ≥ 2+ Show forest plot	1	49

97 V2, Indirect, XDR, culture Show forest plot	1	228

98 V2, Direct, XDR, smear positive Show forest plot	1	164

99 V2, Direct, XDR, smear negative Show forest plot	1	9

Table Tests. Data tables by test

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Resumen

Antecedentes

Objetivos

Métodos de búsqueda

Criterios de selección

Obtención y análisis de los datos

Resultados principales

Conclusiones de los autores

Resumen en términos sencillos

Prueba rápida GenoType® MTBDRsl para detectar la resistencia a los fármacos de segunda línea contra la TB

Resumen visual

Conclusiones de los autores

Implicaciones para la práctica

Implicaciones para la investigación

Summary of findings

Antecedentes

Enfermedad de interés diagnosticada

Prueba/s índice

Vía clínica

Prueba/s previa/s

Función de la/s prueba/s índice

Prueba/s alternativa/s

Fundamento

Objetivos

Objetivos secundarios

Métodos

Criterios de inclusión de estudios para esta revisión

Tipos de estudios

Participantes

Pruebas índice

Enfermedades de interés

Estándares de referencia

Métodos de búsqueda para la identificación de los estudios

Búsquedas electrónicas

Búsqueda de otros recursos

Obtención y análisis de los datos

Selección de los estudios

Extracción y manejo de los datos

Possible results for the GenoType® MTBDRsl assay (as defined by the product manual)

Assignment of results to the fluoroquinolones, second‐line injectable drugs, or both categories

Evaluación de la calidad metodológica

Análisis estadístico y síntesis de los datos

Approach to uninterpretable (indeterminate) MTBDRsl results

Investigación de la heterogeneidad

Análisis de sensibilidad

Evaluación del sesgo de notificación

Other analyses

Assessment of the quality of evidence (certainty of the evidence)

Resultados

Resultados de la búsqueda

Calidad metodológica de los estudios incluidos

Hallazgos

MTBDRsl version 1.0

I. Fluoroquinolone resistance detection

A. Estimates of the diagnostic accuracy of MTBDRsl using culture‐based DST as a reference standard

1. Indirect testing

2. Direct testing

3. Comparison of indirect versus direct testing

B. Investigations of heterogeneity

1. Indirect testing

2. Direct testing

II. Second‐line injectable drug resistance detection

A. Estimates of the diagnostic accuracy of MTBDRsl using culture‐based DST as a reference standard

1. Indirect testing

2. Direct testing

3. Comparison of indirect versus direct testing

B. Investigations of heterogeneity

1. Indirect testing

2. Direct testing

III. XDR‐TB detection

A. Estimates of the diagnostic accuracy of MTBDRsl using culture‐based DST as a reference standard

1. Indirect testing

2. Direct testing

3. Comparison of indirect versus direct testing

B. Investigations of heterogeneity

1. Indirect testing

2. Direct testing

Sensitivity analyses