Entrando en la era de la farmacogenética: bases para el uso racional de drogas anti-tuberculosas / Coming in the era of pharmacogenetics: basis for the rational use of anti-tuberculosis drugs

INTRODUCCION: En Argentina se reportan alrededor de 11.000 casos nuevos de tuberculosis (TB) por año. El tratamiento con drogas anti-TB produce daño hepático en una gran proporción de los pacientes, y la isoniacida (INH) es la principal inductora de hepatotoxicidad. Algunos polimorfismos de las enzimas NAT-2 y CYP2E1, involucradas en el metabolismo de INH, estarían directamente asociados con el desarrollo de hepatotoxicidad.OBJETIVO: Analizar la distribución de las variantes alélicas *4, *5, *6, *7 y *14 de NAT-2 y c1/c2 de CYP2E1 en población sana argentina y en pacientes con TB que concurren a hospitales públicos de la ciudad de Buenos Aires y estudiar su asociación con el desarrollo de la hepatotoxicidad.METODOS: Se estudiaron 152 pacientes con TB tratados con drogas anti-TB. La distribución de frecuencias alélicas y genotípicas fue determinada por PCR-RFLP, y los resultados fueron comparados entre pacientes con TB con o sin desarrollo de hepatotoxicidad, usando un análisis de regresión logística binaria.RESULTADOS: El estado acetilador lento resultó la única variable independiente en la predicción de hepatotoxicidad relacionada con las drogas anti-TB (p = 0,019; OR = 2,971).CONCLUSIONES: El presente estudio demuestra que, dada la alta prevalencia del estado acetilador lento en la población argentina y su asociación al riesgo de desarrollar hepatotoxicidad, junto con el aumento en los casos de TB y los costos que conllevan las internaciones por daño hepático asociado a drogas anti-TB, el análisis del estado acetilador previo al tratamiento anti-TB podría ser clave.

INTRODUCTION: In Argentina, about 11.000 new cases of tuberculosis (TB) are reported per year. Treatment with anti-TB drugs produces liver damage in a large proportion of patients, being isoniazid (INH) the main responsible for hepatotoxicity. Some polymorphisms of the enzymes NAT-2 and CYP2E1, which are involved in the metabolism of INH, might be directly associated with the development of hepatotoxicity.OBJECTIVE: To analyze the distribution of NAT-2 variants *4, *5, *6, *7 and *14, and CYP2E1 alleles c1 and c2 in a healthy population from Argentina and in patients with TB who attend public hospitals in Buenos Aires city, and to stude their association with the development of hepatotoxicity.METHODS: The study included 152 patients with TB treated with anti-TB drugs. The allelic and genotypic frequency distribution was determined by PCR-RFLP, and the results were compared between TB patients with or without development of hepatotoxicity using a binary logistic refression analysis.RESULTS: The slow acetylator status was the only independent variable in the prediction of hepatotoxicity associated with anti-TB drugs (p = 0.019; OR = 2.971).CONCLUSIONS: This study shows that, given the high prevalence of slow acetylator status in Argentine population and its association with the risk of hepatotoxicity, together with the increase in TB cases and the hospitalization costs due to liver damage associated with anti-TB drugas, the analysis of acetylator status before anti-TB treatment could be fundamental.

Entrando en la era de la farmacogenética: bases para el uso racional de drogas anti-tuberculosas / Coming in the era of pharmacogenetics: basis for the rational use of anti-tuberculosis drugs

INTRODUCCION: En Argentina se reportan alrededor de 11.000 casos nuevos de tuberculosis (TB) por año. El tratamiento con drogas anti-TB produce daño hepático en una gran proporción de los pacientes, y la isoniacida (INH) es la principal inductora de hepatotoxicidad. Algunos polimorfismos de las enzimas NAT-2 y CYP2E1, involucradas en el metabolismo de INH, estarían directamente asociados con el desarrollo de hepatotoxicidad.OBJETIVO: Analizar la distribución de las variantes alélicas *4, *5, *6, *7 y *14 de NAT-2 y c1/c2 de CYP2E1 en población sana argentina y en pacientes con TB que concurren a hospitales públicos de la ciudad de Buenos Aires y estudiar su asociación con el desarrollo de la hepatotoxicidad.METODOS: Se estudiaron 152 pacientes con TB tratados con drogas anti-TB. La distribución de frecuencias alélicas y genotípicas fue determinada por PCR-RFLP, y los resultados fueron comparados entre pacientes con TB con o sin desarrollo de hepatotoxicidad, usando un análisis de regresión logística binaria.RESULTADOS: El estado acetilador lento resultó la única variable independiente en la predicción de hepatotoxicidad relacionada con las drogas anti-TB (p = 0,019; OR = 2,971).CONCLUSIONES: El presente estudio demuestra que, dada la alta prevalencia del estado acetilador lento en la población argentina y su asociación al riesgo de desarrollar hepatotoxicidad, junto con el aumento en los casos de TB y los costos que conllevan las internaciones por daño hepático asociado a drogas anti-TB, el análisis del estado acetilador previo al tratamiento anti-TB podría ser clave.

INTRODUCTION: In Argentina, about 11.000 new cases of tuberculosis (TB) are reported per year. Treatment with anti-TB drugs produces liver damage in a large proportion of patients, being isoniazid (INH) the main responsible for hepatotoxicity. Some polymorphisms of the enzymes NAT-2 and CYP2E1, which are involved in the metabolism of INH, might be directly associated with the development of hepatotoxicity.OBJECTIVE: To analyze the distribution of NAT-2 variants *4, *5, *6, *7 and *14, and CYP2E1 alleles c1 and c2 in a healthy population from Argentina and in patients with TB who attend public hospitals in Buenos Aires city, and to stude their association with the development of hepatotoxicity.METHODS: The study included 152 patients with TB treated with anti-TB drugs. The allelic and genotypic frequency distribution was determined by PCR-RFLP, and the results were compared between TB patients with or without development of hepatotoxicity using a binary logistic refression analysis.RESULTS: The slow acetylator status was the only independent variable in the prediction of hepatotoxicity associated with anti-TB drugs (p = 0.019; OR = 2.971).CONCLUSIONS: This study shows that, given the high prevalence of slow acetylator status in Argentine population and its association with the risk of hepatotoxicity, together with the increase in TB cases and the hospitalization costs due to liver damage associated with anti-TB drugas, the analysis of acetylator status before anti-TB treatment could be fundamental.

[Evaluation of the control measures adopted against an epidemic of AIDS-related multidrug-resistant tuberculosis in a Latin-American hospital]. / Evaluación de las medidas de control adoptadas frente a la epidemia de tuberculosis multirresistente asociada al sida en un hospital hispanoamericano.

BACKGROUND: Since 1992 AIDS-related multidrug-resistant tuberculosis (MDRTB) has been detected among patients admitted to the Hospital Muñiz in Buenos Aires (Argentina). The aim of the present study was to evaluate the effectiveness of the control measures adopted against the nosocomial spread of MDRTB/AIDS, which affected 803 patients between 1992 and 2002. METHODS: An action plan was applied that included bacilloscopy screening on admission, isolation rooms for patients with TB/AIDS, an isolation ward for patients with MDRTB/AIDS, a radiometric method for the diagnosis of multidrug-resistance, a reserve supply of second line drugs, and respiratory protection for health care workers. RESULTS: Between 1995 and 2002, a statistically significant decreasing trend in cases of MDRTB/AIDS and admissions for TB/AIDS was observed (33.9% vs 80.5%). Mortality among patients with MDRTB/AIDS also significantly decreased. Bacilloscopy screening allowed the diagnosis of 63.4% of patients admitted with TB/AIDS. Respiratory isolation facilities and effective treatment of patients with MDRTB diagnosed through the radiometric method were progressively implemented. Admission of patients with AIDS showed no significant variations throughout the study period. The CD41 count of patients requiring admission did not vary significantly. CONCLUSION: The nosocomial epidemic curve of MDRTB in patients with AIDS significantly decreased, despite the persistence of susceptible patients with low CD41 levels. The decreasing tendency of MDRTB/AIDS cases could be attributed to the impact of the control measures implemented.

Evaluación de las medidas de control adoptadas frente a la epidemia de tuberculosis multirresistente asociada al sida en un hospital hispanoamericano / Evaluation of the control measures adopted against an epidemic of AIDS-related multidrug-resistant tuberculosis in a latin-american hospital

Desde 1992 se detectaron pacientes con tuberculosis multirresistente (TBMR) asociada al sida internados en el Hospital Muñiz (Buenos Aires). El objetivo del trabajo es evaluar la eficacia de las medidas adoptadas frente a la expansión nosocomial de la TBMR/sida, que afectó a 803 enfermos entre 1992-2002. Métodos. Se aplicó un plan de acción que incluyó: cribado baciloscópico de admisión, habitaciones de aislamiento para TB/sida, sala de aislamiento para TBMR/sida, diagnóstico de multirresistencia mediante método radiométrico; banco de fármacos de segunda línea y protección respiratoria del personal de salud. Resultados. Entre 1995 y 2002, se observó una tendencia estadísticamente significativa en la disminución de casos de TBMR/sida y de los internamientos por TB/sida (33,9% frente a 80,5%, respectivamente), así como una disminución significativa en la mortalidad de los primeros. El cribado baciloscópico permitió diagnosticar el 63,4% de los casos de TB/sida internados. Progresivamente fueron empleados los recursos de aislamiento respiratorio y tratamiento eficaz de los casos de TBMR diagnosticados por método radiométrico. Respecto de la población susceptible, el ingreso de pacientes con sida al hospital no varió significativamente a lo largo del período estudiado, tampoco lo hizo el recuento de linfocitos T CD41 de los pacientes que requirieron internamiento. Conclusión. Se observó una disminución significativa de la curva epidémica nosocomial de TBMR en pacientes con sida, pese a la persistencia de pacientes susceptibles con bajo nivel de linfocitos T CD41. Se considera que esta evolución decreciente de la TBMR/sida puede ser atribuida al impacto de las medidas de control implementadas (AU)

Since 1992 AIDS-related multidrug-resistant tuberculosis (MDRTB) has been detected among patients admitted to the Hospital Muñiz in Buenos Aires (Argentina). The aim of the present study was to evaluate the effectiveness of the control measures adopted against the nosocomial spread of MDRTB/AIDS, which affected 803 patients between 1992 and 2002. Methods. An action plan was applied that included bacilloscopy screening on admission, isolation rooms for patients with TB/AIDS, an isolation ward for patients with MDRTB/AIDS, a radiometric method for the diagnosis of multidrug-resistance, a reserve supply of second line drugs, and respiratory protection for health care workers. Results. Between 1995 and 2002, a statistically significant decreasing trend in cases of MDRTB/AIDS and admissions for TB/AIDS was observed (33.9% vs 80.5%). Mortality among patients with MDRTB/AIDS also significantly decreased. Bacilloscopy screening allowed the diagnosis of 63.4% of patients admitted with TB/AIDS. Respiratory isolation facilities and effective treatment of patients with MDRTB diagnosed through the radiometric method were progressively implemented. Admission of patients with AIDS showed no significant variations throughout the study period. The CD41 count of patients requiring admission did not vary significantly. Conclusion. The nosocomial epidemic curve of MDRTB in patients with AIDS significantly decreased, despite the persistence of susceptible patients with low CD41 levels. The decreasing tendency of MDRTB/AIDS cases could be attributed to the impact of the control measures implemented (AU)