Avances en tuberculosis en el 54º congreso chileno de enfermedades respiratorias. 2ª parte: nuevas normas técnicas chilenas para el control y eliminación de la tuberculosis / New Chilean technical standards for the control and elimination of tuberculosis

La incidencia de la tuberculosis (TBC) en Chile se ha ido incrementando en el último quinquenio, excepto al inicio de la pandemia de Covid-19, donde la pesquisa de TBC se redujo en forma importante. El escenario epidemiológico actual dista del objetivo propuesto en la Estrategia Nacional de Salud (ENS) de la década 2011-2020 (un plan nacional de gobierno para enfermedades relevantes en la población) que consistía en alcanzar una tasa de incidencia de todas las formas de TBC menor a 5 / 100.000 habitantes. La nueva ENS para la década 2021-2030 propone reducir la incidencia de la enfermedad mediante el diagnóstico oportuno y precoz focalizando las intervenciones en las poblaciones de riesgo de la enfermedad (grupos vulnerables), a modo de pesquisa activa y no solo como pesquisa por consultas espontáneas de sintomáticos respiratorios, o tamizajes masivos que pueden no seleccionar a la población de riesgo. También propone intervenir en la prevención priorizando el estudio y tratamiento de la población con Infección Tuberculosa Latente (ITL) de mayor riesgo de progresión hacia la enfermedad. Por último, se pretende mejorar la eficiencia del proceso de tratamiento de la TBC, optimizando el acceso y adherencia a las terapias de los casos activos de TBC como medida de incrementar la proporción de curación. Una nueva norma ministerial para el manejo y control de la TBC puede ayudar enormemente a esta propuesta. Esta norma entrada plenamente en vigencia el año 2022 entrega las herramientas operacionales para cumplir el objetivo señalado para la nueva ENS. La norma incorpora actividades tendientes a lograr una mayor cobertura de estudio y tratamiento de la ITL en grupos específicos, donde se incluyen, además de los contactos infantiles, a los contactos adultos y a otros grupos vulnerables. La terapia para esta condición se realizará utilizando la asociación de Isoniazida con Rifapentina de preferencia. Esta terapia se aplica bajo supervisión en una dosis semanal durante 3 meses (12 dosis) y ha demostrado mejor adherencia y menor toxicidad hepática. Para el diagnóstico oportuno de TBC la pesquisa se ha focalizado en los sintomáticos respiratorios (tos con expectoración) de más de 2 semanas en personas que pertenecen a alguno de los grupos vulnerables, o que tienen rasgos clínicos muy sugerentes de la enfermedad (fiebre, sudoración vespertina, hemoptisis, compromiso del estado general). Como herramienta diagnóstica deja de utilizarse la baciloscopía por su baja sensibilidad y es sustituida por pruebas moleculares, siendo la plataforma automatizada de amplificación de ADN del complejo M. tuberculosis más utilizada y disponible en los servicios de salud públicos el GeneXpert MTB/RIF Ultra, que además entrega información de la susceptibilidad a la rifampicina a través de la identificación de una mutación específica del genoma (gen rpoB). Con esta tecnología se agiliza el proceso diagnóstico (puede obtener resultados durante el día de ejecución, habitualmente no demoraría más de 2 horas) y es de alta sensibilidad (sensibilidad muy similar al cultivo). El tratamiento de la TBC sensible a los fármacos del esquema primario (rifampicina = R, isoniazida = H, etambutol = E y pirazinamida = Z) consiste en la administración diaria en la fase inicial (con los 4 fármacos) durante 2 meses y en la fase de continuación (con isoniazida y rifampicina) durante 4 meses, totalmente supervisado. La TBC con resistencia a rifampicina tiene tratamiento con un esquema acortado oral de 9 meses con nuevos fármacos: bedaquilina, linezolid, clofazimina y levofloxacino (6 meses con los 4 fármacos, seguido de 3 meses con clofazimina y levofloxacino). Estas terapias de alta calidad son seguras y prometen mejores resultados de curación. La nueva norma significa una mayor cobertura para la erradicación de los reservorios de la enfermedad y una mayor precisión en el diagnóstico de las fuentes de trasmisión comunitaria de la enfermedad, siendo un aporte significativo hacia la eliminación de la TBC en el país.

The incidence of tuberculosis (TB) in Chile has been increasing in the last five years except at the beginning of the Covid-19 pandemic where TB screening has clearly decreased. The current epidemiological scenario is far from the goal proposed in the National Health Strategy (NHS) of the decade 2011-2020 (a national government plan for relevant diseases in the population) which was to achieve an incidence rate of all forms of TB less than 5/100,000 inhabitants. The new NHS for the decade 2021-2030 proposes to reduce the incidence of the disease through timely and early diagnosis by focusing interventions on populations at risk of the disease (vulnerable groups), as an active screening and not only as screening for spontaneous consultations of respiratory symptomatic or mass screenings that may not select the population at risk. It also proposed to intervene in prevention prioritizing the study and treatment of the population with Latent Tuberculosis Infection (LTI) at higher risk of progression to the disease. Finally, it intends to improve the efficiency of the TB treatment process, optimizing access and adherence to therapies of active TB cases as a measure to increase the cure rate. A new ministerial standard for the management and control of TB can greatly help this proposal. This standard, fully effective in 2022, provides the operational tools to meet the objective set for the new NHS. The standard incorporates activities aimed at achieving greater coverage of study and treatment of LTI in specific groups, which include, in addition to child contacts, adult contacts and other vulnerable groups. Therapy for this condition will be performed using the combination of isoniazid with rifapentine preferably. Therapy is administered under supervision and patients receive therapy once a week for 12 doses for 3 months. This therapy has shown better adherence and lower liver toxicity. For the timely diagnosis of TB, case finding has focused on respiratory symptoms (cough and expectoration) for more than 2 weeks, in individuals that belong to one of the vulnerable groups, or that have additional clinical features very suggestive of the disease (fever, afternoon sweats, hemoptysis, compromise of the general condition). Smear sputum as a diagnostic tool is no longer used due to low sensitivity and it was replaced by molecular tests in automated platform for DNA amplification of the mycobacterium TB complex. The more used and available in public health services is GeneXpert MTB / RIF Ultra, which also provides information on susceptibility to rifampicin through the identification of a specific genome mutation (rpoB gene). With this technology, the diagnostic process is streamlined (you can obtain results during the day of execution, usually it would not take more than 2 hours) and sensitivity is high (sensitivity very similar to culture). Treatment of TB sensitive to first line drugs (rifampicin, isoniazid, ethambutol and pyrazinamide) consists of daily administration in the initial phase (with four drugs) for 2 months and in the continuation phase (with isoniazid and rifampicin) for 4 months, fully supervised. In rifampicin resistant TB, the treatment is a shortened oral regimen of 9 months with new drugs: bedaquiline, linezolid, clofazimine and levofloxacin (six months with four drugs, followed by three months with clofazimine and levofloxacin). These high-quality therapies are safe and promise better healing results. The new national standards mean a greater coverage for the eradication of the reservoirs of the disease and a greater precision in the diagnosis of the sources of community transmission of tuberculosis, being a significant contribution towards the path of control and elimination of TB in the country.

Experiencia piloto con esquema rifapentina-isoniazida semanal por 3 meses para tratamiento de la infección tuberculosa latente en el Programa Nacional de Tuberculosis de Chile / Pilot experience with weekly rifapentine-isoniazid treatment for 3 months for latent tuberculosis infection at the Tuberculosis National Program of Chile

INTRODUCCIÓN: La prevención de la tuberculosis activa en los grupos de riesgo es clave para el control y eliminación de la tuberculosis. El tratamiento de la infección tuberculosa latente (TITL) con rifapentina e isoniazida en dosis semanales por 12 semanas es más corto que con otros esquemas, tiene menor hepatotoxicidad, mejor adherencia y es costo-efectivo. El OBJETIVO del estudio es evaluar la factibilidad de implementar este esquema a nivel programático en Chile. MÉTODOS: Se hizo una intervención piloto en territorios seleccionados entre mayo de 2018 y marzo de 2019. En esos territorios se reemplazó el esquema normado de TITL con isoniazida 6 meses por el esquema rifapentina-isoniazida 12 semanas. Además, se amplió la población objetivo, incluyendo a contactos mayores de 14 años. El tratamiento consistió en la administración conjunta de isoniazida y rifapentina por vía oral con frecuencia semanal, por 12 semanas, de forma supervisada por personal de salud. RESULTADOS: Ingresaron 238 pacientes al piloto, de los cuales 53% fueron mujeres y 54,2% fueron mayores de 14 años. Del total de pacientes, 203 (85,3%) completaron el tratamiento, 22 (9,2%) lo abandonaron, 8 (3,4%) presentaron reacciones adversas y 5 tuvieron otros motivos de egreso. CONCLUSIÓN: Tanto el TITL con rifapentinaisoniazida por 3 meses en dosis semanales supervisadas, como la incorporación de contactos adultos a TITL, son factibles de implementar a nivel programático en Chile.

INTRODUCTION: Prevention of active tuberculosis in risk groups is crucial in tuberculosis control and elimination. Treatment of latent tuberculosis (TITL) with rifapentine and isoniazid in weekly doses for 12 weeks is shorter than other pharmacological treatments, with less liver toxicity, better patient compliance and it is cost-effective. The OBJECTIVE of this study is to evaluate the feasibility to implement this treatment at a programmatic level in Chile. METHODS: A pilot intervention was conducted in selected territories between May 2018 and March 2019. Within these territories, the regulated treatment with isoniazid 6 months was replaced by the 12 weeks treatment with weekly rifapentine-isoniazide. Additionally, the target population was expanded to include contacts over 14 years old, currently not included in the national guidelines. Treatment consisted in oral administration of rifapentine and isoniazide together once a week for 12 weeks, under supervision of trained health workers. RESULTS: From 238 patients entered to the protocol, 53% of them were women and 54.2% were older than 14 years-old. Out of the total number of patients, 203 (85.3%) completed treatment, 22 (9.2%) abandoned, 8 (3.4%) had adverse drug reactions, and 5 ended treatment for different causes. CONCLUSION: Both TITL with rifapentine-isoniazide in 12 supervised weekly doses, and the inclusion of adult contacts in TITL, are feasible to implement at a programmatic level in Chile.

Efficacy and safety of levofloxacin and rifapentine for elderly initial treatment pulmonary tuberculosis / 中国生化药物杂志

Objective To investigate the efficacy and safety of levofloxacin and rifapentine for elderly initial treatment pulmonary tuberculosis.Methods 120 cases of elderly initial treatment pulmonary tuberculosis patients January 2015 to January 2016 in our hospital were randomly divided into A,B,C three groups,with 40 cases in each group.Treatment regimen of group A: 2HRZE/4HR; treatment regimen of group B: 2Rft(rifapentine capsules)HZE/4HRft; treatment regimen of group C: 2Rft(rifapentine capsules)HELfx/4HRft.The clinical symptoms,signs and adverse drug reactions were compared between the three groups of patients,observation the changes of blood,urine,liver and kidney function,perform imaging and bacteriological examination to determine the treatment effect.Results Five cases in group A and one case in group B abandoned treatment because of liver damage and severe gastrointestinal reaction,but no one in the 40 cases of group C abandoned treatment.There was no statistically significant difference among three groups in sputum negative conversion rate and focus absorption.The number of cases presenting gastrointestinal reaction and liver damage in group C was significantly smaller than that in group A and group B(P<0.05).Rifampicin was replaced by levofloxacin in two cases of group A as a result of allergy,and no allergy occurred in the other two groups.Conclusion Levofloxacin and rifapentine have good efficacy and few side effects for elderly initial treatment pulmonary tuberculosis,initial treatment regimen for elderly pulmonary tuberculosis patients should be individualized,drugs with few side effects can be used to guarantee smooth proceeding of treatment.

Comparison of the curative effect and safety of rifapentine and rifampicin in smear positive pulmonary tuberculosis patients / 中国生化药物杂志

Objective To compare the clinical therapeutic effect and safety of rifapentine and rifampicin in smear positive pulmonary tuberculosis patients.Methods A total of 80 patients with smear positive pulmonary tuberculosis were chosen in Changshan People's Hospital from June 2015 to July 2016,the patients were randomly divided into control group(n=40)and observation group(n=40).The control group used rifampicin treatment,observation group were treated with rifapentine therapy,the therapeutic effect and incidence of complications between two groups were compared.Results Proportion of the sputum smear negative,cavity closure and lesions absorption in the observation group after 6 months of treatment were significantly higher than those in the control group; peripheral blood T lymphocyte subsets CD3+,CD4+,CD8+ levels in two groups before treatment had no statistically significant differences; peripheral blood of T lymphocyte subsets CD3+,CD4+,CD8+ levels in the observation group after treatment were significantly higher than those in the control group(P<0.05); incidence of complications in observation group(7.5％)after treatment was significantly lower than that in the control group(17.5％)(P<0.05).Conclusion Compared with rifampicin in treatment of smear positive pulmonary tuberculosis patients,rifapentine has ideal treatment effect,can improve the immune function,low incidence of complications.

Effect of Rifabutin Combined with Multi-drugs in the Treatment of Multi-drug Resistant Tuberculosis with Long-term Therapy / 中国药师

Objective:To evaluate the effect and safety of rifabutin combined with multi-drugs in the treatment of multi-drug resist-ant tuberculosis with long-term therapy. Methods:Totally 86 cases of patients with multi-drug resistant tuberculosis were divided into the control group and the treatment group with 43 ones in each according to a random number table method. The two groups were trea-ted with levofloxacin, pasiniazid, ethambutol, protionamide and amikacin etc. The control group was treated with rifapentine, and the treatment group was treated with rifabutin additionally. After 18-month treatment, the negative conversion ratio of sputum smear and sputum mycobacterium tuberculosis culture, lesion absorption rate and cavity closure rate of X-ray chest radiograph and adverse reac-tions in the two groups were compared. Results:The negative conversion ratio of sputum smear and sputum mycobacterium tuberculosis culture in the treatment group was 41. 86% and 32. 56%, respectively, which were similar with those in the control group ( P >0. 05). There were no significant differences in lesion absorption rate and cavity closure rate of X-ray chest radiograph and adverse re-actions between the two groups (P>0. 05). Conclusion:Rifapentine or rifabutin combined with multi-drugs in the treatment of multi-drug resistant tuberculosis can improve the negative conversion rate of sputum mycobacterium and lesion absorption and cavity closure with high safety.

Prepartion and performance in vitro of a novel p-aminomethyl benzoicacid and calcium alginate microspheres of rifapentine / 中国药学杂志

OBJECTIVE: To prepare p-aminomethylbenzoic acid and calcium alginate composite microspheres with rifapentine as model drug, and characterize and evaluate the drug release performance. METHODS: The high-voltage electrostatic liquid drop device was used to prepare the P-aminomethylbenzoic acid and calcium alginate microspheres of rifapentine. The particle size, loading efficiency, entrapment efficiency, swelling ratio and drug-releasing of the microspheres were measured. RESULTS: The particle size of the microspheres was 163.12 μm, the loading efficiency and entrapment efficiency were 51.5% and 89.3% Respectively. The swelling rate was 19 after swelling 70 h in saline, the total drug release rate was 75% after 120 h in saline under the condition of 37°C and 150 r·min-1. CONCLUSION: The addition of p-aminomethylbenzoic acid slows down the fast-corrosion of calcium alginate microspheres in saline, improves the drug release properties.

STUDY ON THE PHARMACOKINETIC OF RIFAPENTINE IN VOLUNTEERS / 中国药理学通报

The pharmacokinetic study of Rifapentine by daily oral administration for 10d and followed by twice weekly for another 3 weeks in 9 volunteers and in comparism with Rifandin were reported. The results showed that the absorption and excretion of Rifapentine were markedly slower than that of Rifandin, its T1/2 was 15h. The Peak plasma level and T1/2 decreased after repeated administration of the drug. This suggested that Rifapentine and Rifandin in similar to Ri-fampin were hepatic microsomal enzyme inducers.