RESUMEN

BACKGROUND: Tuberculosis (TB) is a leading cause of death in patients with human immunodeficiency virus (HIV)/AIDS. About 60% of HIV-positive individuals with latent TB infection (LTBI) develop active TB. Isoniazid preventive therapy (IPT) is recommended by the World Health Organization to prevent the progression of active TB in people living with HIV/AIDS (PLWHA). However, IPT implementation has been limited in some countries like Indonesia. The objective of this study was to assess the effect of IPT administration on the incidence of active TB in HIV patients with latent TB. METHODS: This was a quasi-experimental prospective cohort study conducted in an academic hospital in Indonesia. Interferon-gamma release assay-positive HIV-TB patients were randomly divided into an IPT group (received 6 months of IPT) and a non-IPT group. The incidence of active pulmonary TB was compared between the two groups after 6 months of follow-up. RESULTS: Of the 23 eligible patients, 22 were enrolled (10 in the IPT group, 12 in the non-IPT group). The incidence of active pulmonary TB was 0% in both groups. Factors associated with the absence of TB in both groups were the use of antiretroviral therapy for >4 years and a CD4+ T lymphocyte count >200 cells/µL. IPT was found to be safe with minimal adverse effects. CONCLUSIONS: In this setting, the use of long-term antiretroviral therapy and higher CD4+ counts, rather than just IPT, were the key factors associated with preventing active TB in latent HIV-TB patients. These findings suggest that comprehensive HIV management may be more important than IPT alone for TB control in PLWHA. Further research is needed to optimize TB prevention strategies in this high-risk population.

Asunto(s)

Antituberculosos , Infecciones por VIH , Isoniazida , Tuberculosis Latente , Tuberculosis Pulmonar , Humanos , Isoniazida/uso terapéutico , Isoniazida/administración & dosificación , Tuberculosis Latente/complicaciones , Masculino , Antituberculosos/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Adulto , Femenino , Estudios Prospectivos , Tuberculosis Pulmonar/prevención & control , Tuberculosis Pulmonar/complicaciones , Tuberculosis Pulmonar/tratamiento farmacológico , Indonesia/epidemiología , Incidencia , Persona de Mediana Edad , Ensayos de Liberación de Interferón gamma

RESUMEN

Due to interindividual variability in drug metabolism and pharmacokinetics, traditional isoniazid fixed-dose regimens may lead to suboptimal or toxic isoniazid concentrations in the plasma of patients with tuberculosis, contributing to adverse drug reactions, therapeutic failure, or the development of drug resistance. Achieving precision therapy for isoniazid requires a multifaceted approach that could integrate various clinical and genomic factors to tailor the isoniazid dose to individual patient characteristics. This includes leveraging molecular diagnostics to perform the comprehensive profiling of host pharmacogenomics to determine how it affects isoniazid metabolism, such as its metabolism by N-acetyltransferase 2 (NAT2), and studying drug-resistant mutations in the Mycobacterium tuberculosis genome for enabling targeted therapy selection. Several other molecular signatures identified from the host pharmacogenomics as well as other omics-based approaches such as gut microbiome, epigenomic, proteomic, metabolomic, and lipidomic approaches have provided mechanistic explanations for isoniazid pharmacokinetic variability and/or adverse drug reactions and thereby may facilitate precision therapy of isoniazid, though further validations in larger and diverse populations with tuberculosis are required for clinical applications. Therapeutic drug monitoring and population pharmacokinetic approaches allow for the adjustment of isoniazid dosages based on patient-specific pharmacokinetic profiles, optimizing drug exposure while minimizing toxicity and the risk of resistance. Current evidence has shown that with the integration of the host pharmacogenomics-particularly NAT2 and Mycobacterium tuberculosis genomics data along with isoniazid pharmacokinetic concentrations in the blood and patient factors such as anthropometric measurements, comorbidities, and type and timing of food administered-precision therapy approaches in isoniazid therapy can be tailored to the specific characteristics of both the host and the pathogen for improving tuberculosis treatment outcomes.

Asunto(s)

Antituberculosos , Isoniazida , Mycobacterium tuberculosis , Medicina de Precisión , Tuberculosis , Humanos , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Medicina de Precisión/métodos , Isoniazida/farmacocinética , Isoniazida/administración & dosificación , Isoniazida/efectos adversos , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Monitoreo de Drogas/métodos , Arilamina N-Acetiltransferasa/genética , Arilamina N-Acetiltransferasa/metabolismo , Farmacogenética , Farmacorresistencia Bacteriana/genética

RESUMEN

A 78-year-old woman with rheumatoid arthritis, who was started on baricitinib five or six months earlier, was referred to our hospital due to a subcutaneous abscess in her right axilla. Contrast-enhanced chest, abdomen, and pelvis computed tomography showed subcutaneous abscesses in her right axilla and lymphadenopathy with calcification. Cultures from the subcutaneous abscess and skin biopsy specimens were positive for Mycobacterium tuberculosis. These findings led to the diagnosis of scrofuloderma associated with tuberculous lymphadenitis. She was started on an antitubercular regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol as the initial phase treatment (first 2 months), followed by isoniazid and rifampicin for 4 months (total 6 months). After 6 months of antitubercular treatment, the abscesses and lymphadenitis disappeared. Although cases of tuberculosis during JAK inhibitor treatment are rare, they are serious adverse events that require caution.

Asunto(s)

Antituberculosos , Artritis Reumatoide , Inhibidores de las Cinasas Janus , Pirazoles , Sulfonamidas , Tuberculosis Ganglionar , Humanos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/complicaciones , Femenino , Anciano , Inhibidores de las Cinasas Janus/efectos adversos , Antituberculosos/efectos adversos , Antituberculosos/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/administración & dosificación , Pirazoles/efectos adversos , Tuberculosis Ganglionar/tratamiento farmacológico , Tuberculosis Ganglionar/diagnóstico , Purinas/efectos adversos , Purinas/administración & dosificación , Azetidinas/efectos adversos , Azetidinas/administración & dosificación , Tuberculosis Cutánea/diagnóstico , Tuberculosis Cutánea/tratamiento farmacológico , Resultado del Tratamiento , Mycobacterium tuberculosis/aislamiento & purificación , Quimioterapia Combinada , Isoniazida/efectos adversos , Isoniazida/administración & dosificación

RESUMEN

BACKGROUND: Isoniazid preventive therapy (IPT) decreases risk of tuberculosis (TB) disease; impact on long-term infant growth is unknown. In a recent randomized trial (RCT), we assessed IPT effects on infant growth without known TB exposure. METHODS: The infant TB Infection Prevention Study (iTIPS) trial was a non-blinded RCT among HIV-exposed uninfected (HEU) infants in Kenya. Inclusion criteria included age 6-10 weeks, birthweight ≥2.5 kg, and gestation ≥37 weeks. Infants in the IPT arm received 10 mg/kg isoniazid daily for 12 months, while the control trial received no intervention; post-trial observational follow-up continued through 24 months of age. We used intent-to-treat linear mixed-effects models to compare growth rates (weight-for-age z-score [WAZ] and height-for-age z-score [HAZ]) between trial arms. RESULTS: Among 298 infants, 150 were randomized to IPT, 47.6% were females, median birthweight was 3.4 kg (interquartile range [IQR] 3.0-3.7), and 98.3% were breastfed. During the 12-month intervention period and 12-month post-RCT follow-up, WAZ and HAZ declined significantly in all children, with more HAZ decline in male infants. There were no growth differences between trial arms, including in sex-stratified analyses. In longitudinal linear analysis, mean WAZ (ß = 0.04 [95% CI:-0.14, 0.22]), HAZ (ß = 0.14 [95% CI:-0.06, 0.34]), and WHZ [ß = -0.07 [95% CI:-0.26, 0.11]) z-scores were similar between arms as were WAZ and HAZ growth trajectories. Infants randomized to IPT had higher monthly WHZ increase (ß to 24 months 0.02 [95% CI:0.01, 0.04]) than the no-IPT arm. CONCLUSION: IPT administered to HEU infants did not significantly impact growth outcomes in the first two years of life.

Asunto(s)

Antituberculosos , Infecciones por VIH , Isoniazida , Tuberculosis , Humanos , Isoniazida/uso terapéutico , Isoniazida/administración & dosificación , Femenino , Lactante , Masculino , Antituberculosos/uso terapéutico , Antituberculosos/administración & dosificación , Infecciones por VIH/prevención & control , Tuberculosis/prevención & control , Kenia , Preescolar , Recién Nacido

RESUMEN

Central nervous system tuberculosis (CNS-TB) is a severe form of extra-pulmonary tuberculosis with high mortality and morbidity rates. The standard treatment regimen for CNS-TB parallels that of pulmonary TB, despite the challenge posed by the blood-brain barrier (BBB), which limits the efficacy of first-line anti-TB drugs (ATDs). Nose-to-brain (N2B) drug delivery offers a promising solution for achieving high ATD concentrations directly at infection sites in the brain while bypassing the BBB. This study aimed to develop chitosan nanoparticles encapsulating ATDs, specifically isoniazid (INH) and rifampicin (RIF). These nanoparticles were further processed into micro-sized chitosan nano-aggregates (NA) via spray drying. Both INH-NA and RIF-NA showed strong mucoadhesion and significantly higher permeation rates across RPMI 2650 cells compared to free ATDs. Intranasal administration of these NAs to TB-infected mice for four weeks resulted in a significant reduction of mycobacterial load by approximately ∼2.86 Log 10 CFU compared to the untreated group. This preclinical data highlights the efficacy of intranasal chitosan nano-aggregates in treating CNS-TB, demonstrating high therapeutic potential, and addressing brain inflammation challenges. To our knowledge, this study is the first to show nasal delivery of ATD nano-formulations for CNS-TB management.

Asunto(s)

Antituberculosos , Quitosano , Isoniazida , Nanopartículas , Rifampin , Tuberculosis del Sistema Nervioso Central , Animales , Ratones , Tuberculosis del Sistema Nervioso Central/tratamiento farmacológico , Barrera Hematoencefálica , Quitosano/administración & dosificación , Quitosano/química , Nanopartículas/administración & dosificación , Nanopartículas/química , Administración Intranasal , Células Epiteliales/efectos de los fármacos , Antituberculosos/administración & dosificación , Antituberculosos/química , Ratones Endogámicos BALB C , Adhesivos/administración & dosificación , Adhesivos/química , Mucinas/química , Encéfalo/efectos de los fármacos , Encéfalo/patología , Humanos , Línea Celular , Isoniazida/administración & dosificación , Rifampin/administración & dosificación , Sistemas de Liberación de Medicamentos

RESUMEN

The coexistence of TB and diabetes mellitus (DM) (TB-DM) is associated with an increased risk of treatment failure, death, delayed culture conversion, and drug resistance. Because plasma concentrations may influence clinical outcomes, we evaluated the evidence on the pharmacokinetic (PK) of TB drugs in individuals with DM to guide management.We performed a systematic review and meta-analysis through searches of major databases from 1946 to 6 July 2023. PROSPERO (CRD42022323566).Of 4,173 potentially relevant articles, we identified 16 studies assessing rifampicin (RIF) PK, 9 on isoniazid (INH), 8 on pyrazinamide (PZA), and 3 on ethambutol (EMB). Two studies reported on second-line anti-TB drugs. According to our meta-analysis, RIF time to maximum concentration (Tmax) was significantly prolonged in patients with DM compared with non-DM patients. We found no significant differences for RIF Cmax, area under the curve (AUC) 0-24 or drug concentration at 2 h (C2h), INH C2h, PZA C2h, PZA Tmax, and EMB Tmax. Although RIF C2h was slightly reduced in patients with TB-DM, this finding was not statistically significant.This review comprehensively examines the impact of DM on the PK of TB drugs. We observed significant heterogeneity among the studies. Given the association between lower plasma concentrations and poor clinical outcomes among patients with DM, we recommend a higher dose limit to compensate for the larger body weight of patients with DM..

Asunto(s)

Antituberculosos , Diabetes Mellitus , Tuberculosis , Humanos , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Diabetes Mellitus/metabolismo , Isoniazida/farmacocinética , Isoniazida/administración & dosificación , Pirazinamida/farmacocinética , Rifampin/farmacocinética , Rifampin/administración & dosificación , Tuberculosis/tratamiento farmacológico

RESUMEN

WHO guidance to defer isoniazid preventive therapy (IPT) among those with regular alcohol use because of hepatotoxicity concerns may exclude many people living with HIV (PLWH) at high TB risk in these settings.To evaluate hepatotoxicity during TB preventive therapy (TPT) in PLWH who report alcohol use in Uganda over 10 years.We developed a Markov model of latent TB infection, isoniazid preventive therapy (IPT - a type of TPT), and TB disease using data from the Alcohol Drinkers' Exposure to Preventive Therapy for TB (ADEPTT) study. We modeled several treatment scenarios, including no IPT, IPT with liver enzyme monitoring (AST/ALT) during treatment, and IPT with pre-screening using the tuberculin skin test (TST).The no IPT scenario had 230 TB deaths/100,000 population over 10 years, which is more than that seen in any IPT scenario. IPT, even with no monitoring, was preferred over no IPT when population TB disease incidence was >50 in 100,000.For PLWH who report alcohol use in high TB burden settings, IPT should be offered, ideally with regular AST/ALT monitoring. However, even if regular monitoring is not possible, IPT is still preferable to no IPT in almost every modeled scenario..

Asunto(s)

Consumo de Bebidas Alcohólicas , Antituberculosos , Infecciones por VIH , Isoniazida , Tuberculosis Latente , Humanos , Isoniazida/administración & dosificación , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Uganda/epidemiología , Tuberculosis Latente/tratamiento farmacológico , Masculino , Infecciones por VIH/tratamiento farmacológico , Femenino , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Adulto , Cadenas de Markov , Prueba de Tuberculina , Tuberculosis/prevención & control , Tuberculosis/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Adulto Joven , Persona de Mediana Edad

RESUMEN

Introduction: the National Tuberculosis Control Program (NTP) in Cameroon participated between 2016 and 2018 in a multi-country operational study of the Union against Tuberculosis and Lung Disease (The UNION) aiming at demonstrating the efficiency and feasibility of systematic tuberculosis preventive treatment (TPT) with 3 months of an isoniazid/rifampicin (3RH) combination in under-five child contacts of bacilliferous TB patients. Cameroon was one of the participating countries of the study. Despite the promising results communicated following this study, the coverage of TPT with 3RH in Cameroon remains low. We explored the intervention under aspects of acceptability and perceived feasibility. Methods: key participants and stakeholders in this descriptive interpretative study in Cameroon were interviewed in five focus groups or individually (31 individuals). The Focus Group Discussion (FGD) and interview transcripts were analysed for different components of acceptability using a theoretical framework and the results discussed confronting them with the main objective of the study, i.e. demonstrating feasibility. Results: the children's parents expressed overall positive feelings about and acceptance of the intervention, emphasizing the unexpected empathy shown by the health staff. The involved field staff, too, showed unreserved acceptance. On the other hand, managers at the intermediate and central levels showed scepticism as to the process of initiation of the study as well as to its feasibility in the given context, neglecting aspects of resources necessary for a scaling-up and of prioritisation. Conclusion: the adoption of a public health strategy, also internationally recognized as an effective and efficient intervention, requires more than the demonstration of its acceptability or feasibility during the term of a showcase project introduced by an external development partner. Adoption is conditioned by adoption and circumspect planning involving at each stage the stakeholders on all levels of the program.

Asunto(s)

Antituberculosos , Estudios de Factibilidad , Grupos Focales , Isoniazida , Salud Pública , Tuberculosis , Humanos , Camerún , Antituberculosos/administración & dosificación , Tuberculosis/prevención & control , Isoniazida/administración & dosificación , Preescolar , Femenino , Masculino , Padres/psicología , Entrevistas como Asunto , Lactante , Aceptación de la Atención de Salud , Adulto

RESUMEN

INTRODUCTION: Isoniazid is a first-line antituberculosis agent with high variability, which would profit from individualized dosing. Concentrations of isoniazid at 2 h (C2h), as an indicator of safety and efficacy, are important for optimizing therapy. OBJECTIVE: The objective of this study was to establish machine learning (ML) models to predict the C2h, that can be used for establishing an individualized dosing regimen in clinical practice. METHODS: Published population pharmacokinetic (PopPK) models for adults were searched based on PubMed and ultimately four reliable models were selected for simulating individual C2h datasets under different conditions (demographics, genotype, ethnicity, etc.). Machine learning models were trained on simulated C2h obtained from the four PopPK models. Five different algorithms were used for ML model building to predict C2h. Real-world data were used for predictive performance evaluations. Virtual trials were used to compare ML-optimized doses with PopPK model-optimized doses. RESULTS: Categorical boosting (CatBoost) exhibited the highest prediction ability. Target C2h can be predicted using the ML model combined with the dosing regimen and three covariates (N-acetyltransferase 2 [NAT2] genotypes, weight and race [Asians and Africans]). Real-world data validation results showed that the ML model can achieve an overall prediction accuracy of 93.4%. Using the final ML model, the mean absolute prediction error value decreased by 45.7% relative to the average of PopPK models. Using the ML-optimized dosing regimen, the probability of target attainment increased by 43.7% relative to the PopPK model-optimized dosing regimens. CONCLUSION: Machine learning models were developed with great predictive performance, which can be used to determine the individualized initial dose of isoniazid in adult patients.

Asunto(s)

Antituberculosos , Isoniazida , Aprendizaje Automático , Tuberculosis , Humanos , Isoniazida/farmacocinética , Isoniazida/administración & dosificación , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Tuberculosis/tratamiento farmacológico , Modelos Biológicos , Adulto , Medicina de Precisión/métodos , Relación Dosis-Respuesta a Droga , Arilamina N-Acetiltransferasa/genética , Algoritmos

RESUMEN

BACKGROUND: Tuberculosis (TB) lymphadenitis is the most common form of extra-pulmonary TB, and the treatment duration is six months. This non-inferiority based randomized clinical trial in South India evaluated the efficacy and safety of a four-month ofloxacin containing regimen in tuberculosis lymphadenitis (TBL) patients. METHODS: New, adult, HIV-negative, microbiologically and or histopathologically confirmed superficial lymph node TB patients were randomized to either four-month oflaxacin containing test regimen [ofloxacin (O), isoniazid (H), rifampicin (R), pyrazinamide (Z) -2RHZO daily/ 2RHO thrice-weekly] or a six-month thrice-weekly control regimen (2HRZ, ethambutol/4RH). The treatment was directly observed. Clinical progress was monitored monthly during and up to 12 months post-treatment, and thereafter every three months up to 24 months. The primary outcome was determined by response at the end of treatment and TB recurrence during the 24 months post-treatment. RESULTS: Of the 302 patients randomized, 298 (98.7%) were eligible for modified intention-to-treat (ITT) analysis and 294 (97%) for per-protocol (PP) analysis. The TB recurrence-free favourable response in the PP analysis was 94.0% (95% CI: 90.1-97.8) and 94.5% (95% CI: 90.8-98.2) in the test and control regimen respectively, while in the ITT analysis, it was 92.7% and 93.2%. The TB recurrence-free favourable response in the test regimen was non-inferior to the control regimen 0.5% (95% CI: -4.8-5.9) in the PP analysis based on the 6% non-inferiority margin. Treatment was modified for drug toxicity in two patients in the test regimen, while one patient had a paradoxical reaction. CONCLUSION: The 4-month ofloxacin containing regimen was found to be non-inferior and as safe as the 6-month thrice-weekly control regimen.

Asunto(s)

Antituberculosos , Ofloxacino , Tuberculosis Ganglionar , Humanos , Ofloxacino/administración & dosificación , Ofloxacino/efectos adversos , Ofloxacino/uso terapéutico , Adulto , Masculino , Femenino , Tuberculosis Ganglionar/tratamiento farmacológico , Antituberculosos/uso terapéutico , Antituberculosos/efectos adversos , Antituberculosos/administración & dosificación , Resultado del Tratamiento , Persona de Mediana Edad , India , Rifampin/uso terapéutico , Rifampin/administración & dosificación , Rifampin/efectos adversos , Adulto Joven , Isoniazida/uso terapéutico , Isoniazida/administración & dosificación , Isoniazida/efectos adversos , Quimioterapia Combinada , Pirazinamida/uso terapéutico , Pirazinamida/administración & dosificación , Pirazinamida/efectos adversos , Etambutol/uso terapéutico , Etambutol/administración & dosificación , Etambutol/efectos adversos , Esquema de Medicación , Adolescente

RESUMEN

Objective: To evaluate the efficacy and safety of first-line anti-tuberculosis (TB) drugs combined with linezolid in treatment of children with tuberculous meningitis (TBM). Methods: A retrospective cohort study design was performed. Eight-nine Children diagnosed as TBM during January 1st 2016 and December 31st 2023 in Department of Infectious Disease, Children's Hospital of Chongqing Medical University were enrolled in the study. According to different treatment regimens, children were divided into a group of first-line anti-tuberculous drugs (isoniazid, rifampicin, pyrazinamide, ethambutol (HRZE)) and a group of HRZE and linezolid combination (HRZEL). The efficacy and safety of the 2 regimens were compared and the relationship between linezolid drug concentration and adverse reactions were analyzed. Comparisons between groups were performed using χ2 test and Mann-Whitney U test. Results: The 89 children with TBM included 53 males and 36 females with an onset age of 4.6 (1.4, 9.6) years. There were 27 cases in the HZREL group and 62 cases in the HRZE group. Before treatment, positive rate of interferon-gamma release assays (IGRA) in HRZEL group was lower than that in HRZE group (64% (16/25) vs.92% (55/60), χ2=9.82, P<0.05), but protein level of cerebrospinal fluid (CSF) was higher than that in HRZE group (1.2 (1.0, 2.0) vs.0.8 (0.4,1.4) g/L, Z=0.32, P<0.05). By the end of the intensive phase, there were no significant differences of rates of CSF improvement and etiology negativity between HRZEL group and HRZE group (both P>0.05).The 44 TBM children with high CSF protein (>1 g/L) included 25 males and 19 females with an onset age of 6.7 (3.0, 11.8) years. There were 21 cases in the HZREL group and 23 cases in the HRZE group accordingly. Before treatment, there were no significant differences of positive rate of IGRA test and CSF protein level between the 2 groups (62% (13/21) vs. 87% (20/23), 1.7 (1.1, 2.2) vs. 1.5 (1.2, 1.9) g/L, χ2=3.67, Z=0.23, both P>0.05). There were no significant differences in CSF indicators, etiology negativity or imaging remission between the two groups by the end of intensive phase (all P>0.05). Higher frequencies of granulocytopenia, gastrointestinal symptoms as well as withdrawal or change of drugs were found in HRZEL group when compared to those in HRZE group (44% (12/27) vs. 19% (12/62), 7% (2/27) vs. 0, 33% (9/27) vs. 3% (2/62), χ2=6.01, 4.70, 15.74, all P<0.05). Conclusions: The efficacy of HRZEL regimen is similar to conventional HRZE regimen in children with TBM, but with higher adverse effect. Prudentially evaluating the pros and cons of linezolid in the usage of drug-susceptible TB and carefully monitoring of linezolid associated adverse effects is suggested.

Asunto(s)

Antituberculosos , Quimioterapia Combinada , Linezolid , Tuberculosis Meníngea , Humanos , Tuberculosis Meníngea/tratamiento farmacológico , Estudios Retrospectivos , Masculino , Femenino , Linezolid/uso terapéutico , Linezolid/administración & dosificación , Antituberculosos/uso terapéutico , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Niño , Preescolar , Resultado del Tratamiento , Lactante , Rifampin/uso terapéutico , Rifampin/administración & dosificación , Etambutol/uso terapéutico , Etambutol/administración & dosificación , Pirazinamida/uso terapéutico , Pirazinamida/administración & dosificación , Isoniazida/uso terapéutico , Isoniazida/administración & dosificación , Isoniazida/efectos adversos

RESUMEN

Introduction: tuberculosis (TB) and Human Immunodeficiency Virus (HIV) remain major public health threats globally and worse when they co-exist in susceptible individuals. The study examined TB treatment outcomes and their predictive factors among people living with HIV (PLHIVs). Methods: a review of TB/HIV co-infected patients who had TB treatments across comprehensive antiretroviral therapy (ART) sites with ≥500 patients was conducted in seven United States of America President's Emergency Plan for AIDS Relief (PEPFAR)-supported States in Nigeria. Data on patient background, HIV and TB care, and TB treatment outcomes were collected using an Excel abstraction template. The data was analyzed using SPSS and an association was examined using a chi-square test while binary logistic regression was used to determine predictors of TB treatment outcomes (P< 0.05). Results: two thousand six hundred and fifty-two co-infected patients participated in the study. The mean age of participants was 37 ± 14 years. A majority had TB treatment success (cured = 1059 (39.9%), completed = 1186 (44.7%)). Participants who had pulmonary TB, virally suppressed and commenced isoniazid (INH) before TB diagnosis were more likely to have a favorable TB treatment outcome compared to those who had extrapulmonary TB (AOR = 7.110, 95% CI = 1.506 - 33.565), virally unsuppressed (AOR = 1.677, 95% CI = 1.036 - 2.716) or did not commence INH before TB diagnosis (AOR = 1.486, 95% CI = 1.047 - 2.109). Conclusion: site of infection, immune status, exposure to ART, and INH prophylaxis were found to predict TB treatment outcomes among PLHIVs. Stakeholders should ensure early commencement of ART and INH prophylaxis for PLHIVs.

Asunto(s)

Antituberculosos , Coinfección , Infecciones por VIH , Tuberculosis , Humanos , Nigeria , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/complicaciones , Adulto , Femenino , Antituberculosos/administración & dosificación , Masculino , Tuberculosis/tratamiento farmacológico , Tuberculosis/epidemiología , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven , Fármacos Anti-VIH/administración & dosificación , Isoniazida/administración & dosificación , Estudios Retrospectivos , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/epidemiología

RESUMEN

BACKGROUND: The treatment regimen for tuberculous meningitis (TBM) remains unclear and requires optimization. There are some reports on successful adjunct intrathecal dexamethasone and isoniazid (IDI) treatment strategies for TBM, however, there is equivocal evidence on their efficacy and safety. METHODS: A comprehensive search of English and Chinese databases was conducted from inception to February 2024. A meta-analysis was performed on randomized controlled trials (RCTs) estimating the effects of adjunct IDI on conventional anti-TB (C anti-TB) treatments or C anti-TB alone. Efficacy, adverse reaction rate, cerebrospinal fluid (CSF) leukocytes, and CSF protein were used as primary outcome indicators. CSF glucose, CSF chlorides, CSF pressure, recovery time for laboratory indicators and recovery time for clinical symptoms were used as secondary outcome indicators. RESULTS: A total of 17 studies involving 1360 (IDI group vs. C anti-TB group: 392 vs. 372; higher-dose IDI group vs. lower-dose IDI group: 319 vs. 277) patients were included in our analysis. Efficacy was significantly higher (RR 1.3, 95% CI 1.2-1.4, P < 0.001) and adverse reaction rate was significantly lower in the IDI groups (RR 0.59, 95% CI 0.37-0.92, P = 0.021). Furthermore, CSF leukocytes (WMD - 29.33, 95% CI [- 40.64 to-18.02], P < 0.001) and CSF protein (WMD - 0.79, 95%CI [-0.96 to-0.61], P < 0.001) were significantly lower in the IDI groups. Recovery time indicators were all shorter in the IDI groups, fever (SMD - 2.45, 95% CI [-3.55 to-1.35], P < 0.001), coma (SMD-3.75, 95% CI [-4.33 to-3.17], P < 0.001), and headache (SMD  - 3.06, 95% CI [- 4.05 to-2.07], P < 0.001), respectively. Higher-dose IDI was more effective than lower-dose IDI (RR 1.23, 95% CI 1.14-1.33, P < 0.001), with no significant difference in adverse reaction rate between the two (RR 0.82, 95%CI 0.43-1.56, P = 0.544). CONCLUSION: Adjunct IDI with C anti-TB can enhance therapeutic outcomes and reduce adverse reaction rate in adult TBM patients, with higher-dose IDI showing superior efficacy. These findings highlight the potential of IDI as an adjunctive therapy in TBM management. However, more high-quality RCTs from more regions should be conducted to support our results. TRIAL REGISTRATION: Retrospectively registered in PROSPERO  https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023388860 .

Asunto(s)

Antituberculosos , Dexametasona , Quimioterapia Combinada , Inyecciones Espinales , Isoniazida , Tuberculosis Meníngea , Humanos , Tuberculosis Meníngea/tratamiento farmacológico , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Isoniazida/administración & dosificación , Isoniazida/uso terapéutico , Isoniazida/efectos adversos , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , Inyecciones Espinales/métodos , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos

RESUMEN

BACKGROUND: Insufficient exposure and poor compliance with anti-tuberculosis (TB) medications are risk factors for treatment failure and the development of drug resistance. Measurement of drugs in biological samples, such as blood and saliva, can be used to assess adherence and make dose adjustments by therapeutic drug monitoring (TDM). Finger sweat testing is a convenient and non-invasive method to monitor patients. OBJECTIVES: To assess the feasibility of finger sweat testing for medication adherence and as a semi-quantitative tool for TDM analysis. METHODS: Ten patients provided finger sweat, blood and saliva samples following a controlled dose of isoniazid. Samples were analysed by liquid chromatography-mass spectrometry. RESULTS: Isoniazid can be detected in finger sweat 1-6 h following administration at typically prescribed dosages. The normalisation of isoniazid to creatinine increases the correlation between finger sweat and serum isoniazid concentration and provides a means to account for inconsistent sample volumes. CONCLUSION: We describe the time-course measurement of isoniazid (or drug-to-creatinine ratio) in finger sweat compared to the pharmacokinetic profile in blood for the first time. This technique, adaptable for other drugs, could reduce the burden on clinics and improve patient experience.

Asunto(s)

Antituberculosos , Creatinina , Monitoreo de Drogas , Isoniazida , Sudor , Tuberculosis , Humanos , Isoniazida/farmacocinética , Isoniazida/administración & dosificación , Sudor/química , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Creatinina/sangre , Monitoreo de Drogas/métodos , Masculino , Femenino , Adulto , Tuberculosis/tratamiento farmacológico , Persona de Mediana Edad , Cromatografía Liquida/métodos , Espectrometría de Masas , Cumplimiento de la Medicación , Adulto Joven , Saliva/química

RESUMEN

BACKGROUND: Despite several incremental improvements in the management of tuberculous meningitis (TBM), the mortality rates remain high. In spite of national and international guidelines, variation in the choice, dose, and duration of drugs exist between countries and clinicians. We propose to evaluate a shorter and more effective regimen containing agents with augmented intracerebral drug exposure and anti-inflammatory approaches to improve disability-free survival among patients with TBM. Our strategy incorporates the various developments in the field of TBM over the last two decades and only few trials have evaluated a composite of these strategies in the overall outcomes of TBM. METHODS: An open label, parallel arms, randomized controlled superiority trial will be conducted among 372 participants across 6 sites in India. Eligible participants will be randomly allocated in 1:1:1 ratio into one of the three arms. The intervention arm consists of 2 months of high-dose rifampicin (25 mg/kg), moxifloxacin (400 mg), pyrazinamide, isoniazid, aspirin (150 mg), and steroids followed by rifampicin, isoniazid, and pyrazinamide for 4 months. The second intervention arm includes all the drugs as per the first arm except aspirin and the patients in the control arm will receive treatment according to the National TB Elimination Program guidelines. All participants will be followed up for 1 year after the treatment.  DISCUSSION: Current WHO regimens have agents with poor central nervous system drug exposure and is too long. It does not reflect the accumulating evidence in the field. We propose a comprehensive clinical trial incorporating the emerging evidence accrued over the last two decades to shorten the duration and improve the treatment outcomes. This multi-centric trial may generate crucial evidence with policy and practice implications in the treatment of TBM. TRIAL REGISTRATION: Clinical Trial Registry India CTRI/2023/05/053314. Registered on 31 May 2023 ( https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=ODYzMzg=&Enc=&userName=CTRI/2023/05/053314 ). CLINICALTRIALS: gov NCT05917340. Registered on 6 August 2023 ( https://classic. CLINICALTRIALS: gov/ct2/show/NCT05917340 ). PROTOCOL VERSION: Version 1.3 dated 12 July 2023.

Asunto(s)

Antituberculosos , Estudios Multicéntricos como Asunto , Tuberculosis Meníngea , Humanos , Tuberculosis Meníngea/tratamiento farmacológico , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , India , Isoniazida/administración & dosificación , Isoniazida/uso terapéutico , Quimioterapia Combinada , Adulto , Rifampin/administración & dosificación , Rifampin/uso terapéutico , Estudios de Equivalencia como Asunto , Resultado del Tratamiento , Esquema de Medicación , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo , Pirazinamida/administración & dosificación , Pirazinamida/uso terapéutico , Aspirina/administración & dosificación , Aspirina/uso terapéutico

RESUMEN

BACKGROUND: Screening for tuberculosis (TB) and providing TB preventive treatment (TPT) along with antiretroviral therapy is key components of human immune deficiency virus (HIV) care. The uptake of TPT during the coronavirus disease 2019 (COVID-19) period has not been adequately assessed in Addis Ababa City Administration. This study aimed at assessing TPT uptake status among People living with HIV (PLHIV) newly initiated on antiretroviral therapy during the COVID-19 period at all public hospitals of Addis Ababa City Administration, Ethiopia. METHODS: A retrospective data review was conducted from April-July 2022. Routine District Health Information System 2 database was reviewed for the period from April 2020-March 2022. Proportion and mean with standard deviation were computed. Logistic regression analysis was conducted to assess factors associated with TPT completion. A p-value of < 0.05 was considered statistically significant. RESULTS: A total of 1,069 PLHIV, aged 18 years and above were newly initiated on antiretroviral therapy, and of these 1,059 (99.1%) underwent screening for TB symptoms. Nine hundred twelve (86.1%) were negative for TB symptoms. Overall, 78.8% (719) of cases who were negative for TB symptoms were initiated on TPT, and of these 70.5% and 22.8% were completed and discontinued TPT, respectively. Of 719 cases who were initiated on TPT, 334 (46.5%) and 385 (53.5%) were initiated on isoniazid plus rifapentine weekly for three months and Isoniazid preventive therapy daily for six months, respectively. PLHIV who were initiated on isoniazid plus rifapentine weekly for three months were more likely to complete TPT (adjusted odds ratio [AOR],1.68; 95% confidence interval [CI], 1.01, 2.79) compared to those who were initiated on Isoniazid preventive therapy daily for six months. CONCLUSION: While the proportion of PLHIV screened for TB was high, TPT uptake was low and far below the national target of achieving 90% TPT coverage. Overall a considerable proportion of cases discontinued TPT in this study. Further strengthening of the programmatic management of latent TB infection among PLHIV is needed. Therefore, efforts should be made by the Addis Ababa City Administration Health Bureau authorities and program managers to strengthen the initiation and completion of TPT among PLHIV in public hospitals.

Asunto(s)

Antituberculosos , COVID-19 , Infecciones por VIH , Tuberculosis , Humanos , Estudios Retrospectivos , Etiopía/epidemiología , Adulto , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/complicaciones , Femenino , Masculino , Tuberculosis/prevención & control , Tuberculosis/epidemiología , Tuberculosis/tratamiento farmacológico , Persona de Mediana Edad , COVID-19/prevención & control , COVID-19/epidemiología , Antituberculosos/uso terapéutico , Antituberculosos/administración & dosificación , Adulto Joven , Adolescente , Isoniazida/uso terapéutico , Isoniazida/administración & dosificación , SARS-CoV-2 , Tamizaje Masivo/estadística & datos numéricos

RESUMEN

Rationale: Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis. However, its activity against Mycobacterium tuberculosis (M.tb) with katG mutations (which typically confer high-level resistance) is not established. Objectives: To characterize the early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG-mutated M.tb. Methods: A5312 was a phase IIA randomized, open-label trial. Participants with tuberculosis caused by katG-mutated M.tb were randomized to receive 15 or 20 mg/kg isoniazid daily for 7 days. Daily sputum samples were collected for quantitative culture. Intensive pharmacokinetic sampling was performed on Day 6. Data were pooled across all A5312 participants for analysis (drug-sensitive, inhA-mutated, and katG-mutated M.tb). EBA was determined using nonlinear mixed-effects modeling. Measurements and Main Results: Of 80 treated participants, 21 had katG-mutated M.tb. Isoniazid pharmacokinetics were best described by a two-compartment model with an effect of NAT2 acetylator phenotype on clearance. Model-derived maximum concentration and area under the concentration-time curve in the 15 and 20 mg/kg groups were 15.0 and 22.1 mg/L and 57.6 and 76.8 mg ⋅ h/L, respectively. Isoniazid bacterial kill was described using an effect compartment and a sigmoidal maximum efficacy relationship. Isoniazid potency against katG-mutated M.tb was approximately 10-fold lower than in inhA-mutated M.tb. The highest dose of 20 mg/kg did not demonstrate measurable EBA, except against a subset of slow NAT2 acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events. Conclusions: This study found negligible bactericidal activity of high-dose isoniazid (15-20 mg/kg) in the majority of participants with tuberculosis caused by katG-mutated M.tb. Clinical trial registered with www.clinicaltrials.gov (NCT01936831).

Asunto(s)

Antituberculosos , Proteínas Bacterianas , Isoniazida , Mutación , Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Isoniazida/farmacocinética , Isoniazida/administración & dosificación , Isoniazida/farmacología , Isoniazida/uso terapéutico , Humanos , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Femenino , Masculino , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Adulto , Persona de Mediana Edad , Proteínas Bacterianas/genética , Catalasa/genética , Relación Dosis-Respuesta a Droga , Anciano , Pruebas de Sensibilidad Microbiana

RESUMEN

Personalized medicine aims to effectively and efficiently provide customized drugs that cater to diverse populations, which is a significant yet challenging task. Recently, the integration of artificial intelligence (AI) and three-dimensional (3D) printing technology has transformed the medical field, and was expected to facilitate the efficient design and development of customized drugs through the synergy of their respective advantages. In this study, we present an innovative method that combines AI and 3D printing technology to design and fabricate customized capsules. Initially, we discretized and encoded the geometry of the capsule, simulated the dissolution process of the capsule with classical drug dissolution model, and verified it by experiments. Subsequently, we employed a genetic algorithm to explore the capsule geometric structure space and generate a complex multi-layer structure that satisfies the target drug release profiles, including stepwise release and zero-order release. Finally, Two model drugs, isoniazid and acetaminophen, were selected and fused deposition modeling (FDM) 3D printing technology was utilized to precisely print the AI-designed capsule. The reliability of the method was verified by comparing the in vitro release curve of the printed capsules with the target curve, and the f2 value was more than 50. Notably, accurate and autonomous design of the drug release curve was achieved mainly by changing the geometry of the capsule. This approach is expected to be applied to different drug needs and facilitate the development of customized oral dosage forms.

Asunto(s)

Inteligencia Artificial , Cápsulas , Preparaciones de Acción Retardada , Liberación de Fármacos , Medicina de Precisión , Impresión Tridimensional , Medicina de Precisión/métodos , Preparaciones de Acción Retardada/química , Acetaminofén/química , Acetaminofén/administración & dosificación , Isoniazida/química , Isoniazida/administración & dosificación , Tecnología Farmacéutica/métodos , Composición de Medicamentos/métodos , Algoritmos

RESUMEN

In this paper, we presented a mathematical model for tuberculosis with treatment for latent tuberculosis cases and incorporated social implementations based on the impact they will have on tuberculosis incidence, cure, and recovery. We incorporated two variables containing the accumulated deaths and active cases into the model in order to study the incidence and mortality rate per year with the data reported by the model. Our objective is to study the impact of social program implementations and therapies on latent tuberculosis in particular the use of once-weekly isoniazid-rifapentine for 12 weeks (3HP). The computational experimentation was performed with data from Brazil and for model calibration, we used the Markov Chain Monte Carlo method (MCMC) with a Bayesian approach. We studied the effect of increasing the coverage of social programs, the Bolsa Familia Programme (BFP) and the Family Health Strategy (FHS) and the implementation of the 3HP as a substitution therapy for two rates of diagnosis and treatment of latent at 1% and 5%. Based of the data obtained by the model in the period 2023-2035, the FHS reported better results than BFP in the case of social implementations and 3HP with a higher rate of diagnosis and treatment of latent in the reduction of incidence and mortality rate and in cases and deaths avoided. With the objective of linking the social and biomedical implementations, we constructed two different scenarios with the rate of diagnosis and treatment. We verified with results reported by the model that with the social implementations studied and the 3HP with the highest rate of diagnosis and treatment of latent, the best results were obtained in comparison with the other independent and joint implementations. A reduction of the incidence by 36.54% with respect to the model with the current strategies and coverage was achieved, and a greater number of cases and deaths from tuberculosis was avoided.

Asunto(s)

Antituberculosos , Teorema de Bayes , Isoniazida , Tuberculosis Latente , Cadenas de Markov , Conceptos Matemáticos , Método de Montecarlo , Rifampin , Humanos , Brasil/epidemiología , Incidencia , Isoniazida/administración & dosificación , Antituberculosos/administración & dosificación , Rifampin/administración & dosificación , Rifampin/análogos & derivados , Rifampin/uso terapéutico , Tuberculosis Latente/epidemiología , Tuberculosis Latente/tratamiento farmacológico , Tuberculosis Latente/mortalidad , Modelos Biológicos , Tuberculosis/mortalidad , Tuberculosis/epidemiología , Tuberculosis/tratamiento farmacológico , Simulación por Computador

RESUMEN

INTRODUCTION: Melasma is a chronic hyperpigmentation disorder, and its treatment poses a challenge to dermatologists due to its chronicity and resistance to conventional therapies. Oral isoniazid is used for the treatment of tuberculosis. One of us had previously showed that topical isoniazid exerts a strong depigmenting action in animal models. In this clinical trial, we assessed the therapeutic effect of topical isoniazid on melasma. METHODS: Twenty female patients suffering from epidermal melasma were enrolled and divided equally into two groups. The treatment group received topical isoniazid 10%, and the control group received the cold cream vehicle as the placebo. All participants were advised to avoid sunlight and used SPF 50 sunscreen. Patients applied topical agents once daily at night for 3 months. The melanin and erythema indices were measured by colorimetric evaluations at baseline and after 4, 8, and 12 weeks of treatment. At these time points, the (mMASI) score was also determined, as was the subjective evaluation through Melasma Quality of Life Scale (MELASQOL) scores. Blood tests were performed to evaluate CBC and the liver enzymes. RESULTS: All patients completed the 12-week study. In the treatment group, a significant decrease in melanin index from 63.77 ± 6.27 at baseline to 55.92 ± 5.79 was recorded (p = 0.001). Very minimal clinical changes were also seen in the control group and melanin index was decreased from 62.65 ± 2.23 to 61.25 ± 2.34 (p = 0.004). Clinically significant differences were observed in the rate of changes between both groups. These findings indicate that topical isoniazid has significant depigmenting effects compared to the placebo (p = 0.001). The erythema index remained unchanged in both groups. In the treatment group, the mMASI score was 5.63 ± 3.28 at baseline and 2.13 ± 1.71 at the last follow-up, significantly reduced compared to the control group (p = 0.002). The MELASQOL score indicated a significant improvement in the quality of life in the treatment group. CONCLUSION: This clinical trial shows for the first time that topical isoniazid is effective in treating melasma. Further clinical trials are necessary to confirm the efficacy and tolerability of topical isoniazid in comparison with other skin-depigmenting compounds.

Asunto(s)

Isoniazida , Melanosis , Calidad de Vida , Humanos , Femenino , Adulto , Método Doble Ciego , Melanosis/tratamiento farmacológico , Isoniazida/administración & dosificación , Isoniazida/efectos adversos , Resultado del Tratamiento , Administración Cutánea , Persona de Mediana Edad , Melaninas/análisis , Melaninas/metabolismo , Adulto Joven , Eritema/tratamiento farmacológico , Eritema/etiología , Índice de Severidad de la Enfermedad