Bedaquiline versus injectable containing regimens for rifampicin-resistant and multidrug-resistant tuberculosis in a reference center in Brazil - a real-world evidence study using a retrospective design.

BACKGROUND: Drug resistance (DR) is one of the several challenges to global tuberculosis (TB) control. The implementation of bedaquiline (BED) for DR-TB after more than 40 years was expected to improve treatment outcomes as well as microbiologic conversion and adverse events (AE) occurrence. METHODS: Retrospective cohort study based on secondary data of patients with rifampicin-resistant (RR) or multidrug-resistant (MDR) TB reported to the Outpatient Clinic of Mycobacterial Diseases of the Thorax Diseases Institute - Federal University of Rio de Janeiro - Brazil, between 2016 and 2023. We aimed to evaluate microbiologic conversion, AE and TB treatment outcomes and compare them according to the treatment regimen used for RR/MDR-TB patients under routine conditions [Injectable Containing Regimens (ICR) versus BED Containing Regimens (BCR)]. Logistic regression and survival analysis using Cox regression and Kaplan Meier curve were used for statistical analysis. RESULTS: Of the 463 DR-TB patients notified during the study period, 297 (64.1%) were included for analysis (ICR = 197 and BCR = 100). Overall AEs were more frequent (83.7 vs. 16.3%, p < 0.001) and occurred earlier in the ICR group (15 days vs. 65 days, p = 0.003). There were no cases of cardiotoxicity requiring interruption of BED treatment. None of the regimens of treatment tested were associated with smear or culture conversion on Cox regression analysis (p = 0.60 and 0.88, respectively). BED-containing regimens were also associated with favorable outcomes in multivariable logistic regression [adjusted odds ratio (aOR) = 2.63, 95% confidence interval (CI)1.36-5.07, p = 0.004], as higher years of schooling, primary drug resistance, and no previous TB treatment. In the survival analysis, BCR was inversely associated with the occurrence of AE during treatment follow-up (aHR 0.24, 95% CI 0.14-0.41, p < 0.001). In addition, TB treatment regimens with BED were also associated with favorable outcomes (aHR 2.41, 95% CI 1.62-3.57, p < 0.001), along with no illicit drug use and primary drug resistance. CONCLUSIONS: The implementation of a fully oral treatment for RR/MDR-TB in a reference center in Brazil was safe and associated with favorable outcomes under routine conditions, despite social, demographic, and behavioral factors that may influence TB treatment completion.

DRESS syndrome and tuberculosis: Implementation of a desensitization and re-desensitization protocol to recover antituberculosis drugs in a case series at a specialized TB Unit in Lima, Peru.

RATIONALE: Antituberculosis drugs (ATDs) could cause severe and rare reactions, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Recovering ATDs might guarantee a higher cure rate for tuberculosis patients. Our aim was to evaluate the results of desensitization and re-desensitization to recover ATDs in a case series of patients with DRESS syndrome. PATIENT CONCERNS AND DIAGNOSES: A retrospective case series study was conducted on patients with DRESS syndrome due to therapy with ATDs from 2021 to 2023. Desensitization and re-desensitization protocols, designed with an algorithm proposed by the Tuberculosis Specialized Unit of the Dos de Mayo National Hospital in Lima, Peru, were implemented. INTERVENTIONS AND OUTCOMES: A total of 18 patients underwent desensitization or re-desensitization protocols, achieving an overall success rate of 72.2%. The average time for the development of DRESS syndrome due to ATDs was 19 days. Rifampicin (84.2%), isoniazid (68.4%), and pyrazinamide (26.3%) were identified as the main drugs responsible for this adverse reaction. All patients presented with fever and skin rash, with an average eosinophil percentage of 16.7% (interquartile range: 4.5-28.8). Organ involvement (liver, kidney, and heart) was observed in 8 patients, but only 2 patients experienced severe complications due to DRESS syndrome. A significant association was found between the number of ATDs used and eosinophil levels (P =.03). LESSONS: The study introduced a desensitization and re-desensitization algorithm for the treatment of DRESS syndrome, notable for its safety, adaptability, and high success rate. This advancement provided healthcare professionals with safer and more effective therapeutic approaches for managing this complex condition.

Differential distribution of NAT2 polymorphisms and NAT2 acetylator phenotypes among indigenous populations of the Brazilian Amazon.

OBJECTIVES: We report, for the first time, the distribution of four no-function NAT2 single nucleotide polymorphisms and inferred NAT2 acetylator phenotypes in three indigenous groups (Munduruku, Paiter-Suruí, and Yanomami), living in reservation areas in the Brazilian Amazon. METHODS: Two hundred and seventy-six participants from three indigenous groups (92 for each group) were included and genotyped for four NAT2 polymorphisms (rs1801279, rs1801280, rs1799930, and rs1799931) by the TaqMan system. Minor Allele Frequency (MAF) was determined and NAT2 acetylator phenotypes were inferred. RESULTS: NAT2 rs1801279G>A was absent in all cohorts; rs1799930G>A was absent in Yanomami and rare (MAF 0.016) in Munduruku and Paiter-Suruí; MAF of rs1801280T>C ranged five-fold (0.092-0.433), and MAF of rs1799931G>A varied between 0.179 and 0.283, among the three groups. The distribution of NAT2 phenotypes differed significantly across cohorts; the prevalence of the slow acetylator phenotype ranged from 16.3% in Yanomami to 33.3% in Munduruku to 48.9% in Paiter-Suruí. This three-fold range of variation is of major clinical relevance because the NAT2 slow phenotype is associated with higher risk of hepatotoxicity with antituberculosis chemotherapy and high incidence rates of tuberculosis and burden of latent infection among Munduruku, Paiter-Surui, and Yanomami peoples. According to the frequency of the NAT2 slow acetylator phenotype, the estimated number of individuals needed to be genotyped to prevent one additional event of hepatotoxicity range from 31 (Munduruku) to 39 (Paiter-Surui) and to 67 (Yanomami). CONCLUSION: The rs1801279 polymorphism was not found in any of the cohorts, while the MAF of the other polymorphisms showed significant variation between the cohorts. The difference in the prevalence of the NAT2 slow acetylator phenotype, which is linked to isoniazid-induced hepatotoxicity, was observed in the different study cohorts.

Pharmacogenetic variability of tuberculosis biomarkers in native and mestizo Peruvian populations.

In Peru, 29 292 people were diagnosed with tuberculosis in 2022. Although tuberculosis treatments are effective, 3.4%-13% are associated with significant adverse drug reactions, with drug-induced liver injury (DILI) considered the most predominant. Among the first-line antituberculosis drugs, isoniazid is the main drug responsible for the appearance of DILI. In liver, isoniazid (INH) is metabolized by N-acetyltransferase-2 (NAT2) and cytochrome P450 2E1 (CYP2E1). Limited information exists on genetic risk factors associated with the presence of DILI to antituberculosis drugs in Latin America, and even less is known about these factors in the native and mestizo Peruvian population. The aim of this study was to determine the prevalence of NAT2 and CYP2E1 genotypes in native and mestizo population. An analytical cross-sectional analysis was performed using genetic data from mestizo population in Lima and native participants from south of Peru. NAT2 metabolizer was determined as fast, intermediate and slow, and CYP2E1 genotypes were classified as c1/c1, c1/c2 and c2/c2, from molecular tests and bioinformatic analyses. Of the 472 participants, 36 and 6 NAT2 haplotypes were identified in the mestizo and native population, respectively. In mestizo population, the most frequent NAT2*5B and NAT2*7B haplotypes were associated with DILI risk; while in natives, NAT2*5G and NAT2*13A haplotypes were associated with decreased risk of DILI. For CYP2E1, c1/c1 and c1/c2 genotypes are the most frequent in natives and mestizos, respectively. The linkage disequilibrium of NAT2 single nucleotide polymorphisms (SNPs) was estimated, detecting a block between all SNPs natives. In addition, a block between rs1801280 and rs1799929 for NAT2 was detected in mestizos. Despite the limitations of a secondary study, it was possible to report associations between NAT2 and CYP2E alleles with Peruvian native and mestizo by prevalence ratios. The results of this study will help the development of new therapeutic strategies for a Tuberculosis efficient control between populations.

Isoniazid use, effectiveness, and safety for treatment of latent tuberculosis infection: a systematic review.

BACKGROUND: The treatment strategy for latent tuberculosis infection is to reduce the number of tuberculosis cases and consequently reduce the transmission of pathogenic bacteria. This study aimed to determine the safety, effectiveness, and adherence of isoniazid use for latent tuberculosis infection treatment. METHODS: To identify studies on isoniazid use for latent tuberculosis infection, five electronic databases were searched. The methods and results are presented in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Most studies (53) used isoniazid for 9 months. The prevalence of use and adherence to treatment varied considerably (18% to 100%), and were evaluated by participant completion of isoniazid treatment for latent tuberculosis infection. The adverse events most frequently reported were hepatotoxicity, gastric intolerance, and neuropathy; the rates of occurrence ranged from < 1% to 48%. In the studies that evaluated the effectiveness of isoniazid for latent tuberculosis infection, the rate varied from 0 to 19.7% for patients who did not have active tuberculosis after the follow-up period. CONCLUSIONS: The importance of maintaining follow up for patients using isoniazid should be emphasized due to the risk of developing adverse events. Despite the treatment challenges, the rates of patients who used isoniazid and developed active tuberculosis during the follow-up period were low. We believe that isoniazid continues to contribute to tuberculosis control worldwide, and better care strategies are required.

Role of the IL8 rs4073 polymorphism in central nervous system toxicity in patients receiving multidrug-resistant tuberculosis treatment.

OBJECTIVE: To determine the role of the IL8 rs4073 polymorphism in predicting the risk of central nervous system (CNS) toxicity in patients receiving standard pharmacological treatment for multidrug-resistant tuberculosis (MDR-TB). METHODS: A cohort of 85 consenting MDR-TB patients receiving treatment with second-line antituberculosis drugs had their blood samples amplified for the IL8 (rs4073) gene and genotyped. All patients were clinically screened for evidence of treatment toxicity and categorized accordingly. Crude and adjusted associations were assessed. RESULTS: The chief complaints fell into the following categories: CNS toxicity; gastrointestinal toxicity; skin toxicity; and eye and ear toxicities. Symptoms of gastrointestinal toxicity were reported by 59% of the patients, and symptoms of CNS toxicity were reported by 42.7%. With regard to the genotypes of IL8 (rs4073), the following were identified: AA, in 64 of the study participants; AT, in 7; and TT, in 11. A significant association was found between the dominant model of inheritance and CNS toxicity for the crude model (p = 0.024; OR = 3.57; 95% CI, 1.18-10.76) and the adjusted model (p = 0.031; OR = 3.92; 95% CI, 1.13-13.58). The AT+TT genotype of IL8 (rs4073) showed a 3.92 times increased risk of CNS toxicity when compared with the AA genotype. CONCLUSIONS: The AT+TT genotype has a tendency to be associated with an increased risk of adverse clinical features during MDR-TB treatment.

Prediction Models for Adverse Drug Reactions During Tuberculosis Treatment in Brazil.

BACKGROUND: Tuberculosis (TB) treatment-related adverse drug reactions (TB-ADRs) can negatively affect adherence and treatment success rates. METHODS: We developed prediction models for TB-ADRs, considering participants with drug-susceptible pulmonary TB who initiated standard TB therapy. TB-ADRs were determined by the physician attending the participant, assessing causality to TB drugs, the affected organ system, and grade. Potential baseline predictors of TB-ADR included concomitant medication (CM) use, human immunodeficiency virus (HIV) status, glycated hemoglobin (HbA1c), age, body mass index (BMI), sex, substance use, and TB drug metabolism variables (NAT2 acetylator profiles). The models were developed through bootstrapped backward selection. Cox regression was used to evaluate TB-ADR risk. RESULTS: There were 156 TB-ADRs among 102 of the 945 (11%) participants included. Most TB-ADRs were hepatic (n = 82 [53%]), of moderate severity (grade 2; n = 121 [78%]), and occurred in NAT2 slow acetylators (n = 62 [61%]). The main prediction model included CM use, HbA1c, alcohol use, HIV seropositivity, BMI, and age, with robust performance (c-statistic = 0.79 [95% confidence interval {CI}, .74-.83) and fit (optimism-corrected slope and intercept of -0.09 and 0.94, respectively). An alternative model replacing BMI with NAT2 had similar performance. HIV seropositivity (hazard ratio [HR], 2.68 [95% CI, 1.75-4.09]) and CM use (HR, 5.26 [95% CI, 2.63-10.52]) increased TB-ADR risk. CONCLUSIONS: The models, with clinical variables and with NAT2, were highly predictive of TB-ADRs.

Severe esophagitis induced by antituberculosis drugs: a case report.

Tuberculosis stands as one of humanity's oldest afflictions, intrinsically intertwined with social disparities. This formidable disease spares no age group and remains the prevailing cause of infection-induced mortality worldwide, particularly in developing nations. We present a case of a 56-year-old woman with diabetes who was diagnosed with Pulmonary Tuberculosis. After receiving antituberculosis drugs as part of her treatment, she experienced a range of systemic manifestations and suffered from severe ulcerative esophagitis. This adverse reaction led to uncontrollable gastrointestinal intolerance, tragically resulting in her untimely demise. The incident underscores the potential seriousness of adverse reactions that can arise from tuberculosis treatment medications.

[DRESS syndrome induced by anti-TB drugs]. / Síndrome de DRESS inducido por fármacos antituberculosos.

OBJETIVE: To describe the phenotype of DRESS syndrome induced by antituberculosis drugs. METHODS: Descriptive study, withdrawn from the review of the records of patients with DRESS syndrome, identified in the interconsultation of the Department of Research in Immunogenetics and Allergy, of the Insti-tuto Nacional de Enfermedades Respiratorias (INER) Ismael Cosío Villegas, among 2014 and 2020. Frequency analysis was performed. The associations between biomarkers and latency are calculated with the χ2 test and log-rank, and the evaluation of the change in the biomarkers with the Wilcoxon test. The value of p < 0.05 is considered statistically significant. For data analysis, the SPSS v.21 program was obtained. RESULTS: 15 patients were identified; represented by 0.02% of total cases treated in the Department for so-meimmuno-allergic condition (15/7052); the main symptomatology were: rash (100%), eosinophilia (93%), fe-ver (80%), adenomegaly (60%), kidney damage (40%), liver damage (33%), and latency of 21 days. Liver damage was associated with prolonged latency (p = 0.02). After treatment, the total levels of eosinophils (p < 0.001) and liver and kidney biomarkers (p < 0.04) decreased. DRESS syndrome induced by antituberculosis drugs is not associated with the number of drugs prescribed or with the pattern of resistance of Mycobacterium tuberculosis. CONCLUSIONS: DRESS syndrome induced by antituberculosis drugs is an atypical clinical reaction, similar to other types of DRESS syndrome that respond favorably to systemic corticosteroids.

OBJETIVO: Describir el fenotipo del síndrome de DRESS inducido por fármacos antituberculosos. MÉTODOS: Estudio descriptivo efectuado a partir de la revisión de los expedientes de pacientes con síndrome de DRESS, identificados en la interconsulta del Departamento de Investigación en Inmunogénetica y Alergia, del Instituto Nacional de Enfermedades Respiratorias (INER) Ismael Cosío Villegas, entre 2014 y 2020. Se realizó análisis de frecuencias. Las asociaciones entre biomarcadores y latencia se calcularon con la prueba de χ2 y log-rank, y la evaluación del cambio en los biomarcadores con la prueba de Wilcoxon. Se consideró esta-dísticamente significativo el valor de p < 0.05. Para el análisis de los datos se utilizó el programa SPSS v.21. RESULTADOS: Se identificaron 15 pacientes, que representaron el 0.2% de los casos atendidos en el Departa-mento por algún padecimiento inmuno-alérgico (15/7052); las principales manifestaciones fueron: exantema (100%), eosinofilia (93%), fiebre (80%), adenomegalia (60%), daño renal (40%), daño hepático (33%) y latencia de 21 días. El daño hepático se asoció con latencia prolongada (p = 0.02). Posterior al tratamiento disminu-yeron las concentraciones totales de eosinófilos (p < 0.001) y biomarcadores hepáticos y renales (p < 0.04). El síndrome de DRESS inducido por fármacos antituberculosos no se asoció con la cantidad de fármacos prescritos ni con el patrón de resistencia de Mycobacterium tuberculosis. CONCLUSIONES: El síndrome de DRESS inducido por fármacos antituberculosos es una reacción clínica atípica, similar a otros tipos de síndrome de DRESS que responden favorablemente a corticosteroides sisté-micos.

Gastroparesis associated to isoniazid. First description.

Isoniazid, a central compound in the treatment of active or latent tuberculosis, is associated with various adverse reactions, including hepatitis and polyneuropathy. The latter is due to functional pyridoxine depletion and can be avoided by appropriate doses and supplementation with pyridoxine. We present the case of a patient with several previous treatment abandonments for active pulmonary tuberculosis who evolved with late postprandial vomiting due to gastroparesis documented by nuclear medicine gastric emptying tests after a new treatment onset. Gastroparesis improved with discontinuation of isoniazid and levosulpiride, reappeared with re-exposure, and improved with definitive withdrawal of isoniazid. Morbidity associated with vomiting led to prolonged hospitalization and treatment failure without the emergence of antituberculosis drug resistance. The association of gastroparesis with isoniazid was considered definitive when applying at least two causality protocols. Gastroparesis associated with isoniazid should be added to the list of adverse effects associated with this drug, even in patients receiving pyridoxine supplementation. Its recognition is initially clinical, can be confirmed with nuclear medicine studies, and affects the eradication of Mycobacterium tuberculosis.

Adverse reactions to antituberculosis drugs presenting as DRESS syndrome and acute liver failure.

Drug induced liver injury (DILI) can be can be triggered by many medications including antituberculosis drugs. We present the case of a 37-year-old woman with a smear- positive pulmonary tuberculosis who started treatment with first-line antituberculosis drugs and 4 weeks later presented jaundice, somnolence and a morbilliform generalized rash with progressive neurologic deterioration which had a fatal outcome. Antituberculosis drugs can cause DILI in 2 to 28% of patients and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) in 1.2%. Acute liver failure (ALF) can occur in 35% of patients with DILI with an overall mortality of 9.7%. If the ALF is unresponsive to medical treatment, liver transplantation has shown promising results and can avoid progression of complications. DILI can be a serious medical condition in patients receiving antituberculosis drugs. If ALF develops and is unresponsive to medical treatment, liver transplantation should be considered as the treatment of choice.

GSTT1/GSTM1 Genotype and Anti-Tuberculosis Drug-Induced Hepatotoxicity in Peruvian Patients.

In Peru, 24,581 people were diagnosed with tuberculosis (TB) in 2020. Although TB treatments are effective, 3.4-13% are associated with significant adverse drug reactions (ADRs), with drug-induced liver injury (DILI) considered the most predominant. Among the first-line antituberculosis drugs, isoniazid (INH) is the main drug responsible for the appearance of DILI. In the liver, INH is metabolized by the enzymes N-acetyltransferase-2 (NAT2), cytochrome P450 2E1 (CYP2E1), and glutathione S-transferase (GST) with two isoforms, GSTT1 and GSTM1. Based on previous studies, we hypothesized that interactions between the GSTT1 and GSTM1 null genotypes induce DILI in TB patients. In this cross-sectional study of 377 participants who completed their anti-TB treatment, we genotyped by revealing the presence or absence of 215- and 480-bp bands of GSTM1 and GSTT1, respectively. We found that the prevalence of the GSTM1 genotype was 52.79% and 47.21% for presence and null, respectively, and for GSTT1 it was 69.76% and 30.24% for presence and null, respectively. Neither genotype was prevalent in the patients who developed DILI (n = 16). We did not confirm our hypothesis; however, we found that the combination of GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype had a significant risk for the development of ADR (OR 11; p = 0.017; 95% CI: (0.54-186.35)). We propose that the presence of the GSTM1 present genotype, GSTT1 null genotype, fast NAT2 acetylators, and CYP2E1 c1/c1 genotype in the Peruvian population could be considered a risk factor for the development of ADR due to therapeutic drug intake.

Testing and Treating Mycobacterium tuberculosis Infection.

After infection with Mycobacterium tuberculosis, a minority of individuals will progress to tuberculosis disease (TB). The risk is higher among persons with well-established risk factors and within the first year after infection. Testing and treating individuals at high risk of progression maximizes the benefits of TB preventive therapy; avoiding testing of low-risk persons will limit potential harms. Several treatment options are available; rifamycin-based regimens offer the best efficacy-safety balance. In this review, we present an overview of the diagnosis and treatment of TB infection, and summarize common clinical scenarios.

Use of bedaquiline in spinal osteomyelitis and soft tissue abscess caused by multidrug-resistant Mycobacterium tuberculosis: A case report.

INTRODUCTION: Spinal Tuberculosis (STB) represents between 1% and 2% of total tuberculosis cases. STB management remains challenging; the first-line approach consists of medical treatment, while surgery is reserved for patients with complications. No data regarding STB treatment with bedaquiline-containing regimens are available in the literature. CASE DESCRIPTION: Herein, we report the case of a 21-year-old man from Côte d'Ivoire with a multidrug resistance STB with subcutaneous abscess. After approval of the hospital off-label drug committee, we started bedaquiline 400 mg daily for two weeks, followed by 200 mg three times per week, for 22 weeks, associated with linezolid 600 mg daily, rifabutin 450 mg daily, and amikacin 750 mg daily (interrupted after eight weeks). During treatment, we performed a weekly EKG. No QT prolongation was shown, but inverted T waves appeared, requiring several cardiological consultations and cardiac MRI, but no cardiac dysfunction was found. After 24 weeks, bedaquiline was replaced with moxifloxacin 400 mg daily. The patient continued treatment for another year. We performed another computer tomography at the end of treatment, confirming the cure. DISCUSSION: A salvage regimen containing bedaquiline proved effective in treating multidrug-resistance tuberculosis spinal infection without causing severe adverse effects. However, further studies are needed to evaluate better bedaquiline bone penetration and the correct duration of treatment with bedaquiline in MDR spinal tuberculosis.

NAT2 and CYP2E1 polymorphisms and antituberculosis drug-induced hepatotoxicity in Peruvian patients.

BACKGROUND: In Peru, 32,970 people were diagnosed with tuberculosis (TB) in 2019. Although TB treatment is effective, 3.4%-13% is associated with significant adverse drug reactions (ADR), considering drug-induced liver injury (DILI) as the most prevalent. Among the first-line anti-TB drugs, isoniazid (INH) is primarily responsible for the occurrence of DILI. INH is metabolized in the liver by the enzymes N-acetyltransferase-2 (NAT2) and Cytochrome P450 2E1 (CYP2E1). Based on the previous studies, we hypothesized that the interactions between slow CYP2E1 genotype and NAT2 slow acetylators will induce DILI in TB patients. METHODS: In this cross-sectional study, all 377 participants completed their anti-TB treatment, and we genotyped SNPs: rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 for NAT2 and rs3813867 and rs2031920 for CYP2E1. RESULTS: We found that rapid, intermediate, and slow NAT2 acetylator were 15%, 38%, and 47%, respectively, in the general population. Intermediate NAT2 acetylator is the least prevalent among patients with adverse reactions (p = 0.024). We did not confirm our hypothesis, however, we found that the combination of intermediate NAT2 acetylators and CYP2E1 c1/c1 genotype significantly protected (OR = 0.16; p = 0.049) against the development of DILI in our population. CONCLUSION: We propose that the presence of NAT2 intermediate and CYP2E1 c1/c1 genotype could help in therapeutic drug monitoring, and optimize its therapeutic benefits while minimizing its risk for side effects or toxicity.

Homozygotes NAT2*5B slow acetylators are highly associated with hepatotoxicity induced by anti-tuberculosis drugs.

BACKGROUND: Distinct N-acetyltransferase 2 (NAT2) slow acetylators genotypes have been associated with a higher risk to develop anti-tuberculosis drug-induced hepatotoxicity (DIH). However, studies have not pointed the relevance of different acetylation phenotypes presented by homozygotes and compound heterozygotes slow acetylators on a clinical basis. OBJECTIVES: This study aimed to investigate the association between NAT2 genotypes and the risk of developing DIH in Brazilian patients undergoing tuberculosis treatment, focusing on the discrimination of homozygotes and compound heterozygotes slow acetylators. METHODS/FINDINGS: The frequency of NAT2 genotypes was analysed by DNA sequencing in 162 patients undergoing tuberculosis therapy. The mutation analyses revealed 15 variants, plus two new NAT2 mutations, that computational simulations predicted to cause structural perturbations in the protein. The multivariate statistical analysis revealed that carriers of NAT2*5/*5 slow acetylator genotype presented a higher risk of developing anti-tuberculosis DIH, on a clinical basis, when compared to the compound heterozygotes presenting NAT2*5 and any other slow acetylator haplotype [aOR 4.97, 95% confidence interval (CI) 1.47-16.82, p = 0.01]. CONCLUSION: These findings suggest that patients with TB diagnosis who present the NAT2*5B/*5B genotype should be properly identified and more carefully monitored until treatment outcome in order to prevent the occurrence of anti-tuberculosis DIH.

Efficacy and safety of daily treatments for drug-susceptible pulmonary tuberculosis: a systematic review and network meta-analysis.

OBJECTIVES: To evaluate and update the evidence on the comparative efficacy and safety of antimicrobial drugs regimens for treating pulmonary drug-susceptible tuberculosis (DS-TB). METHODS: A systematic review was performed with searches in PubMed and Scopus (PROSPERO-CRD42019141463). We included randomised controlled trials comparing the effect of any antimicrobial regimen lasting at least 2 weeks. The outcomes of interest were culture conversion and incidence of adverse events. Bayesian network meta-analyses and surface under the cumulative ranking curve (SUCRA) analyses were performed. Results were reported as odds ratio with 95% credibility intervals. KEY FINDINGS: Fifteen studies were included the meta-analysis (n = 7560 patients). No regimen was statistically more effective than the WHO standard approach (rifampicin, isoniazid, ethambutol, and pyrazinamide). The use of rifapentine 450 mg instead of rifampicin in the standard regimen demonstrated to be statistically safer than all other options for serious adverse events (e.g. hepatotoxicity, arthralgia) (OR ranging from 0.0 [Crl 0.00-0.04] to 0.0 [0.00-0.97]; SUCRA probabilities of 10%). Therapies containing rifapentine (Rp1500HEZ, Rp900HEZ) and moxifloxacin (RMEZ, RHMZ) are effective regarding culture conversion, but statistical uncertainty on their safety profile exists. CONCLUSION: The WHO standard regimen remains an overall effective and safe alternative for DS-TB. For intensive phase treatments, drugs combinations with rifapentine and moxifloxacin seem to reduce treatment duration while maintaining efficacy.

Pre-Treatment Neutrophil Count as a Predictor of Antituberculosis Therapy Outcomes: A Multicenter Prospective Cohort Study.

Background: Neutrophils have been associated with lung tissue damage in many diseases, including tuberculosis (TB). Whether neutrophil count can serve as a predictor of adverse treatment outcomes is unknown. Methods: We prospectively assessed 936 patients (172 HIV-seropositive) with culture-confirmed pulmonary TB, enrolled in a multicenter prospective cohort study from different regions in Brazil, from June 2015 to June 2019, and were followed up to two years. TB patients had a baseline visit before treatment (month 0) and visits at month 2 and 6 (or at the end of TB treatment). Smear microscopy, and culture for Mycobacterium tuberculosis (MTB) were performed at TB diagnosis and during follow-up. Complete blood counts were measured at baseline. Treatment outcome was defined as either unfavorable (death, treatment failure or TB recurrence) or favorable (cure or treatment completion). We performed multivariable logistic regression, with propensity score regression adjustment, to estimate the association between neutrophil count with MTB culture result at month 2 and unfavorable treatment outcome. We used a propensity score adjustment instead of a fully adjusted regression model due to the relatively low number of outcomes. Results: Among 682 patients who had MTB culture results at month 2, 40 (5.9%) had a positive result. After regression with propensity score adjustment, no significant association between baseline neutrophil count (103/mm3) and positive MTB culture at month 2 was found among either HIV-seronegative (OR = 1.06, 95% CI = [0.95;1.19] or HIV-seropositive patients (OR = 0.77, 95% CI = [0.51; 1.20]). Of 691 TB patients followed up for at least 18 months and up to 24 months, 635 (91.9%) were either cured or completed treatment, and 56 (8.1%) had an unfavorable treatment outcome. A multivariable regression with propensity score adjustment found an association between higher neutrophil count (103/mm3) at baseline and unfavorable outcome among HIV-seronegative patients [OR= 1.17 (95% CI= [1.06;1.30]). In addition, adjusted Cox regression found that higher baseline neutrophil count (103/mm3) was associated with unfavorable treatment outcomes overall and among HIV-seronegative patients (HR= 1.16 (95% CI = [1.05;1.27]). Conclusion: Increased neutrophil count prior to anti-TB treatment initiation was associated with unfavorable treatment outcomes, particularly among HIV-seronegative patients. Further prospective studies evaluating neutrophil count in response to drug treatment and association with TB treatment outcomes are warranted.

Prevalence of latent tuberculosis in patients with hematological neoplasms in a cancer referral hospital in Mexico City.

OBJECTIVE: To determine the prevalence of Latent Tuberculosis in patients with hematological neoplasms at the Instituto Nacional de Cancerología in Mexico City using the Tuberculin skin test (TST). METHODS: This retrospective study included all patients with a recent diagnosis of hematological neoplasms who were admitted for treatment from 2017 to 2018 and who were screened for latent tuberculosis with the TST. The prevalence of latent tuberculosis in this group, tolerance and therapeutic adherence in treated patients are described. RESULTS: The files of 446 patients with hematological malignancy who had a TST were reviewed. The prevalence of latent tuberculosis was 31.2% (n = 139). Ninety-three patients received isoniazid, 15.1% had some adverse reactions, but only 4 (4.3%) had to discontinue treatment. Two patients with latent tuberculosis under treatment with Isoniazid reactivated tuberculosis infection. CONCLUSIONS: The prevalence in our study was within the range of other similar Mexican populations. Isoniazid treatment had an adequate tolerance and adherence. Longer follow-up could offer more information on the risk of reactivation in both groups.