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1.
N Engl J Med ; 381(14): 1333-1346, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31577875

RESUMO

BACKGROUND: The safety, efficacy, and appropriate timing of isoniazid therapy to prevent tuberculosis in pregnant women with human immunodeficiency virus (HIV) infection who are receiving antiretroviral therapy are unknown. METHODS: In this multicenter, double-blind, placebo-controlled, noninferiority trial, we randomly assigned pregnant women with HIV infection to receive isoniazid preventive therapy for 28 weeks, initiated either during pregnancy (immediate group) or at week 12 after delivery (deferred group). Mothers and infants were followed through week 48 after delivery. The primary outcome was a composite of treatment-related maternal adverse events of grade 3 or higher or permanent discontinuation of the trial regimen because of toxic effects. The noninferiority margin was an upper boundary of the 95% confidence interval for the between-group difference in the rate of the primary outcome of less than 5 events per 100 person-years. RESULTS: A total of 956 women were enrolled. A primary outcome event occurred in 72 of 477 women (15.1%) in the immediate group and in 73 of 479 (15.2%) in the deferred group (incidence rate, 15.03 and 14.93 events per 100 person-years, respectively; rate difference, 0.10; 95% confidence interval [CI], -4.77 to 4.98, which met the criterion for noninferiority). Two women in the immediate group and 4 women in the deferred group died (incidence rate, 0.40 and 0.78 per 100 person-years, respectively; rate difference, -0.39; 95% CI, -1.33 to 0.56); all deaths occurred during the postpartum period, and 4 were from liver failure (2 of the women who died from liver failure had received isoniazid [1 in each group]). Tuberculosis developed in 6 women (3 in each group); the incidence rate was 0.60 per 100 person-years in the immediate group and 0.59 per 100 person-years in the deferred group (rate difference, 0.01; 95% CI, -0.94 to 0.96). There was a higher incidence in the immediate group than in the deferred group of an event included in the composite adverse pregnancy outcome (stillbirth or spontaneous abortion, low birth weight in an infant, preterm delivery, or congenital anomalies in an infant) (23.6% vs. 17.0%; difference, 6.7 percentage points; 95% CI, 0.8 to 11.9). CONCLUSIONS: The risks associated with initiation of isoniazid preventive therapy during pregnancy appeared to be greater than those associated with initiation of therapy during the postpartum period. (Funded by the National Institutes of Health; IMPAACT P1078 TB APPRISE ClinicalTrials.gov number, NCT01494038.).


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Antituberculosos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Isoniazida/uso terapêutico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Resultado da Gravidez , Tuberculose/prevenção & controle , Adolescente , Adulto , Antituberculosos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Isoniazida/efeitos adversos , Testes de Função Hepática , Período Pós-Parto , Gravidez , Nascimento Prematuro/epidemiologia , Estudos Prospectivos , Adulto Jovem
3.
BMC Infect Dis ; 19(1): 715, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409277

RESUMO

BACKGROUND: Gynecomastia is known to occur in some men taking an efavirenz-based antiretroviral therapy (ART) regimen. However, the incidence and outcomes of gynecomastia are not known in Zimbabwe. We described the characteristics and outcomes of gynecomastia among male patients on an efavirenz-based ART regimen. METHODS: We conducted a retrospective cohort review of data of all male patients aged ≥18 years taking an efavirenz-based regimen at Newlands Clinic, Harare, Zimbabwe before 31 March 2017. The primary outcome was gynecomastia as defined by breast/nipple enlargement reported by patient and confirmed by clinical palpation. Routinely collected data on demographics, baseline CD4, body mass index, duration on efavirenz, clinical presentation and outcomes were extracted from the clinic database and analysed using STATA 12.1. We investigated for any associations with concomitant medicines using cox regression. RESULTS: We analysed data for 1432 men with a median age of 40 years (IQR: 33-48). Half of the patients were in WHO stage 1 at ART commencement. Median body mass index and CD4 count at efavirenz commencement was 21 (IQR: 19-23) and 260 cells/mm3 (IQR: 126-412) respectively. The incidence of gynecomastia was 22/1000 person-years (IQR: 17.3-27.8). Over half of the cases (58%) were bilateral and 75% of all cases developed within two years of starting efavirenz. There were no significant associations with concomitant use of isoniazid (HR: 0.95, p = 0.87) or amlodipine (HR: 0.43, p = 0.24). Gynecomastia resolved in 83.5% of cases following withdrawal of efavirenz with a median time to resolution of 3 months (IQR: 2-9). CONCLUSION: The incidence of gynecomastia among patients taking efavirenz-based ART was low with most cases developing early on during treatment. Most cases resolved completely after withdrawing efavirenz.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/efeitos adversos , Ginecomastia/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Adulto , Anlodipino/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Ginecomastia/epidemiologia , Humanos , Incidência , Isoniazida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/efeitos adversos , Zimbábue/epidemiologia
4.
World J Gastroenterol ; 25(26): 3291-3298, 2019 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-31341356

RESUMO

Solid organ transplantation (SOT) is the best treatment option for end-stage organ disease. Newer immunosuppressive agents have reduced the incidence of graft rejection but have increased the risk of infection, particularly due to the reactivation of latent infections due to opportunistic agents such as Mycobacterium tuberculosis. Active tuberculosis (TB) after SOT is a significant cause of morbidity and mortality. Most cases of posttransplant TB are secondary to reactivation of latent tuberculosis infection (LTBI) due to the effects of long-term immunosuppressive therapy. Risk minimization strategies have been developed to diagnose LTBI and initiate treatment prior to transplantation. Isoniazid with vitamin B6 supplementation is the treatment of choice. However, liver transplantation (LT) candidates and recipients have an increased risk of isoniazid-induced liver toxicity, leading to lower treatment completion rates than in other SOT populations. Fluoroquinolones (FQs) exhibit good in vitro antimycobacterial activity and a lower risk of drug-induced liver injury than isoniazid. In the present review, we highlight the disease burden posed by posttransplant TB and summarize the emerging clinical evidence supporting the use of FQs for the treatment of LTBI in LT recipients and candidates.


Assuntos
Antituberculosos/administração & dosagem , Fluoroquinolonas/administração & dosagem , Tuberculose Latente/tratamento farmacológico , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Aloenxertos , Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Terminal/cirurgia , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Incidência , Isoniazida/efeitos adversos , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Fígado , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/isolamento & purificação , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/microbiologia , Fatores de Risco , Resultado do Tratamento
5.
PLoS One ; 14(5): e0216234, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31112542

RESUMO

INTRODUCTION: In 2015, 4062 unaccompanied minor refugees were registered in Berlin, Germany. According to national policies, basic clinical examination and tuberculosis (TB) screening is a prerequisite to admission to permanent accommodation and schooling for every refugee. This article evaluates the use of an interferon-γ-release-assay (IGRA) during the initial examination and TB screening of 970 unaccompanied minor refugees. RESULTS: IGRA test were obtained during TB screening for 301 (31.0%) of 970 adolescents not previously screened for TB. Positive IGRA results were obtained in 13.9% (42/301). Most of the 42 IGRA-positive refugees originated from Afghanistan or Syria (n?20 and 10 respectively). Two IGRA-positive adolescents were lost to follow-up, 2 were diagnosed with TB and the remaining 38 diagnosed with latent TB infection (LTBI). Demographic features of the 40 patients with positive IGRA result were as follows: 39 male, median age 16.8 years (IQR 16.0-17.2y), none meeting underweight criteria (median BMI 21.3kg/m2). On initial chest X-ray 2/40 participants had signs of active TB, while in 38 active disease was excluded and the diagnosis of latent TB infection (LTBI) made. Active hepatitis B-co-infection was diagnosed in 3/38 patients. All patients with LTBI received Isoniazid and Rifampicin for 3 months without occurrence of severe adverse events. The most frequently observed side effect was transient upper abdominal pain (n = 5). Asymptomatic elevation of liver transaminases was seen in 2 patients. 29 patients completed treatment with no signs of TB disease at the end of chemoprevention and 9 were lost to follow up. CONCLUSION: Screening for TB infection in minor refugees was feasible in our setting with a relatively high rate of TB infection detected. Chemopreventive treatment was tolerated well regardless of underlying hepatitis-B-status. Minor refugees migrating to Germany should be screened for TB infection, instead of TB disease only, regardless of the background TB incidence.


Assuntos
Quimioprevenção/métodos , Refugiados , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Adolescente , Berlim , Feminino , Alemanha , Hepatite B/complicações , Humanos , Isoniazida/efeitos adversos , Isoniazida/uso terapêutico , Tuberculose Latente/diagnóstico , Masculino , Programas de Rastreamento/métodos , Menores de Idade , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Tuberculose/complicações
6.
Tuberculosis (Edinb) ; 116S: S66-S70, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31076322

RESUMO

Although isoniazid (INH) has been successful in treating Tuberculosis (TB) since its introduction in 1952, there has been continual reports of drug-associated hepatotoxicity in TB patients. These toxic side effects may reveal more about the recipient of the drug, than the drug itself. A combination of pharmacogenetic and pharmacokinetic studies have identified polymorphisms within enzymes involved in INH metabolism and detoxification. These essential metabolic enzymes include N-acetyltransferase 2, Cytochrome P450 2E1, and glutathione S transferases. Different phenotypes of these enzymes can affect the rate of INH metabolism, resulting in production of hepatotoxic metabolites. This review is intended to elucidate the pharmacokinetics of INH by examining its Administration, Distribution, Metabolism, and Elimination, while suggesting potential alternatives within INH personalized treatment to help reduce hepatotoxicity.


Assuntos
Antituberculosos/efeitos adversos , Antituberculosos/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Isoniazida/efeitos adversos , Isoniazida/farmacocinética , Tuberculose/tratamento farmacológico , Animais , Biotransformação , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/genética , Tomada de Decisão Clínica , Substituição de Medicamentos , Humanos , Seleção de Pacientes , Variantes Farmacogenômicos , Medição de Risco , Fatores de Risco , Toxicocinética , Tuberculose/diagnóstico , Tuberculose/microbiologia
7.
J Clin Lab Anal ; 33(5): e22880, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30924187

RESUMO

BACKGROUND: Little knowledge about the biological functions of RP11-37B2.1, a newly defined long noncoding RNA (lncRNA) molecule, is currently available. Previous studies have shown rs160441, located in the RP11-37B2.1 gene, is significantly associated with tuberculosis (TB) in a Ghanaian and the Gambian populations. METHODS: We investigated the influence of single-nucleotide polymorphisms (SNPs) within lncRNA RP11-37B2.1 on the risk of TB and the possible correlation with adverse drug reactions (ADRs) from TB treatment in a Western Chinese population. Four SNPs within lncRNA RP11-37B2.1 were genotyped in 554 TB cases and 561 healthy subjects using the improved multiplex ligation detection reaction method, and the patients were followed up monthly to monitor the development of ADRs. RESULTS: No significant association between the SNPs of lncRNA RP11-37B2.1 and TB susceptibility was observed (all P > 0.05). Surprisingly, significant association was observed between two SNPs (rs218916 and rs160441) and thrombocytopenia development during anti-TB therapy under the dominant model (P = 0.003 and 0.014, respectively). CONCLUSIONS: Our findings firstly exhibit that rs218916 and rs160441 within lncRNA RP11-37B2.1 significantly associate with the occurrence of thrombocytopenia and suggest RP11-37B2.1 genetic variants are potential biosignatures for thrombocytopenia during anti-TB treatment.


Assuntos
Antituberculosos/efeitos adversos , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Tuberculose/tratamento farmacológico , Tuberculose/genética , Adulto , Anemia/induzido quimicamente , Anemia/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Humanos , Isoniazida/efeitos adversos , Leucopenia/induzido quimicamente , Leucopenia/genética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Rifampina/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/genética
8.
Zhonghua Gan Zang Bing Za Zhi ; 27(2): 133-139, 2019 Feb 20.
Artigo em Chinês | MEDLINE | ID: mdl-30818919

RESUMO

Objective: To investigate the interventional effect of bicyclol on isoniazid-induced liver injury in rats and the expression of endoplasmic reticulum stress (ERS) protein, glucose regulatory protein 78 (GRP78), and growth arrest and DNA-damage-inducible gene 153(CHOP). Methods: Eighty Wistar rats were randomly divided into control group (8 rats) and model group (72 rats). After 10 days of intragastric administration of isoniazid, the model group rats were randomly divided into treatment group (A), natural recovery group (B), etiological persistence group (C) and etiological persistence plus treatment group (D). Sixteen rats from each group were sacrificed after 1 and 2 weeks of intervention with different methods. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected. Liver pathological morphology was observed. Apoptotic cells were detected by TUNEL assay. ERS protein expression was detected by Western blot. A t-test or randomized block analysis of variance, K-S test and Levene's test were used to analyze the normality and homogeneity of variance. Kruskal-Wallis rank sum test was used for data that did not suit the conditions of t-test and variance analysis. Results: ALT and AST were elevated in the model group, and liver pathological examination showed liver tissue damage. Apoptotic index was higher than control group (7.13% ± 1.55% vs. 0.75% ± 0.71%, Z = -3.411, P < 0.01), and the expression value of ERS protein in model group was significantly higher than control group (GRP78: 1.16 ± 0.30 vs. 0.23 ± 0.05, t = -6.008, P < 0.01; CHOP: 0.98±0.23 vs. 0.20 ± 0.10, t = -6.378, P < 0.01). Serum enzymes, apoptotic index and ERS protein expressions of rats were decreased after treatment with bicyclol, and the pathological damage was eased. Rats in natural recovery group recovered less than the treatment group. Conclusion: Isoniazid-induced liver injury is associated to ERS-related excessive apoptosis and the therapeutic effect of bicyclol on drug-induced liver injury may minimize ERS-induced apoptosis.


Assuntos
Estresse do Retículo Endoplasmático , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico/metabolismo , Isoniazida/efeitos adversos , Fígado , Proteínas de Membrana/metabolismo , Animais , Apoptose , Compostos de Bifenilo , Doença Hepática Induzida por Substâncias e Drogas , DNA , Fígado/efeitos dos fármacos , Fígado/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar
9.
N Engl J Med ; 380(11): 1001-1011, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30865794

RESUMO

BACKGROUND: Tuberculosis is the leading killer of patients with human immunodeficiency virus (HIV) infection. Preventive therapy is effective, but current regimens are limited by poor implementation and low completion rates. METHODS: We conducted a randomized, open-label, phase 3 noninferiority trial comparing the efficacy and safety of a 1-month regimen of daily rifapentine plus isoniazid (1-month group) with 9 months of isoniazid alone (9-month group) in HIV-infected patients who were living in areas of high tuberculosis prevalence or who had evidence of latent tuberculosis infection. The primary end point was the first diagnosis of tuberculosis or death from tuberculosis or an unknown cause. Noninferiority would be shown if the upper limit of the 95% confidence interval for the between-group difference in the number of events per 100 person-years was less than 1.25. RESULTS: A total of 3000 patients were enrolled and followed for a median of 3.3 years. Of these patients, 54% were women; the median CD4+ count was 470 cells per cubic millimeter, and half the patients were receiving antiretroviral therapy. The primary end point was reported in 32 of 1488 patients (2%) in the 1-month group and in 33 of 1498 (2%) in the 9-month group, for an incidence rate of 0.65 per 100 person-years and 0.67 per 100 person-years, respectively (rate difference in the 1-month group, -0.02 per 100 person-years; upper limit of the 95% confidence interval, 0.30). Serious adverse events occurred in 6% of the patients in the 1-month group and in 7% of those in the 9-month group (P = 0.07). The percentage of treatment completion was significantly higher in the 1-month group than in the 9-month group (97% vs. 90%, P<0.001). CONCLUSIONS: A 1-month regimen of rifapentine plus isoniazid was noninferior to 9 months of isoniazid alone for preventing tuberculosis in HIV-infected patients. The percentage of patients who completed treatment was significantly higher in the 1-month group. (Funded by the National Institute of Allergy and Infectious Diseases; BRIEF TB/A5279 ClinicalTrials.gov number, NCT01404312.).


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Antituberculosos/administração & dosagem , Infecções por HIV/tratamento farmacológico , Isoniazida/administração & dosagem , Tuberculose Latente/tratamento farmacológico , Rifampina/análogos & derivados , Tuberculose/prevenção & controle , Adulto , Antituberculosos/efeitos adversos , Contagem de Linfócito CD4 , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/complicações , Humanos , Isoniazida/efeitos adversos , Tuberculose Latente/complicações , Masculino , Adesão à Medicação , Rifampina/administração & dosagem , Rifampina/efeitos adversos
10.
PLoS One ; 14(3): e0213718, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870476

RESUMO

BACKGROUND: Recent evidence suggests that higher rifampicin doses may improve tuberculosis (TB) treatment outcome. METHODS: In this observational cohort study we evaluated all TB patients who were treated with high-dose rifampicin (> 10 mg/kg daily) in our reference centre, from January 2008 to May 2018. Indications, achieved plasma rifampicin exposures, safety and tolerability were evaluated. RESULTS: Eighty-eight patients were included. The main indications were low plasma concentrations (64.7%) and severe illness (29.5%), including central nervous system TB. Adjusted rifampicin dosages ranged from 900 mg to a maximum of 2400 mg (corresponding to 32 mg/kg) per day. Patients with severe illness received high-dose rifampicin immediately, the others had a higher dosage guided by therapeutic drug monitoring. Four patients developed hepatotoxicity, of which two were proven due to isoniazid. Re-introduction of high-dose rifampicin was successful in all four. Eighty-seven patients tolerated high-dose rifampicin well throughout treatment. Only one patient required a dose reduction due to gastro-intestinal disturbance. CONCLUSION: High-dose rifampicin, used in specific groups of patients in our clinical setting, is safe and well-tolerated for the whole treatment duration. Measurement of drug exposures could be used as a tool/guide to increase rifampicin dosage if a reduced medication absorption or a poor treatment outcome is suspected. We suggest to administer high-dose rifampicin to patients with severe manifestations of TB or low rifampicin exposure to improve treatment outcome.


Assuntos
Antituberculosos/administração & dosagem , Rifampina/administração & dosagem , Tuberculose/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/sangue , Área Sob a Curva , Sistema Nervoso Central/efeitos dos fármacos , Estudos de Coortes , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Humanos , Isoniazida/efeitos adversos , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Países Baixos , Segurança do Paciente , Rifampina/sangue , Resultado do Tratamento , Tuberculose Pulmonar/tratamento farmacológico , Adulto Jovem
11.
Int J Tuberc Lung Dis ; 23(3): 371-377, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30871669

RESUMO

SETTING: Sixty-seven government health facilities providing tuberculosis (TB) and human immunodeficiency virus (HIV) services across Ethiopia. OBJECTIVE: To examine clinician barriers to implementing isoniazid preventive therapy (IPT) among people living with HIV. DESIGN: A cross-sectional study to evaluate the provider-related factors associated with high IPT coverage at the facility level. RESULTS: On bivariate analysis, the odds of high IPT implementation were lower when clinicians felt patients were negatively affected by the side effects of IPT (OR 0.18, 95%CI 0.04-0.81) and perceived that IPT increased multidrug-resistant TB (MDR-TB) rates (OR 0.66, 95%CI 0.44-0.98). The presence of IPT guidelines on site (OR 2.93, 95%CI 1.10-7.77) and TB-HIV training (OR 3.08, 95%CI 1.11-8.53) had a positive relationship with high IPT uptake. In the multivariate model, clinician's perception that active TB was difficult to rule out had a negative association with a high IPT rate (OR 0.93; 95%CI 0.90-0.95). CONCLUSIONS: Clinician impression that ruling out active TB among HIV patients is difficult was found to be a significant barrier to IPT uptake. Continued advancement of IPT relies greatly on improving the ability of providers to determine IPT eligibility and more confidently care for patients on IPT. Improved clinician support and training as well as development of new TB diagnostic technologies could impact IPT utilization among providers.


Assuntos
Antituberculosos/administração & dosagem , Infecções por HIV/complicações , Isoniazida/administração & dosagem , Tuberculose/prevenção & controle , Adulto , Antituberculosos/efeitos adversos , Atitude do Pessoal de Saúde , Estudos Transversais , Etiópia/epidemiologia , Feminino , Pesquisas sobre Serviços de Saúde , Humanos , Isoniazida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/estatística & dados numéricos , Tuberculose/epidemiologia , Adulto Jovem
12.
Indian J Pediatr ; 86(3): 229-232, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30515702

RESUMO

OBJECTIVES: To compare the incidence of anti tuberculosis drug-induced hepatotoxicity (ATDH) with those on old vs. revised WHO doses in human immunodeficiency virus (HIV) negative children. The secondary objective was to determine the overall incidence of hepatitis in children on Anti tubercular treatment (ATT) and isoniazid prophylactic therapy (IPT). METHODS: Children attending pediatric outpatient / admitted in wards, on ATT/ IPT between January 2007 and December 2017 (11 y) were included. Children were divided into Group 1 (treated based on old doses, from January 2007 to December 2011) and Group 2 (treated based on revised doses from January 2012 to December 2017). Children with multi drug resistant tuberculosis (MDRTB) and pre-existing liver disease were excluded. RESULTS: A total of 515 children were enrolled. Twelve children developed ATDH with an overall incidence of 2.3%. Five out of 260 (1.9%) developed hepatitis with old doses vs. 7 of the 255 (2.7%) with revised doses; this difference was not statistically significant. When calculated only for active TB (excluding children on IPT), overall incidence of hepatitis was 2.7%. Comparison between group 1 (2.04%) and group 2 (3.5%) was again not statistically significant. Ten out of 12 children who developed hepatitis were restarted on ATT without recurrence. No child on IPT developed hepatitis. There was no mortality. CONCLUSIONS: Revised WHO dosing does not increase incidence of hepatitis compared to old dosing in HIV negative children. Overall incidence was 2.3%. Hepatitis did not occur with IPT.


Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adolescente , Antituberculosos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Criança , Pré-Escolar , Coinfecção , Feminino , HIV , Infecções por HIV/complicações , Hepatite , Humanos , Incidência , Índia , Lactente , Isoniazida/efeitos adversos , Isoniazida/uso terapêutico , Fígado , Testes de Função Hepática , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Tuberculose/complicações , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/complicações
13.
Biosci Rep ; 39(1)2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30509962

RESUMO

Hepatotoxicity is a severe problem generally faced by tuberculosis (TB) patients. It is a well-known adverse reaction due to anti-TB drugs in TB patients undergoing long-term treatment. The studies published previously have explored the connection of N-acetyltransferase 2 (NAT2) gene polymorphisms with isoniazid-induced hepatotoxicity, but the results obtained were inconsistent and inconclusive. A comprehensive trial sequence meta-analysis was conducted employing 12 studies comprising 3613 controls and 933 confirmed TB cases using the databases namely, EMBASE, PubMed (Medline) and Google Scholar till December 2017. A significant association was observed with individuals carrying variant allele at position 481C>T (T vs. C: P = 0.001; OR = 1.278, 95% CI = 1.1100-1.484), at position 590G>A (A vs. G: P = 0.002; OR = 1.421, 95% CI = 1.137-1.776) and at position 857G>A (A vs. G: P = 0.0022; OR = 1.411, 95% CI = 1.052-1.894) to higher risk of hepatotoxicity vis-à-vis wild-type allele. Likewise, the other genetic models of NAT2 gene polymorphisms have also shown increased risk of hepatotoxicity. No evidence of publication bias was observed. These results suggest that genetic variants of NAT2 gene have significant role in isoniazid induced hepatotoxicity. Thus, NAT2 genotyping has the potential to improve the understanding of the drug-enzyme metabolic capacity and help in early predisposition of isoniazid-induced hepatotoxicity.


Assuntos
Antituberculosos/efeitos adversos , Arilamina N-Acetiltransferase/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Isoniazida/efeitos adversos , Polimorfismo de Nucleotídeo Único , Tuberculose Pulmonar/tratamento farmacológico , Alelos , Antituberculosos/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ensaios Clínicos como Assunto , Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Humanos , Isoniazida/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
15.
Int Immunopharmacol ; 67: 348-355, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30578970

RESUMO

Silent information regulator 1 (SIRT1) is a type III histone deacetylase that is related to the inhibition of the inflammatory response. The aim of this study was to investigate the regulation of SIRT1 on isoniazid-induced hepatocyte injury and the possible mechanism of histone modification. We found that compared with the blank control group, expression of SIRT1 was decreased in the isoniazid group and that expression of NF-κB p65 was increased, leading to an increase of the expression of inflammatory cytokines Interleukin-6 (IL-6) and Tumour necrosis factor alpha (TNF-α). The level of histone H3K9 acetylation in the promoter region of IL-6 was increased as well. Addition of a SIRT1 agonist (SRT1720) alleviated the inflammatory reaction caused by isoniazid, while the use of a SIRT1 inhibitor (EX527) aggravated the inflammatory damage to cells. In conclusion, these findings indicated that during the period of isoniazid-induced hepatocyte injury, SIRT1 levels were decreased and inflammatory factor levels were increased. Activation of SIRT1 may reduce hepatocyte injury by reducing the level of histone H3K9 acetylation in the promoter region of the IL-6 gene.


Assuntos
Carbazóis/farmacologia , Hepatócitos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Interleucina-6/metabolismo , Isoniazida/efeitos adversos , Sirtuína 1/metabolismo , Antituberculosos/efeitos adversos , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Histonas/genética , Histonas/metabolismo , Humanos , Interleucina-6/genética , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sirtuína 1/genética
16.
Molecules ; 23(12)2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30486347

RESUMO

In this study, a non-targeted metabolic profiling method based on ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) was used to characterize the plasma metabolic profile associated with the protective effects of the Sagittaria sagittifolia polysaccharide (SSP) on isoniazid (INH)-and rifampicin (RFP)-induced hepatotoxicity in mice. Fourteen potential biomarkers were identified from the plasma of SSP-treated mice. The protective effects of SSP on hepatotoxicity caused by the combination of INH and RFP (INH/RFP) were further elucidated by investigating the related metabolic pathways. INH/RFP was found to disrupt fatty acid metabolism, the tricarboxylic acid cycle, amino acid metabolism, taurine metabolism, and the ornithine cycle. The results of the metabolomics study showed that SSP provided protective effects against INH/RFP-induced liver injury by partially regulating perturbed metabolic pathways.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Isoniazida/efeitos adversos , Metaboloma/efeitos dos fármacos , Polissacarídeos/farmacologia , Rifampina/efeitos adversos , Sagittaria/química , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Isoniazida/farmacologia , Metabolômica , Camundongos , Camundongos Endogâmicos BALB C , Polissacarídeos/química , Rifampina/farmacologia
17.
Int J Tuberc Lung Dis ; 22(11): 1344-1349, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30355415

RESUMO

SETTING: Four New York City (NYC) Health Department tuberculosis (TB) clinics. OBJECTIVE: To assess the effectiveness of preferentially offering two shorter treatment regimens-4 months of daily rifampin (4R) and 3 months of once-weekly isoniazid and rifapentine (3HP)-as an alternative to 9 months of daily isoniazid (9H) for the treatment of latent tuberculous infection (LTBI). DESIGN: Retrospective analysis of patients treated for LTBI from January to June 2015. Poisson regression with robust standard error was used to examine the factors associated with treatment completion. RESULTS: Of the patients on 9H, 49% (27/55) completed treatment compared with 70% (187/269) of patients on 4R (P = 0.003) and 79% (99/125) of patients on 3HP (P < 0.001). When adjusting for age, sex, and TB risk factors, patients on 4R (adjusted risk ratio [aRR] 1.39, 95%CI 1.07-1.81) and 3HP (aRR 1.67, 95%CI 1.27-2.19) were more likely to complete treatment than patients on 9H. Treatment was discontinued due to side effects in 1% (3/269) of patients on 4R, 2% (2/125) of patients on 3HP, and 4% (2/55) of patients on 9H. CONCLUSIONS: Most patients were placed on shorter regimens for LTBI treatment, and higher treatment completion was observed. Encouraging community providers to use shorter regimens for LTBI treatment would reduce the TB disease burden in NYC.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Isoniazida/administração & dosagem , Tuberculose Latente/tratamento farmacológico , Tuberculose Latente/epidemiologia , Rifampina/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Criança , Pré-Escolar , Terapia Diretamente Observada , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Lactente , Recém-Nascido , Isoniazida/efeitos adversos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Estudos Retrospectivos , Rifampina/administração & dosagem , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
19.
BMJ Case Rep ; 20182018 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-30297494

RESUMO

The pure red cell aplasia (PRCA) is an uncommon side effect of isoniazid. We describe a 28-year-old man who developed a severe anaemia caused by PRCA. The patient received antituberculous therapy including isoniazid for his pulmonary tuberculosis. On discontinuation of isoniazid, the anaemia recovered promptly. PRCA should be considered in case of unexplained anaemia during isoniazid treatment.


Assuntos
Antituberculosos/efeitos adversos , Isoniazida/efeitos adversos , Aplasia Pura de Série Vermelha/diagnóstico , Adulto , Diagnóstico Diferencial , Dispneia/etiologia , Fadiga/etiologia , Humanos , Masculino , Aplasia Pura de Série Vermelha/induzido quimicamente , Aplasia Pura de Série Vermelha/complicações , Tuberculose Pulmonar/tratamento farmacológico
20.
Int J Tuberc Lung Dis ; 22(10): 1127-1134, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30236179

RESUMO

OBJECTIVE: To assess the clinical outcomes of patients prescribed the World Health Organization (WHO) Category II retreatment regimen for tuberculosis (TB). DESIGN: A systematic review of the literature was performed by searching Medscape, Embase and Scopus databases for cohort studies and clinical trials reporting outcomes in adult patients on the Category II retreatment regimen. RESULTS: The proportion of patients successfully completing the retreatment regimen varied from 27% to 92% in the 39 studies included in this review. In only 2/39 (5%) studies was the treatment success rate > 85%. There are very few data concerning outcomes in patients categorised as 'other', and outcomes in this subgroup are variable. Of the five studies reporting disaggregated outcomes in human immunodeficiency virus (HIV) positive people, four demonstrated worse outcomes than in HIV-negative people on the retreatment regimen. Only four studies reported disaggregated outcomes in patients with isoniazid (INH) resistance, and treatment success rates varied from 11% to 78%. CONCLUSION: Clinical outcomes on the Category II retreatment regimen are poor across various populations. Improvements in management should consider the holistic treatment of comorbidity and comprehensive approaches to drug resistance in patients with recurrent TB, including a standardised approach for the management of INH resistance in patients who develop recurrent TB in settings without reliable access to comprehensive drug susceptibility testing.


Assuntos
Antituberculosos/uso terapêutico , Isoniazida/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose/tratamento farmacológico , Antituberculosos/efeitos adversos , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Humanos , Isoniazida/efeitos adversos , Testes de Sensibilidade Microbiana , Recidiva , Retratamento , Falha de Tratamento , Resultado do Tratamento , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Organização Mundial da Saúde
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