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1.
BMC Infect Dis ; 21(1): 90, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33478428

RESUMO

BACKGROUND: Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and isoniazid regimen versus daily rifampicin and isoniazid, both self-administered for 12 weeks. METHODS: An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/isoniazid ('intervention') or a daily combination of rifampicin/isoniazid ('standard'), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded. RESULTS: Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7-91.4), compared with 19 of 25 (76.0%, CI 54.9-90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms. CONCLUSION: In this pilot trial, treatment completion was comparable between the weekly rifapentine/isoniazid and the daily rifampicin/isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment. TRIAL REGISTRATION: The trial was funded by the NIHR, UK and registered with ISRCTN ( 26/02/2013-No.04379941 ).


Assuntos
Antituberculosos/uso terapêutico , Tuberculose Latente/tratamento farmacológico , Rifampina/análogos & derivados , Rifampina/uso terapêutico , Adolescente , Adulto , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Isoniazida/administração & dosagem , Isoniazida/efeitos adversos , Isoniazida/uso terapêutico , Londres , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Rifampina/administração & dosagem , Rifampina/efeitos adversos , Autoadministração , Resultado do Tratamento , Adulto Jovem
2.
Lancet HIV ; 8(1): e8-e15, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33387480

RESUMO

BACKGROUND: Isoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups. METHODS: We searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400. FINDINGS: Of 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49-0·95, p=0·02). Risk of all-cause mortality was lower in participants given isoniazid preventive therapy and ART than participants given ART alone, but this difference was non-significant (HR 0·69, 95% CI 0·43-1·10, p=0·12). Participants with baseline CD4 counts of less than 500 cells per µL had increased risk of tuberculosis, but there was no significant difference in the benefit of isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine aminotransferase, but data were insufficient to calculate an HR. INTERPRETATION: Isoniazid preventive therapy with ART prevents tuberculosis across demographic and HIV-specific and tuberculosis-specific subgroups, which supports efforts to further increase use of isoniazid preventive therapy with ART broadly among people living with HIV. FUNDING: National Institutes of Health and National Institute of Allergy and Infectious Diseases.


Assuntos
Antibioticoprofilaxia , Antituberculosos/uso terapêutico , Isoniazida/uso terapêutico , Tuberculose/tratamento farmacológico , Tuberculose/prevenção & controle , Adulto , Antirretrovirais/administração & dosagem , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Contagem de Linfócito CD4 , Coinfecção , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Isoniazida/administração & dosagem , Isoniazida/efeitos adversos , Masculino , Resultado do Tratamento
3.
BMC Infect Dis ; 20(1): 294, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32664847

RESUMO

BACKGROUND: Tuberculosis (TB) is the most common opportunistic infection and the leading cause of death in people living with HIV (PLHIV). HIV-infected children are at a higher risk of TB infection and disease compared to those without HIV. Isoniazid preventive therapy (IPT) is an effective intervention in preventing progression of latent TB infection to active TB. The World Health Organization (WHO) currently recommends that all children aged > 12 months and adults living with HIV in whom active TB has been excluded should receive a 6-months course of IPT as part of a comprehensive package of HIV care. Despite this recommendation, the uptake of IPT among PLHIV has been suboptimal globally. This study sought to determine the factors affecting IPT uptake and completion among HIV-infected children in a large HIV care centre in Nairobi, Kenya. METHOD: This was a cross-sectional mixed methods study comprising of quantitative and qualitative study designs. Medical records of 225 HIV-infected children aged 1 to < 10 years, in care in the Kenyatta National Hospital Comprehensive Care Centre (KNH CCC) were retrospectively reviewed, and 8 purposively selected healthcare providers and 18 consecutively selected caregivers of children were interviewed. RESULTS: IPT uptake among CLHIV in care in the KNH CCC was 68% (152/225) while the treatment completion rate was 82% (94/115). IPT-related health education and counselling were the main facilitators of IPT uptake and completion, while fear of adverse drug reaction, pill burden and lack of an integrated monitoring and evaluation system for IPT were the major barriers. CONCLUSION: The IPT uptake in this study was low and fell short of the set global target of > 90%. The completion rate was however acceptable. There is an urgent need to address the identified barriers.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antituberculosos/uso terapêutico , Isoniazida/uso terapêutico , Tuberculose Latente/tratamento farmacológico , Tuberculose Latente/prevenção & controle , Adulto , Antituberculosos/efeitos adversos , Criança , Pré-Escolar , Aconselhamento , Estudos Transversais , Feminino , Pessoal de Saúde , Humanos , Lactente , Isoniazida/efeitos adversos , Quênia , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Pesquisa Qualitativa , Encaminhamento e Consulta , Estudos Retrospectivos , Resultado do Tratamento , Recusa do Paciente ao Tratamento
4.
Int J Infect Dis ; 96: 550-557, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32434083

RESUMO

BACKGROUND: The detection and treatment of latent tuberculosis infection (LTBI) is a key step in eliminating tuberculosis (TB), but information on safety and on treatment interruption in elderly LTBI patients remains limited. METHODS: This multicenter prospective observational study included individuals with LTBI who underwent preventive therapy. Incidents of systemic adverse reactions (SARs) and treatment interruption rates in an elderly group (≥60 years old) and a young group (<60 years old) were analyzed. RESULTS: A total of 406 LTBI patients, comprising 167 elderly and 239 young patients, were included in the analyses. The incidence of SARs was similar in the elderly group (18%) and the young group (15.1%). Being middle-aged (35-59 years), body mass index <23 kg/m2, a regimen of 3 months of once-weekly rifapentine plus isoniazid, and end-stage renal disease were independent factors associated with SARs. The treatment interruption rate was similar between the elderly group (21.6%) and the young group (15.9%). LTBI patients aged ≥80 years with SARs had the highest risk of treatment interruption. CONCLUSIONS: The occurrence of SARs was similar in the elderly (≥60 years old) and young (<60 years old) LTBI patients receiving preventive therapy. Extremely old (≥80 years old) LTBI patients had a higher treatment interruption rate, especially when they had SARs.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose Latente/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Feminino , Humanos , Incidência , Isoniazida/efeitos adversos , Isoniazida/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Tuberculose Latente/tratamento farmacológico , Tuberculose Latente/epidemiologia , Tuberculose Latente/microbiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Rifampina/efeitos adversos , Rifampina/análogos & derivados , Rifampina/uso terapêutico , Taiwan/epidemiologia
5.
Lancet HIV ; 7(6): e401-e409, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32240629

RESUMO

BACKGROUND: Short-course preventive therapy with 12 doses of once-weekly rifapentine (900 mg) plus isoniazid (900 mg) could greatly improve tuberculosis control, especially in areas with high co-endemicity with HIV. However, a small previous trial of such therapy with dolutegravir in healthy, HIV-negative adults was halted early after two of the four patients developed serious adverse events. Because of the potential use of this therapy, and variable safety outcomes of tuberculosis drugs seen in patients with and without HIV, we aimed to characterise safety, pharmacokinetics, and virological suppression in adults who are HIV positive. METHODS: DOLPHIN was a phase 1/2, single-arm trial done at The Aurum Institute (Tembisa Clinical Research Site, Tembisa, South Africa), with pharmacokinetic visits done at VxPharma (Pretoria, South Africa). Adults (≥18 years) with HIV infection and undetectable viral load (<40 copies per mL) after at least 8 weeks of efavirenz-based or dolutegravir-based regimens were recruited in three consecutive groups, subject to approval by the independent safety monitoring committee. Participants received 50 mg of daily dolutegravir in place of efavirenz for 8 weeks, then began once-weekly rifapentine (900 mg)-isoniazid (900 mg) for 12 weeks. Groups 1A (n=12) and 1B (n=18) had intensive dolutegravir pharmacokinetic sampling at week 8 (before rifapentine-isoniazid), at week 11 (after the third dose of rifapentine)-isoniazid and at week 16 after the eighth dose. Group 2 (n=30) were treated with the same schedule and had sparse dolutegravir pharmacokinetic sampling at weeks 8, 11, and 16. Participants were followed 4 weeks after completion of prophylactic tuberculosis treatment. HIV viral loads were measured at baseline and at weeks 11 and 24. Primary endpoints were adverse events (grade 3 or higher) and dolutegravir population pharmacokinetics, assessed in participants who began rifapentine-isoniazid. This trial was registered at ClinicalTrials.gov, NCT03435146. FINDINGS: Between Jan 24, 2018, and Nov 25, 2018, 61 participants were enrolled into three groups; one participant withdrew (from group 1A). 43 (70%) of 60 participants were women and all participants were black African. Median age was 40 years (IQR 35-48), CD4 cell count was 683 cells per µL (447-935), and body-mass index was 28·9 kg/m2 (24·0-32·9). Three grade 3 adverse events occurred; two elevated creatinine and one hypertension. Rifapentine-isoniazid increased dolutegravir clearance by 36% (relative standard error 13%) resulting in a 26% decrease in dolutegravir area under the curve. Overall geometric mean ratio of trough concentrations with versus without rifapentine-isoniazid was 0·53 (90% CI 0·49-0·56) though this ratio varied by day after rifapentine-isoniazid dose. All but one trough value was above the 90% maximal inhibitory concentration for dolutegravir and HIV viral loads were less than 40 copies per mL in all patients. INTERPRETATION: Our results suggest 12 doses of once-weekly rifapentine-isoniazid can be given for tuberculosis prophylaxis to patients with HIV taking dolutegravir-based antiretroviral therapy, without dose adjustments. Further exploration of the pharmacokinetics, safety, and efficacy in children and pharmacodynamics in individuals naive to antiretroviral therapy is needed. FUNDING: UNITAID.


Assuntos
Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Isoniazida/administração & dosagem , Rifampina/análogos & derivados , Tuberculose/prevenção & controle , Adulto , Esquema de Medicação , Feminino , Infecções por HIV/virologia , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Isoniazida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Piridonas , Rifampina/administração & dosagem , Rifampina/efeitos adversos , África do Sul , Resultado do Tratamento , Carga Viral
6.
BMC Pharmacol Toxicol ; 21(1): 22, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32178728

RESUMO

BACKGROUND: The cardiotoxicity of isoniazid on zebrafish embryos and its underlying mechanism is unclear. METHODS: Here, we exposed zebrafish embryos at 4 h post-fertilization to different levels of isoniazid and recorded the morphology and number of malformed and dead embryos under the microscope. RESULTS: The high concentration of isoniazid group showed more malformed and dead embryos than the low concentration of isoniazid group and control group. The morphology of the heart and its alteration were visualized using transgenic zebrafish (cmlc2: GFP) and confirmed by in situ hybridization. The negative effects of isoniazid on the developing heart were characterized by lower heart rate and more heart looping disorders. Mechanistically, PCR showed decreased expression of heart-specific transcription factors when exposed to isoniazid. Oxidative stress was induced by isoniazid in cardiomyocytes, mediated by decreased activities of catalase and superoxide dismutase, which were rescued by scavengers of reactive oxygen species. CONCLUSION: In conclusion, this study demonstrated that isoniazid led to heart looping disturbance by the downregulation of cardiac-specific transcription factors and induction of cardiomyocyte apoptosis.


Assuntos
Antituberculosos/efeitos adversos , Desenvolvimento Embrionário/efeitos dos fármacos , Cardiopatias Congênitas/induzido quimicamente , Isoniazida/efeitos adversos , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Regulação para Baixo , Embrião não Mamífero/anormalidades , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiopatologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/genética , Peixe-Zebra
7.
Med Sci Monit ; 26: e920350, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32145061

RESUMO

BACKGROUND The aim of this study was to investigate the clinical characteristics and the risk factors associated with anti-tuberculosis (anti-TB) drug-induced liver injury (DILI). MATERIAL AND METHODS This retrospective study enrolled 140 hospitalized patients diagnosed with anti-TB DILI during January 2009 to December 2015. We assessed the baseline characteristics and performed regular follow-up up to the 24th week to assess the possible risk factors associated with the condition. RESULTS The study population was 58.6% male and 41.4% female patients; 20.7% were diagnosed with grades 4-5 DILI and 79.3% with grades 1-3 DILI. Female patients were significantly more likely to be diagnosed with grades 4-5 DILI than with grades 1-3 DILI (58.6% vs. 36.9%, p=0.036). Patients treated with a multidrug anti-TB regimen were more commonly affected with grades 4-5 DILI (86.2% vs. 68.5%, p=0.045). A significant number of patients who reinitiated anti-TB therapy suffered severe liver injury in comparison to patients with grades 1-3 DILI (41.4% vs. 10.8%, P<.001). Laboratory examinations revealed significantly higher values for total bilirubin (TBL), International normalized ratio (INR), and Hy's law (P<.001) in the grades 4-5 group compare to the grades 1-3 group. CONCLUSIONS Female gender, combination therapy for antitubercular drugs (isoniazid, rifampicin and pyrazinamide), re-challenge were the risk factors associated with the severity of anti-TB DILI.


Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Adulto , Antituberculosos/uso terapêutico , Feminino , Humanos , Isoniazida/efeitos adversos , Isoniazida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pirazinamida/efeitos adversos , Pirazinamida/uso terapêutico , Estudos Retrospectivos , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Fatores de Risco , Tuberculose/tratamento farmacológico , Adulto Jovem
8.
Eur J Pharm Sci ; 144: 105216, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31945451

RESUMO

With the purpose of overcoming the serious hepatotoxicity of antituberculosis drug isoniazid (INH), a cocrystallization strategy based on complementary advantages was implemented by choosing the hepatoprotective nutraceutical quercetin (QCT) as the cocrystal former. The strategy plays the solubility advantage of INH to improve the bioavailability of the insoluble QCT, thereby significantly enhancing the QCT's hepatoprotective effects. The optimized protective effects of QCT, in turn, feed back to INH to reduce its hepatotoxicity. Along this line, a novel INH-QCT cocrystal was successfully prepared and structurally characterized. The systematic evaluation results of the in vitro/in vivo revealed that, due to the advantage of INH's solubility, the dissolution efficiency of QCT from the cocrystal was increased 51.67-fold compared with that of coarse quercetin, and the oral bioavailability of the cocrystal in rats was enhanced by 28.91 times. As a result, the INH-QCT cocrystal almost removed INH induced serious hepatotoxicity, which has been demonstrated by the hepatotoxicity studies in rats. These findings present new opportunities for the advantageous solid forms of low-toxic antituberculosis drugs, and open new avenues against toxic side effects of drugs through the cocrystallization mean.


Assuntos
Isoniazida/química , Isoniazida/farmacologia , Quercetina/química , Quercetina/farmacologia , Animais , Antituberculosos/química , Antituberculosos/farmacologia , Cristalização , Isoniazida/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Ratos , Ratos Sprague-Dawley
10.
Regul Toxicol Pharmacol ; 111: 104553, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31843592

RESUMO

New effective compounds to treat tuberculosis are urgently needed. IQG-607 is an orally active anti-tuberculosis drug candidate, with promising preliminary safety profile and anti-mycobacterial activity in both in vitro and in vivo models of tuberculosis infection. Here, we evaluated the mutagenic and genotoxic effects of IQG-607, and its interactions with CYP450 isoforms. Moreover, we describe for the first time a combination study of IQG-607 in Mycobacterium tuberculosis-infected mice. Importantly, IQG-607 had additive effects when combined with the first-line anti-tuberculosis drugs rifampin and pyrazinamide in mice. IQG-607 presented weak to moderate inhibitory potential against CYP450 isoforms 3A4, 1A2, 2C9, 2C19, 2D6, and 2E1. The Salmonella mutagenicity test revealed that IQG-607 induced base pair substitution mutations in the strains TA100 and TA1535. However, in the presence of human metabolic S9 fraction, no mutagenic effect was detected in any strain. Additionally, IQG-607 did not increase micronucleus frequencies in mice, at any dose tested, 25, 100, or 250 mg/kg. The favorable activity in combination with first-line drugs and mild to moderate toxic events described in this study suggest that IQG-607 represents a candidate for clinical development.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Ferrosos/efeitos adversos , Compostos Ferrosos/farmacologia , Isoniazida/análogos & derivados , Mycobacterium tuberculosis/efeitos dos fármacos , Salmonella typhimurium/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Animais , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Aberrações Cromossômicas , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Compostos Ferrosos/administração & dosagem , Isoniazida/administração & dosagem , Isoniazida/efeitos adversos , Isoniazida/farmacologia , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Testes de Mutagenicidade , Mycobacterium tuberculosis/genética , Salmonella typhimurium/genética , Tuberculose/microbiologia
11.
Ann Pharmacother ; 54(5): 457-463, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31729245

RESUMO

Background: Centers for Disease Control and Prevention recommends 3 months of once-weekly rifapentine/isoniazid (3HP) for latent tuberculosis infection (LTBI) treatment given by directly observed therapy (DOT) or self-administered therapy (SAT) in patients ≥2 years old. 3HP has been associated with increased incidence of hepatic, gastrointestinal, flu-like, and cutaneous adverse drug reactions (ADRs) compared with isoniazid monotherapy. Objective: This study evaluated 3HP completion rates and tolerability for LTBI treatment in a real-world setting. Methods: A single-center retrospective cohort with a nested case-control study, comparing patients experiencing ADRs with those who did not, evaluated patients ≥18 years old receiving 3HP by DOT or SAT for LTBI at Cleveland Clinic from October 2011 through July 2018. Information on baseline characteristics, 3HP administrations, and ADRs were collected. Results: Of 199 patients screened, 144 were included (111 DOT, 33 SAT). 3HP completion rates were high at 82.6% and similar between DOT and SAT groups. During treatment, 92/144 (63.9%) patients experienced any ADR. The most common ADR included flu-like symptoms (38.2%) and gastrointestinal (31.9%) and hepatic (2.1%) reactions. Despite high rate of overall ADRs, rates of significant ADRs (grade 2 or higher) were 4.2%. Overall, 9% of patients discontinued 3HP because of ADRs. After adjusting for other factors associated with ADRs at baseline, SAT was not associated with increased incidence of ADRs, but female sex was a significant predictor (odds ratio = 2.61 [95% CI, 1.23 to 5.56]). Conclusion and Relevance: This study observed high 3HP treatment completion rates, low incidence of significant ADRs, and low discontinuation rates resulting from ADRs.


Assuntos
Antituberculosos/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Isoniazida/uso terapêutico , Tuberculose Latente/tratamento farmacológico , Rifampina/análogos & derivados , Adulto , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Estudos de Casos e Controles , Terapia Diretamente Observada/métodos , Esquema de Medicação , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Isoniazida/administração & dosagem , Isoniazida/efeitos adversos , Tuberculose Latente/epidemiologia , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rifampina/administração & dosagem , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Autoadministração
13.
Lancet Infect Dis ; 20(3): 318-329, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31866327

RESUMO

BACKGROUND: An important problem limiting treatment of latent tuberculosis infection is the occurrence of adverse events with isoniazid. We combined populations from phase 2 and phase 3 open-label, randomised controlled trials, to establish risk factors for adverse events during latent tuberculosis infection treatment. METHODS: We did a post-hoc safety analysis based on data from two open-label, randomised controlled trials done in health-care facilities in Australia, Benin, Brazil, Canada, Ghana, Guinea, Indonesia, Saudi Arabia, and South Korea. Participants were consenting adults (aged ≥18 years) with a positive latent tuberculosis infection diagnostic test, indication for treatment, and without contraindications to rifampicin or isoniazid. Patients were centrally randomly assigned 1:1 to 4 months of daily 10 mg/kg rifampicin or 9 months of daily 5 mg/kg isoniazid. The primary outcome evaluated was adverse events (including grade 1-2 rash and all events of grade 3-5) resulting in permanent discontinuation of study medication and judged possibly or probably related to study drug by a masked, independent, three-member adjudication panel (trial registration: NCT00170209; NCT00931736). FINDINGS: Participants were recruited from April 27, 2004, up until Jan 31, 2007 (phase 2), and Oct 1, 2009, up until Dec 31, 2014 (phase 3). The safety populations for each group comprised 3205 individuals receiving isoniazid and 3280 receiving rifampicin. Among those receiving isoniazid, 86 (2·7%) of 3205 had grade 1-2 rash or any grade 3-5 adverse events, more than the 50 (1·5%) of 3280 who had these events with rifampicin (risk difference -1·2%, 95% CI -1·9 to -0·5). Age was associated with adverse events in adults receiving isoniazid. Compared with individuals aged 18-34 years, the adjusted odds ratio (OR) for adverse events was 1·8 (95% CI 1·1-3·0) for individuals aged 35-64 years and 3·0 (1·2-6·8) for individuals aged 65-90 years. With rifampicin, adverse events were associated with inconsistent medication adherence (adjusted OR 2·0, 1·1-3·6) and concomitant medication use (2·8, 1·5-5·2), but not age, with an adjusted OR of 1·1 (0·6-2·1) for individuals aged 35-64 years and 1·7 (0·5-4·7) for individuals aged 65-90 years. One treatment-related death occurred in the isoniazid group. INTERPRETATION: In patients without a contraindication, rifampicin is likely to be the safest latent tuberculosis infection treatment option. With more widespread use of rifampicin, rare, but serious adverse events might be seen. However, within these randomised trials, rifampicin was safer than isoniazid and adverse events were not associated with older age. Therefore, rifampicin should become a primary treatment option for latent tuberculosis infection based on its safety. FUNDING: Canadian Institutes of Health Research.


Assuntos
Antituberculosos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Isoniazida/efeitos adversos , Tuberculose Latente/tratamento farmacológico , Rifampina/efeitos adversos , Adulto , África , América , Antituberculosos/uso terapêutico , Ásia , Austrália , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Isoniazida/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Rifampina/uso terapêutico , Fatores de Risco
15.
BMJ Case Rep ; 12(11)2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31678927

RESUMO

Isoniazid preventative therapy is widely used for latent tuberculosis infection. Isoniazid is highly effective but has many adverse effects, including neuropsychiatric. We describe the case of an 80-year-old woman with mania. She had received isoniazid preventative therapy during steroid treatment for rheumatoid arthritis and organising pneumonia for the previous 5 months. Her mania resolved after discontinuation of isoniazid. Adverse effects of isoniazid should be considered even if a long time has elapsed since the start of administration. Physicians other than infectious disease and respiratory specialists also must be aware of the adverse effects of isoniazid preventative therapy.


Assuntos
Antituberculosos/efeitos adversos , Transtorno Bipolar/induzido quimicamente , Isoniazida/efeitos adversos , Tuberculose Latente/prevenção & controle , Idoso de 80 Anos ou mais , Antituberculosos/administração & dosagem , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Feminino , Humanos , Isoniazida/administração & dosagem , Pneumonia/complicações , Pneumonia/tratamento farmacológico
16.
J Vet Med Sci ; 81(12): 1842-1849, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31666444

RESUMO

A cat was referred because of diffuse parenchymal lung disease. Close examinations revealed a swollen abdominal lymph node and multiple nodules of the liver. Mycobacterium avium subspecies hominissuis infection was confirmed by culture and single nucleotide polymorphism analysis of samples recovered from the liver and bronchoalveolar lavage. After administration of combination antibiotics for 6 months, culture results were negative. Though atonic seizures were observed during the treatment, it disappeared after isoniazid discontinuation and pyridoxal phosphate administration. On day 771 of illness, no clinical signs, lung diseases, or obvious swelling of lymph nodes was observed. This is the first report to confirm Mycobacterium avium subspecies hominissuis infection in cats through gene analysis and to completely cure it with combination antibiotics.


Assuntos
Doenças do Gato/microbiologia , Pneumopatias/veterinária , Mycobacterium avium/isolamento & purificação , Tuberculose/veterinária , Animais , Antibacterianos/uso terapêutico , Gatos , Quimioterapia Combinada , Isoniazida/efeitos adversos , Isoniazida/uso terapêutico , Fígado/microbiologia , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Masculino , Mycobacterium avium/genética , Polimorfismo de Nucleotídeo Único , Fosfato de Piridoxal/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/veterinária , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
17.
Pharmacogenomics ; 20(18): 1303-1311, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31699005

RESUMO

Aim: We investigated the contribution of NAT2 variants and acetylator status to anti-tuberculosis drug-induced liver injury (AT-DILI) severity. Materials & methods: 100 patients with clinically severe AT-DILI and 210 non-AT-DILI controls were subjected to NAT2 genotyping by direct DNA sequencing. Results: NAT2 slow acetylator was significantly associated with AT-DILI risk (p = 2.7 × 10-7; odds ratio [95% CI] = 3.64 [2.21-6.00]). Subgroup analysis of NAT2 ultra-slow acetylator revealed a stronger association with AT-DILI risk (p = 4.3 × 10-6; odds ratio [95% CI] = 3.37 [2.00-5.68]). Subset analysis of NAT2 acetylator status and severity grade confirmed these results in AT-DILI patients with more severe disease whereas fast and intermediate acetylator phenotypes were associated with a decreased AT-DILI risk. Conclusion: We elucidated the role of NAT2 phenotypes in AT-DILI in Indonesian population, suggesting that NAT2 genotype and phenotype determination are important to reduce AT-DILI risk.


Assuntos
Arilamina N-Acetiltransferase/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Predisposição Genética para Doença , Tuberculose/genética , Acetilação/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Feminino , Humanos , Indonésia/epidemiologia , Isoniazida/administração & dosagem , Isoniazida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Tuberculose/complicações , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Adulto Jovem
18.
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
19.
Indian J Med Res ; 150(1): 33-42, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31571627

RESUMO

Background & objectives: Rapid detection of drug resistance in Mycobacterium tuberculosis (MTB) is essential for the efficient control of tuberculosis. Hence, in this study a nested-allele-specific (NAS) PCR, nested multiple allele-specific PCR (NMAS-PCR) and multiple allele-specific (MAS) PCR assays were evaluated that enabled detection of the most common mutations responsible for isoniazid (INH) and rifampicin (RIF) resistance in MTB isolates directly from clinical specimens. Methods: Six pairs of primers, mutated and wild type, were used for the six targets such as codon 516, 526 and 531 of rpoB, codon 315 of katG and C15-T substitution in the promoter region of mabA-inhA using allele-specific (AS) PCR assays (NAS-PCR, NMAS-PCR and MAS-PCR). The performance of AS PCR method was compared with phenotypic drug susceptibility testing (DST). Results: The usefulness of AS PCR assays was evaluated with 391 clinical specimens (251 Acid fast bacilli smear positive and MTB culture positive; 93 smear negative and MTB culture positive; 47 smear positive and MTB culture negative) and 344 MTB culture positive isolates. With culture-based phenotypic DST as a reference standard, the sensitivity and specificity of the NAS-PCR, NMAS-PCR and MAS-PCR assay for drug resistance-related genetic mutation detection were 98.6 and 97.8 per cent for INH, 97.5 and 97.9 per cent for RIF and 98.9 and 100 per cent for multidrug resistance (MDR). Interpretation & conclusions: The performance of AS PCR assays showed that those could be less expensive and technically executable methods for rapid detection of MDR-TB directly from clinical specimens.


Assuntos
Farmacorresistência Bacteriana Múltipla/genética , Reação em Cadeia da Polimerase Multiplex , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Alelos , Antituberculosos/uso terapêutico , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Catalase/genética , Catalase/isolamento & purificação , RNA Polimerases Dirigidas por DNA/genética , RNA Polimerases Dirigidas por DNA/isolamento & purificação , Feminino , Humanos , Isoniazida/efeitos adversos , Isoniazida/uso terapêutico , Masculino , Mutação , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidade , Oxirredutases/genética , Oxirredutases/isolamento & purificação , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/genética , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
20.
Respir Med ; 158: 42-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31605920

RESUMO

PURPOSE: We investigated the adverse events (AEs) and treatment completion rates of a 3 month course of once-weekly isoniazid and rifapentine (3H1P1) in South Korean health care workers (HCWs) with latent tuberculosis infection (LTBI). METHODS: HCWs who were candidates for LTBI treatment were enrolled from two tertiary referral centers between December 2016 and October 2017. From December 2016 through March 2017, HCWs who agreed were treated with the 3H1P1 regimen (3H1P1 group). Their compliance and AEs were prospectively collected. From April 2017 onward, HCWs who required LTBI treatment received 3 months of isoniazid plus rifampin (3HR group), and their medical records were retrospectively reviewed. RESULTS: During the study period, 406 HCWs were treated, 226 (55.7%) in the 3H1P1 group, and 180 (44.3%) in the 3HR group. The number of subjects with AEs was significantly greater in the 3H1P1 group (75.2% vs 56.7%, P < 0.001), in particular a flu-like syndrome (19.0% vs. 0%, P < 0.001). However, hepatotoxicity occurred less frequently in those receiving 3H1P1 (7.5% vs. 20.0%, P < 0.001). Per protocol definition, anaphylaxis developed in 1.8% of the 3H1P1 group. The overall treatment completion rate was greater in the 3H1P1 group (92.9% vs 86.7%, P = 0.036). CONCLUSIONS: The 3H1P1 regimen had a higher treatment completion rate and lower hepatotoxicity compared with the 3HR regimen. However, it resulted in a higher rate of flu-like syndromes. Additionally, a few subjects had anaphylaxis, although there were no fatalities.


Assuntos
Antituberculosos/administração & dosagem , Pessoal de Saúde , Isoniazida/administração & dosagem , Isoniazida/efeitos adversos , Tuberculose Latente/tratamento farmacológico , Proteínas de Ligação a RNA/administração & dosagem , Proteínas de Ligação a RNA/efeitos adversos , Fatores de Transcrição/administração & dosagem , Fatores de Transcrição/efeitos adversos , Anafilaxia/induzido quimicamente , Antituberculosos/efeitos adversos , Feminino , Humanos , Masculino , Saúde do Trabalhador , República da Coreia , Fatores de Tempo
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