Relationship of anti-tuberculosis drug-induced liver injury and genetic polymorphisms in CYP2E1 and GST

ABSTRACT Setting: Treatment of tuberculosis (TB) can result in Drug-Induced Liver Injury (DILI) since hepatotoxic metabolites are formed during the biotransformation of isoniazid (INH).DILI can be related to the genetic profile of the patient. Single nucleotide polymorphisms in the CYP2E1 gene and GSTM1 and GSTT1 deletion polymorphisms have been associated with adverse events caused by INH. Objective: To characterize the genetic polymorphisms of CYP2E1, GSTT1 and GSTM1 in TB carriers. Design: This is an observational prospective cohort study of 45 patients undergoing treatment of TB. PCR-RFLP and multiplex-PCR were used. Results: The distribution of genotypic frequency in the promoter region (CYP2E1 gene) was: 98% wild genotype and 2% heterozygous. Intronic region: 78% wild genotype; 20% heterozygous and 2% homozygous variant. GST enzyme genes: 24% Null GSTM1 and 22% Null GSTT1. Patients with any variant allele of the CYP2E1 gene were grouped in the statistical analyses. Conclusion: Patients with the CYP2E1 variant genotype or Null GSTT1 showed higher risk of presenting DILI (p = 0.09; OR: 4.57; 95% CI: 0.75-27.6). Individuals with both genotypes had no increased risk compared to individuals with one genotype.

Prevalence of depression among patients with presumptive pulmonary tuberculosis in Rio de Janeiro, Brazil

Objective: To estimate the prevalence of major depressive episode (MDE) in patients with presumptive pulmonary tuberculosis (pre-PTB, defined by cough lasting ≥ 3 weeks) and compare it between patients with pulmonary tuberculosis (PTB) and without PTB. Methods: Patients with pre-PTB (n=260) were screened for depression using the Patient Health Questionnaire (PHQ-9). Those individuals with scores ≥ 10 were subsequently assessed with the depression module of the Mini International Neuropsychiatric Interview (MINI-Plus) to confirm diagnosis. Associations of categorical variables with PTB and MDE were calculated using the chi-square test and OR. Results: PTB was confirmed in 98 patients (37.7%). A high proportion of both groups (active PTB and no PTB) screened positive for depression (60.2 vs. 62.1%, respectively). Among 159 patients who screened positive for depression, a subset of 97 (61.0%) were further evaluated with the MINI-Plus; current MDE was confirmed in 54.6% (53/97). On univariate and multivariate analysis, female sex was the only factor associated with the diagnosis of current MDE (p = 0.04). Conclusion: The prevalence of MDE was high among individuals with prolonged respiratory symptoms, independent of PTB diagnosis. This is consistent with other studies of depression in primary care in Brazil.

Mycobacterium tuberculosis strains of the Beijing genotype are rarely observed in tuberculosis patients in South America

The frequency of the Beijing genotype of Mycobacterium tuberculosis as a cause of tuberculosis (TB) in South America was determined by analyzing genotypes of strains isolated from patients that had been diagnosed with the disease between 1997 and 2003 in seven countries of the subcontinent. In total, 19 of the 1,202 (1.6 percent) TB cases carried Beijing isolates, including 11 of the 185 patients from Peru (5.9 percent), five of the 512 patients from Argentina (1.0 percent), two of the 252 Brazilian cases (0.8 percent), one of the 166 patients from Paraguay (0.6 percent) and none of the samples obtained from Chile (35), Colombia (36) and Ecuador (16). Except for two patients that were East Asian immigrants, all cases with Beijing strains were native South Americans. No association was found between carrying a strain with the Beijing genotype and having drug or multi-drug resistant disease. Our data show that presently transmission of M. tuberculosis strains of the Beijing genotype is not frequent in Latin America. In addition, the lack of association of drug resistant TB and infection with M. tuberculosis of the Beijing genotype observed presently demands efforts to define better the contribution of the virulence and lack of response to treatment to the growing spread of Beijing strains observed in other parts of the world.

Fatores de risco associados à tuberculose pulmonar paucibacilar em pacientes atendidos em centros de saúde da cidade do Rio de Janeiro, Brasil / Risk factors for pulmonary tubercolosis among negative sputum smear patientes attended in community health centers in Rio de Janeiro, Brasil

Objetivo: identificar fatores de risco associados à ocorrência de tuberculose pulmonar (TBP) paubacilar. Métodos: estudo transversal avaliando o resultado dos exames bacteriológicos de pacientes suspeitos de TBP atendidos em onze Centros Municipais de Saúde (CMS) na cidade do Rio de Janeiro, Brasil. Resultados: entre 1°. de Julho e 31 de Dezembro de 1996 foram entrecistados 423 pacientes com diagnóstico clínico-radiológico de TBP ativa. Noventa e quatro por cento (397/423) forneceram pelo menos duas amostras de escarro espontâneo para análise. A cultura foi positiva para Mycobacterium tuberculosis em 84% (333/397), com baciloscopia positiva em 64% (213/333) e baciloscopia negativa em 36% (121/333). Não se observou associação entre lesão pulmonar paucibacilar e gênero, vacinação com BCG, tempo de sintomas respiratórios, admissão prévia em prisão ou em asilos nos últimos 24 meses, comportamento sexual, uso de droga injetável, tratamento anti-TB no passado, contado com paciente tuberculoso pulmonar bacilífero nos últimos 12 meses, condições de moradia e residir em determinada área pragmática. Entretanto, a lesão pulmonar paucibacilar esteve associada significamente a escolaridade superior de 4 anos (1,87; 0,98-3,55; p=0,05), admissão prévia em hospital nos últimos 24 meses (2,53; 1,39-4,60; p=0,001) e sorologia positiva para infecção pelo vírus da imunodeficiência humana (HIV) (4,48;1,74-11,81; p=0,006). Conclusão: tuberculose pulmonar paubacilar deve ser considerada um problema em centros urbanos com elevada co-infecção /TB e HIV, onde a cultura para micobactéria e a testagem anti-HIV dvem ser disponibilizados para os pacientes com tais características.

Objective: to identify risk factors for negative sputum acid -fast bacilli smear among pulmonary tuberculosis (PTB) patients in CHC. Methods: cross sectional study, performed through bacteriological evaluation of mear negative/culture positive PTB cases attended in eleven Community Health Centers (CHC) in Rio de Janeiro City, Brazil. Results: from July 1st to December 31th, 1996, 423 patients with active PTB were interviewed and 397 had their spontaneous sputum evaluated. Afterwards 333 patients presented positive culture results for mycobacterium tuberculosis and among them 121 (36.2%) were smear negative. The agreement results (kappa value) between the first and the second sputa for smear acid-fast bacilli was moderate (0.49) but for culture was fair (0.31). No statistically significant association were identified among smear negative/culture positive results and be following variables: gender, BCG vaccionation, length of respiratory symptoms, previous admission at jails or at shelters in the previous 24 months, sexual behavior, intravenous drug use, anti-TB treatment in the past, contact with infectious PTB patients in the previous 12 months, living conditions and planning City Areas residence. Nevertheless, smear negative/culture positive PTB were observed as associated to 4.60; p=0.001) and, seropositivity for human immunodeficiency virus (HIV) (4.48; 1.74-11.81; p=0.006). Conclusion: Smear negative PTB should be considered a significant clinical problem, particularly in settings affected by dual HIV/TB epidemic. A wider availability of TB culture facilities should be pursued as well HIV testing for PTB suspect smear negative. So, to improve TB control in developing countries is urgently needed to update guidelines by both TB Control Program and AIDS Control Program.

Clinical presentation and survival of smear-positive pulmonary tuberculosis patients of a University General Hospital in a developing country

From January 1995 to August 1997 we evaluated prospectively the clinical presentation, laboratory findings and short-term survival of smear-positive pulmonary tuberculosis (TB) patients who sought care at our hospital. After providing informed, written consent, the patients were interviewed and laboratory tests were performed. Information about survivorship and death was collected through September 1998. Eighty-six smear-positive pulmonary TB patients were enrolled; 26.7 percent were HIV-seropositive. Seventeen HIV-seronegative pulmonary TB patients (19.8 percent) presented chronic diseases in addition to TB. In the multiple logistic regression analysis a CD4+ cell count <= 200 cell/mm was independently associated with HIV seropositivity. In the Cox regression model, fitted to all patients, HIV seropositivity and age > or = 50 years were independently associated with decreased survival. Among HIV-seronegative persons, the presence of an additional disease increased the risk of death of almost six-fold. Use of antiretroviral drugs was associated with a lower risk of death among HIV-seropositive smear-positive pulmonary TB patients (RH = 0.32, 95 percent CI 0.10-0.92). In our study smear-positive pulmonary TB patients had a low short-term survival rate that was strongly associated with HIV infection, age and co-morbidities. Therapy with antiretroviral drugs reduced the short-term risk of death among HIV-seropositive patients after TB diagnosis

Efeitos adversos hepáticos durante o tratamento para tuberculose em hospital geral referência para Aids, Rj, Brasil / Hepatic adverse efects anti-tuberculosis tratment in a geral hospital, Rio de Janeiro, Brasil

Introdução: a frequência de efeitos adversos hepáticos e os fatores associados com a sua ocorrência em um hospital universitário referência para Aids e tuberculose não é completamente conhecida. Métodos: foi realizado um estudo tipo caso-controle com o objetivo de medir prevalência de efeitos hepáticos adversos (EAH) em pacientes sob tratamento medicamentoso anti-tuberculose (TB) e de fatores associados à sua ocorrência. Resultados: foram analisados 588 prontuários médicos de pacientes que fizeram uso de esquema anti-TB com isoniazida, rifampicina e pirazinamida, acrescido ou não de etambutol, atendidos no período de Janeiro de 1994 a dezembro de 1995. EAH foi observado em 40 (6,8%) casos. Foram pareados 200 casos para o grupo controle. Na análise univariada dos grupos caso e controle não houve diferença estatisticamente significativa entre a ocorrência de EAH e os seguintes parâmetros: a idade, gênero esquema inicial de tratamento anti-TB, a história prévia de hepatopatia e/ou presença de alcoolismo. Entretanto, a ocorrência de EAH esteve significamente associada a hospitalização no momento do diagnóstico da TB, a presença de síndrome de imunodeficiência adquirida (SIDA/AIDS), a forma disseminada da TB, a apresentação radiográfica atípica da TB pulmonar, a sorologia positiva para hepatite a vírus B e/ou C, e a evolução clínica desfavorável ou tratamento. Na análise multivariada, somente a hospitalização e o diagnóstico de SIDA permaneceram associados significantemente a EAH. Conclusões: em um hospital Universitário, referência para AIDS e TB, a presença de Aids, de imagem radiológica de TB pulmonar atípica e a TB disseminada estão associados a uma maior taxa de EAH.

Introduction: the frequency of hepatic adverse effects and factors associated with its occurrence in an Universitary Hospital, reference for AIDS and tuberculosis (TB) is not completely known. Methods: a case-control study was conducted to assess the prevalence of hepatic adverse effects of patients using anti-TB treatment and the factors associated with its occurrence. Results: 588 medical charts of TB patients receiving anti-TB treatment with isoniazid, ripampin, pirazinamide, with or without ethambutol attendent betwee January, 1994 and December, 1995 were analyzed. HAE was observed in 40 (6.8%) patients. Two-hundred patients were included as control group. Using univariate analysis to evaluate case and control groups no statistically difference was found between HAE and the following variables: age, gender, anti-TB treatment, liver disease in the past and/or alcohol abuse. However, HAE was significantly associated with hospitalization at the time that TB diagnosis was made, immunosupression, disseminated TB, radiographic atypical presentation of pulmonary TB, seropositivy for B and C hepatitis and clinical unfavorable evolution. In multivariate analysis only hospitalization and Aids were associated to HAE. Conclusion: in a University Hospital, reference for TB and AIDS, the presence of Aids, radiographic atypical presentation of pulmonary TB and disseminated form of TB were associated with higher prevalence of HAE.

Avaliação do desempenho de um teste sorológico rápido utilizando quatro antígenos para o diagnóstico de tuberculose pulmonar / Evaluation of a rapid serologic test with four antigens for the pulmonary tuberculosis diagnosis

Introdução: Os testes sorológicos não fazem parte da rotina da investigação diagnóstica da tuberculose pulmonar. Métodos: Um teste imunocromatográfico (ICT-TB) utilizando quatro diferentes antígenos purificados para a pesquisa de anticorpo IgG foi avaliado em 268 amostras de soro de 69 casos de tuberculose pulmonar, 41 de doença não tuberculosa, 12 de sequela de tuberculose, 107 controles saudáveis e 39 contatos domiciliares de tuberculose pulmonar. Resultados: A sensibilidade foi de 54% e a especificidade 86%. Entre os contatos domiciliares o ICT-TB foi positivo em 10%. Conclusão: concluímos que a sensibilidade e a especificidade do teste sorológico ICT-TB conferiu a ele pouco valor para o diagnóstico de tuberculose pulmonar na nossa amostra.

Introduction: Serologic tests are not routinely used for the diagnostic investigation of pulmonary tuberculosis. Methods: An immunochromatographic test (ICT-TB) using four different purified antigens against an IgG antibody was evaluated in 268 serum samples of 69 patients with pulmonary tuberculosis, 41 with a nontuberculous disease, 12 subjects with healed pulmonary tuberculosis and 107 healthy volunteers and 39 close contacts of pulmonary tuberculosis patients. Results: Sensitivity was 54% and specificity 86%. Among close contacts, ICT-TB was positive in 10%. Conclusion: We concluded that sensitivity and specificity of ICT-TB test made it a poor diagnostic tool for pulmonary tuberculosis diagnosis in our sample.

Taxa de abandono do tratamento antituberculose / Non-adherence rate of anti-tuberculosis treatment

Introdução: São raros os estudos sobre os fatores associados à ocorrência do abandono do tratamento antituberculose (TB) em pacientes atendidos em hospitais nos países em desenvolvimento, aonde, usualmente, inexistem atividades de controle de TB. Objetivos: Identificar fatores associados à ocorrência de abandono do tratamento anti-TB em pacientes atendidos num hospital geral, referência para AIDS. Desenho: estudo caso-controle. Métodos: os pacientes que iniciaram tratamento anti-TB, no período de 01 de janeiro a 31 de dezembro de 1997, foram considerados ilegíveis. Paciente caso foi definido como o indivíduo que não retornou para receber medicação decorridos 60 dias depois de sua última consulta médica. Análise logística condicional foi utilizada para identificar as características que, independentemente, estavam associadas à ocorrência de abandono do tratamento. Resultados: 228 pacientes foram registrados como TB no período. Após a revisão dos prontuários médicos e visita em 189 domicílios, o abandono do tratamento, de 28,9%, baixou para 20,2%. Na análise multivariada, os fatores associados ao abandono foram: a) não fornecimento de cartão retorno (OR =0.099; IC 0.008-1.2; p = 0.07), b) não sentir-se a vontade na consulta médica (OR = 0,16; IC 0.33 - 0.015; p = 0.001) e, c) pressão arterial não foi medida (OR = 0.072; IC 0.036-0,79; p= 0.024). Comentários: Provavelmente, em hospitais gerais na cidade do Rio de Janeiro, torna-se necessária a implementação de programas de controle de TB. Tais programas devem utilizar estratégias específicas para o tipo de paciente atendido visando menores taxas de abandono e de morbi/mortalidade.

Predictive value of the acid fast smear for detection of Mycobacterium tuberculosis in respiratory specimens in a Reference Center of HIV/Aids in Rio de Janeiro, Brazil

In order to evaluate the predictive value of acid fast bacilii (AFB) smear for the diagnosis of Mycobacterium tuberculosis in respiratory specimens in a setting with a high prevalence of Aids and an unknown prevalence of nontuberculous mycobacteria (NTM), we retrospectively examined specimens cultured for mycobacteria between 1 September 1993 and 30 September 1994 and medical records of patients with positive culture in a General Hospital, Aids reference in Rio de Janeiro, Brazil. Seventy three per cent (1517/2077) of samples were respiratory specimens and mycobacteria were recovered from 20.6 percent (313/1517) of these. M. tuberculosis was identified in 94.2 percent (295/313) and NTM in 5.8 percent (18/313). The yield of positive AFB smear and of positive culture was 6.1 pecent (93/1517) and 20.6 percent (313/1517), respectively. The positive predictive value (PPV) of AFB for M. tuberculosis was 98.4 percent in expectorated sputum and 96.4 percent in bronchoalveolar lavage. Forty four percent (130/295) of specimens with positive culture for M. tuberculosis and 66.7 percent (12/18) for NTM were from patients HIV positive. The conclusion was that in our study population, the PPV of AFB for M. tuberculosis in respiratory specimens was high and the prevalence of NTM was low despite the high prevalence of HIV positive

A co-infecçäo TB/HIV / Infection Tuberculosis/HIV

Os autores apresentam uma atualizaçäo do impacto da infecçäo pelo HIV na apresentaçäo clínica, no diagnóstico e no tratamento da tuberculose (TB). Analisam ainda a patogênese da TB e a resistência às drogas neste grupo de pacientes. Finalizam discutindo as pricipais interaçöes medicamentosas e as recomendaçöes de tratamento preventivo para os pacientes com HIV que tiveram contato com a bacilo da TB

Use of the 2,3-diacyl-trehalose and the purified protein derivative in the serodiagnosis of tuberculosis in AIDS

The effect of the human immunodeficiency virus (HIV) infection on IgG production against purified protein derivative (PPD) and 2,3-diacil-trehalose (SL-IV) was investigated by an enzyme-linked immunosorbent assay (ELISA) test. Comparison between the antigens showed that immunocompetent patients produce preferentially antibodies to SL-IV than to PPD (73.3 por cento versus 63.3 por cento). Combination of the these results showed an increase of the sensitivity to 80 por cento, which decreased over the spectrum of immunodepression caused by HIV. In the tuberculous HIV seropositive group the sensitivities of SL-IV and PPD were 36.4 por cento versus 40 por cento and 0 por cento versus 22.2 por cento in the tuberculosis/acquired immunodeficiency syndrome (TB/AIDS) group. Combination of these results gave respectively 54.5 por cento and 20 por cento, showing that serological tests have limited value for diagnosis of tuberculosis in HIV infected patients. High antibody levels were observed in HIV seropositive asymptomatic group, but only two individuals were positive for both antigens. In the follow up, one of them tuberculous lymphadenitis, indicating that further work is needed to access the value of serological tests in predicting tuberculosis in HIV infected individuals.