Anete Trajman

Adverse events with 4 months of rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis infection: a randomized trial.

Context Isoniazid is hepatotoxic and must be taken for 9 months by patients with latent tuberculosis infection. Contribution In this trial comparing 4 months of rifampin therapy with 9 months of isoniazid therapy, patients who took rifampin had fewer adverse events and were more likely to complete treatment. Caution The investigators did not compare efficacy of the 2 treatments. Implication These safety and adherence data justify a larger trial to compare the efficacy of rifampin and isoniazid for latent tuberculosis infection. The Editors After detection and treatment of active tuberculosis cases, the next priority in tuberculosis control is the diagnosis and treatment of persons with latent tuberculosis infection (LTBI) who are at increased risk for active tuberculosis. Treatment of such individuals can provide individual and public health benefits (14). The current recommended standard therapy in most countries is 9 months of isoniazid therapy (4, 5). The drug has more than 90% efficacy if taken the entire 9 months (6), but completion rates under routine practice conditions are about 50% or less (79). Another important disadvantage of isoniazid therapy is the occurrence of serious adverse events, particularly drug-induced hepatitis (10). Drug-induced hepatitis was not recognized as a complication of isoniazid therapy in early trials involving more than 50000 participants (11), but it was a frequent and potentially severe problem after isoniazid was recommended for tuberculosis prevention in 1970 (12) and was subsequently used more widely (13, 14). This complication makes close monitoring necessary, increasing costs. These problems have stimulated considerable interest in finding shorter and safer regimens for the treatment of LTBI (15). One alternative, 2 months of daily rifampinpyrazinamide, was recommended in 2000 (4) on the basis of evidence from several trials (1618). However, subsequent reports of severe and fatal hepatotoxicity (19, 20) have rendered this regimen unacceptable for most patients. The remaining recommended alternative is 4 months of daily rifampin, but published outcome information is limited and systematic reviews on this regimen have not been done. In the only published trial that compared 3 months of daily rifampin therapy with 6 months of daily isoniazid therapy in 332 patients, efficacy and safety were similar (21). In 2 uncontrolled case series, 6 months of daily rifampin was well tolerated in 49 homeless persons in Boston (22) and in 157 high school students in California (23). Two nonrandomized studies have described better treatment completion and less hepatotoxicity with 4 months of rifampin than with 9 months of isoniazid under program conditions (8, 9). However, rifampin has been reported to cause other problemsnotably drug interactions (24), a flu-like syndrome (24), and rare hematologic problems (immune-mediated thrombocytopenia and anemia) (25). Also, development of drug resistance is a theoretical concern. Given the experience with isoniazid and 2 months of rifampinpyrazinamide, both of which were thought to be safe on the basis of early studies but caused deaths when used more widely, we designed a multicenter, randomized trial to compare the frequency of serious adverse events and treatment completion rates in patients given 4 months of daily rifampin or 9 months of daily isoniazid for LTBI. Methods Setting, Study Sample, and Randomization This open-label trial was conducted at 9 university-affiliated hospitals: 7 in Canada and 1 each in Saudi Arabia and Brazil. We considered patients to be eligible if they were age 18 years or older and had a documented tuberculin skin test that met the criteria for a positive result (5) and if their primary treating physician initially recommended isoniazid for LTBI following national or international guidelines (4, 26, 27). Patients were ineligible if they were contacts of isoniazid- or rifampin-resistant cases (28), were allergic to isoniazid or rifamycins, or were taking concomitant medications that had clinically significant potential drug interactions that could not be easily managed. To ensure a realistic assessment of adverse events, we considered all other adults eligible, regardless of age or additional risk factors for adverse events, as long as their treating physician felt that therapy for LTBI was indicated. A Web-based program verified eligibility and randomly assigned participants (by using a random-number generator), after they signed informed consent, to 4 months of daily rifampin (10 mg per kg of body weight, up to 600 mg/d) or 9 months of daily isoniazid (5 mg/kg, up to 300 mg/d) in blocks of varying size, stratified by center. A team at the University of Sherbrooke, Sherbrooke, Quebec, Canada, prepared the Web-based program and allocation sequence. Study personnel in the different centers enrolled and registered participants, obtained consent, verified assignment, and administered treatment. All study participants signed informed consent before randomization. Institutional review boards in each participating institution approved the study. Processes and Outcomes Patients were followed in routine fashion by their usual treating physician, who made all management decisions, including discontinuation of therapy. By study protocol, all patients had blood tests (complete blood count, liver aminotransferase levels [aspartate aminotransferase and alanine aminotransferase], and bilirubin level) before and after 1 and 2 months of therapy and were seen every month for the first 4 months of therapy and (for those receiving 9 months of isoniazid) at physician discretion every 6 weeks thereafter. Adverse events could be detected at any time throughout the course of therapy. When the treating physician suspected an adverse event and therapy was suspended, investigations, including blood tests, were performed according to study protocol. The treating physician decided whether to discontinue, rechallenge with, or restart the study therapy, although the protocol specified that participants with grade 3 or 4 adverse events (Appendix Table 1) were not to be rechallenged. When all investigations were complete, and if therapy was permanently discontinued in response to the event, the patients clinical course and results of investigations and rechallenge (if any) were made available to a 3-member independent review panel who were blinded to study drug. If therapy was resumed (for example, after resolution of a grade 1 or 2 adverse event) and the event did not recur, the patients information was not reviewed by the panel. Appendix Table 1. Grading System for Adverse Events Used by Independent Panel Each review panel member had substantial experience and expertise in clinical and epidemiologic aspects of tuberculosis, and each independently judged the type and severity of the adverse events and its likely relationship to the study drug. We graded adverse events as recommended by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 2.0 (29) (Appendix Table 1). Liver aminotransferase levels that increased to 5 to 10 or 3 to 10 times the upper limit of normal in the presence of compatible symptoms met criteria for grade 3 hepatotoxicity, whereas those that exceeded 10 times the upper limit of normal met criteria for grade 4 toxicity (30). In the event of disagreement, panel members re-reviewed the information; if disagreement remained, the majority opinion was used. The studys primary outcome was the frequency of grade 3 or 4 adverse events that resulted in study drug discontinuation and were judged by the review panel to be probably related to the drug (Appendix Table 1). The studys secondary outcome was on-time treatment completion, defined as taking more than 80% of doses within a maximum of 150 days for 4 months of rifampin or 301 days (43 weeks) for 9 months of isoniazid. Doses taken were measured with the Medical Event Monitoring System, an electronic device in the pill container cap that recorded the date and time of bottle opening (APREX Corporation, Fremont, California). Other secondary outcomes included grade 1 or 2 adverse events that were judged by the independent panel to be probably study drugrelated and resulted in permanent discontinuation of therapy and changes in liver aminotransferase levels and leukocyte and platelet counts before and 1 and 2 months after beginning treatment. Statistical Analysis We initially calculated a trial sample size by assuming that the frequency of serious adverse events would be significantly higher with rifampin. We calculated that 630 patients per group would provide 90% power (2-sided = 0.05) to detect a difference between frequency of adverse events of 9% and 4% in the rifampin and isoniazid groups, respectively. This estimate also accounted for an anticipated 15% dropout rate during therapy. Because we were unsure about the actual frequency of adverse events with rifampin, we also noted that 630 patients per group provided 80% power to detect a statistically significant difference between rates of adverse events in the 2 groups if the event rates were 2% and 5% in the rifampin and isoniazid groups, respectively, and the dropout rate was 15%. To ensure safety of study participants, we planned 3 interim analyses for when 25%, 50%, and 75% of the planned total sample size had been randomly assigned. The data safety and monitoring board, blinded to the identity of the 2 groups, reviewed the overall rate of serious adverse events in each group. If the rate was significantly higher in 1 group, then the results were unblinded and the data safety and monitoring board made a decision, based on clinical judgment and statistical input, about stopping or continuing the trial. We used an value of 0.01 to account for multiple testing (31). We reported summary baseline liver function test results for each group as the ratio of each patients test result to the upper li

Óbitos atribuídos à tuberculose no Estado do Rio de Janeiro

INTRODUCAO:Em 1998, o Rio de Janeiro era o estado de maior incidencia e mortalidade por tuberculose do Brasil. O Sistema de Informacao de Agravos de Notificacao em Tuberculose (SINAN-TB-RJ) nao era confiavel. OBJETIVO: Utilizar o estudo dos obitos por tuberculose como instrumento de avaliacao do programa de controle de tuberculose. METODO: Foram realizados estudos descritivos do SINAN-TB-RJ e do Sistema de Informacao de Mortalidade em tuberculose do Rio de Janeiro (SIM-TB-RJ) e os dois bancos de dados foram cruzados utilizando-se o programa Reclink. Foi tambem realizado um estudo baseado em prontuarios dos cinco hospitais onde ocorreu o maior numero de obitos por tuberculose. RESULTADOS: Em 1998 foram registrados no SINAN-TB-RJ 16.567 casos de tuberculose em maiores de 14 anos. A forma pulmonar estava presente em 13.989 (84,5%) casos, dos quais 8.223 (56,8%) tiveram baciloscopia positiva. A sorologia anti-HIV, recomendada para todos os pacientes com tuberculose, foi solicitada em apenas 4.141 (25%) casos. No SIM-TB-RJ foram registrados 1.146 obitos, dos quais 478 (41,7%) casos haviam sido notificados no SINAN-TB-RJ, entre 1995 e 1998. Dos 302 prontuarios estudados, em 154 (50,9%) o periodo de internacao foi inferior a 10 dias. O tempo entre o inicio dos sintomas e o diagnostico foi superior a 60 dias em 143 (47,3%) pacientes. Dos 125 pacientes em re-tratamento, para apenas 43 (34,4%) foi prescrito o esquema RHZE recomendado pelo Ministerio da Saude. CONCLUSAO: O estudo demonstra que a tuberculose e sub-notificada, o diagnostico e tardio, a utilizacao dos exames laboratoriais recomendados e baixa e as normas do Ministerio da Saude nao sao cumpridas.

Fatores associados ao atraso no diagnóstico da tuberculose pulmonar no estado do Rio de Janeiro

OBJECTIVE: To estimate the total time elapsed between symptom onset and diagnosis of pulmonary tuberculosis (patient delay plus health care system delay), analyzing the factors associated with delayed diagnosis in the state of Rio de Janeiro, Brazil. METHODS: We conducted a questionnaire-based survey involving 218 pulmonary tuberculosis patients treated for two months at 20 health care clinics and 3 hospitals in eight cities within the state of Rio de Janeiro. We collected socioeconomic and demographic data, as well as data regarding the health care system and the medical history of the patients. RESULTS: The median time elapsed from the onset of symptoms to diagnosis was 68 days (interquartile range [IQR]: 35-119 days). The median patient delay (time from symptom onset to initial medical visit) was 30 days (IQR: 15-60 days), and the median health care system delay (time from initial medical visit to diagnosis) was 21 days (IQR: 8-47 days). A cut-off point of 21 days was adopted. The factors independently associated with patient delay were female gender, cough, and unemployment [adjusted OR (95% CI) = 2.7 (1.3-5.6); 11.6 (2.3-58.8); and 2.0 (1.0-3.8), respectively], whereas only female gender was independently associated with health care system delay (OR= 3.2; 95% CI: 1.7-6.0). CONCLUSIONS: Delayed diagnosis of pulmonary tuberculosis remains a problem in Rio de Janeiro, increasing the risk of transmission and mortality, that risk being greater for women and the socioeconomically disadvantaged. Patients might not recognize the significance of chronic cough as a health problem. Tuberculosis education programs targeting women might improve this situation.

Knowledge about STD/AIDS and sexual behavior among high school students in Rio de Janeiro, Brazil

The incidence of AIDS and other sexually transmitted diseases (STDs) is increasing among adolescents. In order to better understand high-risk sexual behavior among students, a cross-sectional study based on a self-answered anonymous questionnaire was conducted in 10 public and private high schools in Rio de Janeiro, Brazil. Data were obtained on sociodemographics, knowledge of STD/AIDS, and sexual behavior. Among 945 students aged 13-21, 59% were sexually initiated, and the median age at first sexual intercourse was 15 years (range: 7-19). Although 94% reported being aware of the need for condom use for protection, only 34% informed always using condoms during sex. Low family income was associated with unsatisfactory knowledge (OR = 9.40; 95% CI = 6.05-14.60) and inconsistent condom use (OR = 11.60; 95% CI = 5.54-24.30). However, unsatisfactory knowledge was not associated with inconsistent condom use. School-based educational programs should focus on sexual behavior more than on transmission of knowledge, as well as targeting low-income students.

Tuberculose e gênero em um município prioritário no estado do Rio de Janeiro

The objective of this study was to compare gender differences among tuberculosis patients in a city with a high incidence of tuberculosis. This was a cross-sectional questionnaire-based study involving 560 tuberculosis patients (373 males and 187 females). Sociodemographic and clinical data, as well as data related to diagnostic criteria and treatment outcome, were collected (from the questionnaires and medical records) and subsequently compared between the genders. The median time from symptom onset to diagnosis was 90 days. There were no differences between the genders regarding the clinical presentation, diagnostic criteria, previous noncompliance with treatment, time from symptom onset, number of medical appointments prior to diagnosis, or treatment outcome. Gender-specific approaches are not a priority in Brazil. However, regardless of patient gender, the delay in diagnosis is a major concern.

Impact of treatment completion, intolerance and adverse events on health system costs in a randomised trial of 4 months rifampin or 9 months isoniazid for latent TB

Rationale Treatment for latent tuberculosis infection with isoniazid for 9 months (9INH) has poor completion and serious adverse events, while treatment for 4 months with daily rifampin (4RIF) has significantly higher completion and fewer adverse events. Objectives To compare the health system costs of 4RIF and 9INH. Methods In a randomised trial conducted in five Canadian centres, one Brazilian and one Saudi Arabian centre, consenting subjects were randomised to receive 4RIF or 9INH. Health system costs were estimated from healthcare utilisation including scheduled and unscheduled visits, investigations and drugs. All activities for all subjects were evaluated using financial information from 2007 from the Montreal Chest Institute. Costs were expressed in Canadian dollars. Results Total health system cost per patient allocated to 4RIF was

Administrative measures for preventing Mycobacterium tuberculosis infection among healthcare workers in a teaching hospital in Rio de Janeiro, Brazil

854 compared with

Preditores dos desfechos do tratamento da tuberculose

970 for 9INH (p<0.0001). The average cost per patient for the 328 of 420 (78%) who completed 4RIF therapy was

Proposta de vigilância de óbitos por tuberculose em sistemas de informação

1094 compared with

Cost-Effectiveness of Quantiferon®-TB Gold-In-Tube Versus Tuberculin Skin Testing for Contact Screening and Treatment of Latent Tuberculosis Infection in Brazil

1625 for the 254 of 427 (60%) completing 9INH (p<0.0001). Costs were modestly increased in patients with minor intolerance and substantially increased if the treating physician stopped treatment because of possible adverse events. Total costs related to management of adverse events with 9INH were