Vernon Hoeppner

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

Appraisal of the monoclonal antibody-based competition test for the serology of tuberculosis in Indonesia

Abstract The pattern of antibody response in pulmonary tuberculosis was investigated in 100 untreated radiographic and smear-positive Indonesian patients and 34 healthy controls. The titre of antibodies with specificity matching six radiolabelled murine monoclonal probes was determined by a competitive inhibition test. Since sera from controls showed diverse antibody levels with different probes, cut-off titres at which all controls are negative were determined. Subsequently, the frequency of tuberculosis patients with antibody levels exceeding the predetermined cut-off titres was evaluated. The best result out of the six tested monoclonals was imparted by TB72 (83% positive) whilst combinations of probes increased the positive yield above 90%. The discrimination between Indonesian patients and controls was better than previous results using this test on subjects from England.

Tuberculosis in Aboriginal Canadians

Endemic tuberculosis (TB) was almost certainly present in Canadian aboriginal people (aboriginal Canadians denotes status Indians, Inuit, nonstatus Indians and metis as reported by Statistics Canada) before the Old World traders arrived. However, the social changes that resulted from contact with these traders created the conditions that converted endemic TB into epidemic TB. The incidence of TB varied inversely with the time interval from this cultural collision, which began on the east coast in the 16th century and ended in the Northern Territories in the 20th century. This relatively recent epidemic explains why the disease is more frequent in aboriginal children than in Canadian-born nonaboriginal people. Treatment plans must account for the socioeconomic conditions and cultural characteristics of the aboriginal people, especially healing models and language. Prevention includes bacillus Calmette-Guerin vaccination and chemoprophylaxis, and must account for community conditions, such as rates of suicide, which have exceeded the rate of TB. The control of TB requires a centralized program with specifically directed funding. It must include a program that works in partnership with aboriginal communities.

Bacterial genetic signatures of human social phenomena among M.tuberculosis from an Aboriginal Canadian population

Despite a widespread global distribution and highly variable disease phenotype, there is little DNA sequence diversity among isolates of Mycobacterium tuberculosis. In addition, many regional population genetic surveys have revealed a stereotypical structure in which a single clone, lineage, or clade makes up the majority of the population. It is often assumed that dominant clones are highly adapted, that is, the overall structure of M. tuberculosis populations is the result of positive selection. In order to test this assumption, we analyzed genetic data from extant populations of bacteria circulating in Aboriginal communities in Saskatchewan, Canada. Demographic parameters of the bacterial population were estimated from archival epidemiological data collected over approximately 130 years since the onset of epidemic tuberculosis in the host communities. Bacterial genetic data were tested against neutral theory expectations and the local evolutionary history of M. tuberculosis investigated by phylogenetic analysis. Our findings are not consistent with positive selection on the bacterial population. Instead, we uncovered founder effects persisting over decades and barriers to gene flow within the bacterial population. Simulation experiments suggested that a combination of these neutral influences could result in the stereotypical structure of M. tuberculosis populations. Some aspects of population structure were suggestive of background selection, and data were on the whole consistent with combined effects of population bottlenecks, subdivision, and background selection. Neutral phenomena, namely, bottlenecks and partitions within populations, are prominent influences on the evolution of M. tuberculosis and likely contribute to restricted genetic diversity observed within this species. Given these influences, a complex evolutionary model will be required to define the relative fitness of different M. tuberculosis lineages and, ultimately, to uncover the genetic basis for its success as a pathogen.

Relationship between radiological classification and the serological and haematological features of untreated pulmonary tuberculosis in Indonesia

Immunological and metabolic responses were studied in 110 patients with newly diagnosed pulmonary tuberculosis and 32 healthy controls from similar socioeconomic backgrounds. The severity of lung involvement was assessed radiologically, but this was not related to the current features of cell mediated immunity or to those of many aspects of the serological response to Mycobacterium tuberculosis. However, the patients with more extensive pulmonary tuberculosis showed higher titres of IgG2 antibody to whole killed M. tuberculosis and to the ML34 epitope shared by many species of mycobacteria. The patients with more extensive pulmonary tuberculosis showed a more marked metabolic response to infection as manifested by changes in serum levels of acute phase reactant proteins. Accordingly, the metabolic responses are considered to be more likely to prove of value in clinical monitoring of patients for severity of infection, or of reactivation of infection with M. tuberculosis, than immunological responses.

Estimating the relative impact of early-life infection exposure on later-life tuberculosis outcomes in a Canadian sample

This article seeks to elucidate effects of early-life influences on later-life tuberculosis outcomes using a dynamic computer simulation model. To illustrate the value of such a model, three research questions are considered: 1) If we implemented an intervention capable of reducing infection rates to varying degrees, what would the impact be on tuberculosis prevalence by age? 2) If there were a temporary increase in the rate of infection, what would the impact be on tuberculosis outcomes for the population? 3) If a fixed number of recently infected individuals were targeted for prophylactic treatment, who should be chosen to maximize impact?

Evaluating the Effectiveness of Contact Tracing on Tuberculosis Outcomes in Saskatchewan Using Individual-Based Modeling

Tuberculosis (TB) is a potentially fatal disease spread by an airborne pathogen infecting approximately one third of the globe. For decades, contact tracing (CT) has served a key role in the control of TB and many other notifiable communicable diseases. Unfortunately, CT is a labor-intensive and time-consuming process and is often conducted by a small and overworked nursing staff. To help improve the effectiveness of CT, we introduce a detailed, individual-based model of CT for the Canadian province of Saskatchewan. The model captures the detailed operation of TB CT, including loss to follow-up, and prophylactic and case treatment. This representation is used to assess the impact on active TB cases and TB infection prevalence of differential scoping, speed, prioritization of the CT process, and reduced loss to follow-up. Scenario results are broadly consistent with—but provide many additional insights beyond—our previously reported findings using an aggregate model. In the context of a stylized northern community, findings suggest that age- and ethnicity-prioritized schemes could improve CT effectiveness compared to unprioritized schemes by dramatically reducing TB infection and preventing on average roughly 11% (p < .0001) of active TB cases over a period of 20 years. Reducing loss to follow-up to 10% could yield 5.4% (p = .02) TB cases prevented on average with lower prevalence of TB infection, but improving the CT speed does not yield significant improvement in TB outcomes. Finally, although the work emphasized the value of social network analysis, we found that caution should be exercised in directly translating social network analysis–observed associations into prioritization recommendations.

Local epidemic history as a predictor of tuberculosis incidence in Saskatchewan Aboriginal communities

BACKGROUND Average tuberculosis (TB) incidence rates are high in Canadian Aboriginal communities, but there is significant variability within this group. OBJECTIVE To determine whether local history of post-contact TB epidemics is predictive of contemporary epidemiology among Aboriginal communities in Saskatchewan, Canada. METHODS TB incidence, age-specific morbidity patterns and rates of clustering of TB genotypes from 1986 to 2004 were compared between two groups of communities: Group 1, in which post-contact epidemics of TB were established around 1870, and Group 2, in which they were delayed until after 1920. Concomitant effects of socio-economic and geographic variables were explored with multivariate models. RESULTS Group 2 communities were characterized by higher annual incidence of TB (median 431 per 100,000 population vs. 38/100,000). In multivariate models that included socio-economic and geographic variables, historical grouping remained a significant independent predictor of community incidence of TB. Clustering of TB genotypes was associated with Group 2 (OR 8.7, 95%CI 3.3-22.7) and age 10-34 years (OR 2.5, 95%CI 1.1-5.7). CONCLUSIONS TB transmission dynamics can vary significantly as a function of a populations historical experience with TB. Populations at different stages along the epidemic trajectory may be amenable to different types of interventions.

Antituberculous drug resistance in western Canada (1993 to 1994)

OBJECTIVES: To estimate the magnitude of antituberculous drug resistance and identify prospectively the risk factors for its development in tuberculosis (TB) patients in western Canada over a one-year period.

A system dynamics model of tuberculosis diffusion with respect to contact tracing investigation

Despite great efforts to control the spread of tuberculosis (TB), the disease remains stubbornly persistent, having infected one third of the world population, and causing more than 1.5 million deaths annually. To better understand the epidemiology of TB, past modeling efforts have sought to understand how TB prevention and control policies affect infection spread in the population. This paper describes a preliminary dynamic model to evaluate the role of current contact tracing policies in managing TB transmission. Through a novel representation of contact tracing dynamics, the model supports investigation of how TB outcomes are affected by changes to the breadth and timeliness of contact investigation. Model results suggest that while successful contact tracing is self-limiting, it plays a critical role in TB control. Results also suggest that expanded breadth of contact tracing offers diminishing returns, and underscores the desirability of highly targeted contact tracing and the desirability of richer models.