Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults.

BACKGROUND: A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic effects. METHODS: In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels. RESULTS: Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval [CI], -0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, -0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were -1.1 percentage points (95% CI, -1.9 to -0.4) for all events and -1.2 percentage points (95% CI, -1.7 to -0.7) for hepatotoxic events. CONCLUSIONS: The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).

Health System Costs of Treating Latent Tuberculosis Infection With Four Months of Rifampin Versus Nine Months of Isoniazid in Different Settings.

BACKGROUND: Four months of rifampin treatment for latent tuberculosis infection is safer, has superior treatment completion rates, and is as effective as 9 months of isoniazid. However, daily medication costs are higher for a 4-month rifampin regimen than a 9-month isoniazid regimen. OBJECTIVE: To compare health care use and associated costs of 4 months of rifampin and 9 months of isoniazid. DESIGN: Health system cost comparison using all health care activities recorded during 2 randomized clinical trials. (ClinicalTrials.gov: NCT00931736 and NCT00170209). SETTING: High-income countries (Australia, Canada, Saudi Arabia, and South Korea), middle-income countries (Brazil and Indonesia), and African countries (Benin, Ghana, and Guinea). PARTICIPANTS: Adults and children with clinical or epidemiologic factors associated with increased risk for developing tuberculosis that warranted treatment for latent tuberculosis infection. MEASUREMENTS: Health system costs per participant. RESULTS: A total of 6012 adults and 829 children were included. In both adults and children, greater health system use and higher costs were observed with 9 months of isoniazid than with 4 months of rifampin. In adults, the ratios of costs of 4 months of rifampin versus 9 months of isoniazid were 0.76 (95% CI, 0.70 to 0.82) in high-income countries, 0.90 (CI, 0.85 to 0.96) in middle-income countries, and 0.80 (CI, 0.78 to 0.81) in African countries. Similar findings were observed in the pediatric population. LIMITATION: Costs may have been overestimated because the trial protocol required a minimum number of follow-up visits, although fewer than recommended by many authoritative guidelines. CONCLUSION: A 4-month rifampin regimen was safer and less expensive than 9 months of isoniazid in all settings. This regimen could be adopted by tuberculosis programs in many countries as first-line therapy for latent tuberculosis infection. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

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.

Empirical treatment of community-acquired pneumonia and the development of fluoroquinolone-resistant tuberculosis.

UNLABELLED: BACKGROUND" Fluoroquinolone (FLQ) antibiotics are not uncommonly prescribed for community-acquired pneumonia that is later proven to be pulmonary tuberculosis (TB). Such FLQ monotherapy may result in FLQ-resistant pulmonary TB. METHODS: To assess outpatient FLQ use by patients with culture-proven pulmonary TB before diagnosis, TB registries in Alberta and Saskatchewan, Canada, were linked with provincial and federal drug benefit plans. To assess FLQ resistance, a case-control study was performed. RESULTS: Of 428 patients with pulmonary TB who were covered by a drug benefit plan, 74 (17.3%) had received > or = 1 FLQ prescription during the 6 months immediately before receipt of the diagnosis. Older patients (age, >64 years) were more likely than younger patients (age, 15-64 years) to be prescribed an FLQ (P < .05). Patients who were prescribed an FLQ received a total of 103 prescriptions. Most (54 [73.0%] of 74) patients who were prescribed an FLQ received a single prescription. Most (69 [67.0%] of 103) FLQ prescriptions were written within 90 days before the diagnosis of pulmonary TB. Patients who were prescribed an FLQ were not statistically significantly more likely than matched patients who were not prescribed an FLQ (control subjects) to be infected with FLQ-resistant Mycobacterium tuberculosis. Of 148 isolates of M. tuberculosis from patients and control subjects, 3 were FLQ resistant; all of these isolates were from patients who had received multiple FLQ prescriptions. Patients who had received multiple FLQ prescriptions were more likely than patients who had received a single FLQ prescription to be infected with FLQ-resistant M. tuberculosis (15.0% vs. 0.0%; odds ratio, 11.4; P = .04). CONCLUSIONS: Outpatient FLQ use, ostensibly for community-acquired pneumonia, is not uncommon among patients with pulmonary TB, especially older patients. Single FLQ prescriptions were not associated with FLQ-resistant M. tuberculosis, whereas multiple FLQ prescriptions were associated with FLQ resistance.

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

BACKGROUND: Treatment of latent tuberculosis infection with isoniazid for 9 months is complicated by poor patient adherence and the need for close follow-up of side effects, especially hepatotoxicity. Shorter and safer regimens are needed. OBJECTIVE: To compare the frequency of adverse events and treatment completion in 2 treatment regimens for latent tuberculosis infection. DESIGN: Multicenter, randomized, open-label trial. SETTING: Tuberculosis clinics located in university hospitals in Canada, Brazil, and Saudi Arabia. PATIENTS: 847 patients without a contraindication for rifampin and requiring treatment for latent tuberculosis infection. INTERVENTION: Four months of daily rifampin therapy or 9 months of daily isoniazid therapy. MEASUREMENTS: Grade 3 to 4 drug-related adverse events resulting in drug discontinuation (primary outcome), and on-time treatment completion, grade 1 to 2 drug-related adverse events, and changes in liver enzymes and hematologic variables (secondary outcomes). RESULTS: Seventeen of 422 participants who started isoniazid therapy developed grade 3 to 4 adverse events compared with 7 of 418 who started rifampin therapy (risk difference [rifampin minus isoniazid], -2.3% [95% CI, -5% to -0.1%]; P = 0.040). Grade 3 or 4 hepatitis occurred in 16 of 422 isoniazid recipients compared with 3 of 418 rifampin recipients (risk difference, -3.1% [CI, -5% to -1%]; P = 0.003). Grade 1 or 2 adverse events attributed to study drugs occurred with similar frequency. Asymptomatic reduction in platelet and leukocyte counts were more frequent in rifampin recipients. More patients completed rifampin treatment (78%) than isoniazid treatment (60%) (difference, 18% [CI, 12% to 24%]; P < 0.001]). LIMITATION: The study did not measure efficacy, and the open-label design may increase the chance of bias in ascertainment of adverse events. CONCLUSION: Treatment of latent tuberculosis with 4 months of rifampin leads to fewer serious adverse events and better adherence than 9 months of isoniazid. These findings justify a large-scale trial to compare the efficacy of rifampin with that of isoniazid.

Tuberculosis in Canada and the United States: a review of trends from 1953 to 2015.

OBJECTIVES: To explore tuberculosis (TB) incidence in Canada and the United States from 1953 to 2015. In the most recent decade, the US incidence was lower than that of Canada. Since both countries are high income and have low TB incidence with similar TB surveillance programs, we hypothesized that rates should be similar. METHODS: TB incidence data from 1953 to 2015 were retrieved for both countries. Joinpoint regression was performed to identify change points in the trend, and direct standardization of US rates using Canadian ethnic population distribution was calculated. Adjusted rate and average annual percent change (AAPC) were estimated. RESULTS: Canada rates/100,000 were higher from 1953 to 1974 and similar from 1975 to 1985. This coincided with a change in US case definition in 1975. US rates were higher from 1986 to 1996. HIV/TB coinfection in the USA was 10.2% compared to that of Canada, 1.6%. Rates were similar from 1997 to 2004. Canada rates were again higher from 2005 to 2015. The Canada average AAPC rate in 1975-2015 was lower, - 2.9%, compared to that of the USA, - 4.1%. Foreign-born and Indigenous population proportions were 20.2% and 4.2% for Canada and 12.9% and 1.7% for the USA. The US rate adjusted to the Canada ethnic composition was 4.8 compared to the Canadian rate of 4.7. CONCLUSION: Case definition change and HIV coinfection contributed to the 1980 US rate increase. TB rates decreased in both countries from 1997, but more rapidly in the USA. The Canada proportion of foreign-born and Indigenous populations was higher. When US rates were standardized by Canada ethnic distribution, the national rates were similar. Further exploration of factors contributing to differences between these countries is needed.

The effect of neonatal bacille Calmette-Guérin vaccination on purified protein derivative skin test results in Canadian aboriginal children.

BACKGROUND: The effect that neonatal bacille Calmette-Guérin (BCG) vaccination has on tuberculin skin test (TST) results is not well evaluated in preschool children. METHODS: This was a retrospective cohort study of TST results in aboriginal children in Saskatchewan reserve communities. Records from the centralized provincial tuberculosis program were searched for aboriginal children aged 0 to 4 years during the time period 1991 to 1999. Only the first TST result reported as part of infant and preschool screening programs was considered. Children with active tuberculosis and those evaluated as part of a contact-tracing program were excluded. The BCG-vaccinated and unvaccinated groups were compared using wheal size cut points of 5 mm, 10 mm, and 15 mm. RESULTS: Data from 1,086 children with neonatal BCG vaccination and 1,867 unvaccinated children were analyzed. The rate of TST reactions was higher in vaccinated children at all ages, using a cut point of 5 mm. The rate of TST reactions was no different in vaccinated children >or= 1 year old when using a cut point of 15 mm. When using a cut point of 10 mm, the rate of TST reactions was higher at age 1 year but not different at age 4 years in the vaccinated children. CONCLUSION: The rate of TST reactions in preschool aboriginal children living on a reserve who have received neonatal BCG vaccination is affected by the cut point and age. The BCG vaccination status and age should therefore be considered when interpreting TST reactivity in the clinical assessment of aboriginal children participating in a tuberculosis control program.

The relationship between diabetes and tuberculosis in Saskatchewan: comparison of registered Indians and other Saskatchewan people.

BACKGROUND: Saskatchewan Aboriginal people are experiencing epidemics of both type 2 diabetes (T2DM) and tuberculosis (TB). The purpose of this study was to determine if a relationship exists between diabetes and TB in Saskatchewan and to establish whether there is a difference in the degree of any association between Aboriginal and non-Aboriginal people. METHODS: Utilizing Saskatchewan Health databases, TB incidence (cases identified from 1986-2001) was compared between four subpopulations identified from 1991-1995: Registered Indians (RI) with and without diabetes, and other Saskatchewan people (OSKP) with and without diabetes. RESULTS: Diabetic women aged 20-59 years had higher average annual incidence rates of TB than non-diabetic women, but within-population rate ratios of TB in diabetic versus non-diabetic women were only significant in those aged 50-59 (2.7 [CI 1.28, 5.72] in RI and 3.9 [CI 1.58, 9.67] in OSKP). No other within-population diabetic subgroup had significantly higher rates of TB. The only male diabetic group that had a higher rate of TB were RI plus OSKP men aged 50-59 years. Overall, diabetes preceded TB in 87/111 individuals with both diseases (p < 0.0001). CONCLUSIONS: Our results suggest that T2DM is a predictor for TB in Saskatchewan women aged 20-59 but particularly in RI and OSKP women aged 50-59 years. This has implications for TB screening and prevention initiatives.

Tuberculosis transmission in the Indigenous peoples of the Canadian prairies.

SETTING: The prairie provinces of Canada. OBJECTIVE: To characterize tuberculosis (TB) transmission among the Indigenous and non-Indigenous Canadian-born peoples of the prairie provinces of Canada. DESIGN: A prospective epidemiologic study of consecutively diagnosed adult (age ≥ 14 years) Canadian-born culture-positive pulmonary TB cases on the prairies, hereafter termed "potential transmitters," and the transmission events generated by them. "Transmission events" included new positive tuberculin skin tests (TSTs), TST conversions, and secondary cases among contacts. RESULTS: In the years 2007 and 2008, 222 potential transmitters were diagnosed on the prairies. Of these, the vast majority (198; 89.2%) were Indigenous peoples who resided in either an Indigenous community (135; 68.2%) or a major metropolitan area (44; 22.2%). Over the 4.5-year period between July 1st, 2006 and December 31st 2010, 1085 transmission events occurred in connection with these potential transmitters. Most of these transmission events were attributable to potential transmitters who identified as Indigenous (94.5%). With a few notable exceptions most transmitters and their infected contacts resided in the same community type. In multivariate models positive smear status and a higher number of close contacts were associated with increased transmission; adjusted odds ratios (ORs) and 95% confidence intervals (CIs), 4.30 [1.88, 9.84] and 2.88 [1.31, 6.34], respectively. Among infected contacts, being Indigenous was associated with disease progression; OR and 95% CI, 3.59 [1.27, 10.14] and 6.89 [2.04, 23.25] depending upon Indigenous group, while being an infected casual contact was less likely than being a close contact to be associated with disease progression, 0.66 [0.44, 1.00]. CONCLUSION: In the prairie provinces of Canada and among Canadian-born persons, Indigenous peoples account for the vast majority of cases with the potential to transmit as well as the vast majority of infected contacts. Active case finding and preventative therapy measures need to focus on high-incidence Indigenous communities.

The lack of association between bacille Calmette-Guerin vaccination and clustering of Aboriginals with tuberculosis in western Canada.

BACKGROUND: Tuberculosis (TB) remains a major health problem for Aboriginal people in Canada, with high rates of clustering of active TB cases. Bacille Calmette-Guerin (BCG) vaccination has been used as a preventive measure against TB in this high-risk population. OBJECTIVES: The study was designed to determine if BCG vaccination in Aboriginal people influenced recent TB transmission through an analysis of the clustering of TB cases. METHODS: A retrospective analysis of all culture-positive Mycobacterium tuberculosis cases in Aboriginal people in western Canada (1995 to 1997) was performed. Isolates were analyzed using standard methodology for restriction fragment length polymorphism and spoligotyping. RESULTS: Of 256 culture-positive Aboriginal TB cases, BCG status was confirmed in 216 (84%) cases; 34% had been vaccinated with BCG, 57% were male and 56% were living on-reserve. Patients who had been vaccinated with BCG were younger than unvaccinated individuals (mean age 32.4+/-1.65 years versus 45.0+/-1.8 years, P<0.0001). Clustering was found in 62% of cases: 59% of non-BCG vaccinated cases were clustered versus 68% of those vaccinated with BCG (P=0.16). Younger patients (younger than 60 years of age) were more likely to be clustered in the univariate analysis (P<0.01). When age, sex, province, and HIV and reserve status were controlled for, BCG vaccination was not associated with clustering (OR 1.3, 95% CI 0.7 to 2.6). CONCLUSIONS: BCG vaccinated Aboriginal people were no less likely to have active TB from recently transmitted disease. BCG vaccination appears to have limited value in preventing clustering of TB cases within this high-risk community.

Pharmacokinetics of antituberculosis medications delivered via percutaneous gastrojejunostomy tube.

We treated a 23-year-old aboriginal woman with drug-resistant pulmonary tuberculosis (TB). She experienced intolerance to her oral anti-TB medications, had subtherapeutic drug levels, and failed to respond to treatment. She then was effectively treated with percutaneous gastrojejunostomy tube (PGJT) administration of drugs. We present our data on the serum drug levels of rifampin, para-aminosalicylic acid, and levofloxacin after PGJT administration, and compare these values to published levels for oral administration of these drugs. In our patient, serum drug levels peaked and began to decline earlier than in the published data for oral administration of the same drugs.

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.

Marked disparity in the epidemiology of tuberculosis among Aboriginal peoples on the Canadian prairies: the challenges and opportunities.

BACKGROUND: While it is established that Aboriginal peoples in the prairie provinces of Canada are disproportionately affected by tuberculosis (TB), little is known about the epidemiology of TB either within or across provincial borders. METHODS: Provincial reporting systems for TB, Statistics Canada censuses and population estimates of Registered Indians provided by Aboriginal Affairs and Northern Development Canada were used to estimate the overall (2004 to 2008) and pulmonary (2007 to 2008) TB rates in the prairie provinces. The place of residence at diagnosis of pulmonary TB cases in 2007 to 2008 was also documented. RESULTS: The age- and sex-adjusted incidence of TB in Registered Indians was 52.6 per 100,000 person-years, 38 times higher than in Canadian-born 'others'. Incidence rates in Registered Indians were highest in Manitoba and lowest in Alberta. In Alberta and Saskatchewan, on-reserve rates were more than twice that of off-reserve rates. Rates in the Métis and Registered Indians were similar in Saskatchewan (50.0 and 52.2 per 100,000 person-years, respectively). In 2007 to 2008, approximately 90% of Canadian-born pulmonary TB cases in the prairie provinces were Aboriginal. Outside of one metropolitan area (Winnipeg, Manitoba), most Registered Indian and Métis pulmonary TB cases were concentrated in a relatively small number of communities north of the 53rd parallel. Rates of pulmonary TB in 11 of these communities were >300 per 100,000 person-years. In Manitoba, 49% of off-reserve Registered Indian pulmonary cases were linked to high-incidence reserve communities. INTERPRETATION: The epidemiology of TB among Aboriginal peoples on the Canadian prairies is markedly disparate. Pulmonary TB is highly focal, which is both a concern and an opportunity.