Cost-effectiveness of Latent Tuberculosis Infection Screening before Immigration to Low-Incidence Countries.

Prospective migrants to countries where the incidence of tuberculosis (TB) is low (low-incidence countries) receive TB screening; however, screening for latent TB infection (LTBI) before immigration is rare. We evaluated the cost-effectiveness of mandated and sponsored preimmigration LTBI screening for migrants to low-incidence countries. We used discrete event simulation to model preimmigration LTBI screening coupled with postarrival follow-up and treatment for those who test positive. Preimmigration interferon-gamma release assay screening and postarrival rifampin treatment was preferred in deterministic analysis. We calculated cost per quality-adjusted life-year gained for migrants from countries with different TB incidences. Our analysis provides evidence of the cost-effectiveness of preimmigration LTBI screening for migrants to low-incidence countries. Coupled with research on sustainability, acceptability, and program implementation, these results can inform policy decisions.

Patient preference for latent tuberculosis infection preventive treatment: a discrete choice experiment.

OBJECTIVES: To quantify patient preferences when making decisions as to whether to accept latent tuberculosis infection (LTBI) preventive treatment, using a discrete choice experiment (DCE). METHODS: A DCE survey was developed and administered to LTBI patients. Each patient was given 10 random choices along with two fixed choices to check consistency. Two hypothetical treatment options and one opt-out option were presented in each choice task. Latent class analysis was conducted to estimate preferences for six key treatment attributes. RESULTS: Among the 214 respondents, 194 (90.7%) who provided valid DCE responses and complete sociodemographic information were included. Results consistently suggested that respondents were averse to higher risk of active tuberculosis and side effects and longer treatment. A three-latent-class model with five covariates was chosen. Forty-seven percent of the respondents were assigned to class 1, 32% to class 2, and 21% to class 3. Although all six attributes were shown to significantly influence the respondents' treatment decision, the risk of active tuberculosis, chance of liver damage, and frequency of clinic visits were the most important ones. Significant preference heterogeneity was observed in two attributes: frequency of clinic visits (P < 0.01) and chance of liver damage developing (P < 0.01). Class 1 individuals were most likely to have children. Class 2 had the highest employment rate. Class 3 respondents tended to choose the opt-out option on DCE tasks and were more likely to be born outside Canada, have higher education, and be unemployed. CONCLUSION: Respondents consistently preferred preventive treatment with higher effectiveness, fewer side effects, and shorter length. Substantial preference heterogeneity existed among respondents.

Health-related quality of life trajectories among adults with tuberculosis: differences between latent and active infection.

BACKGROUND: Tuberculosis (TB) remains a public health threat with significant annual impacts on morbidity and mortality. However, few studies have examined the impact of active and latent TB infection (LTBI) on health-related quality of life (HRQL). METHODS: Patients with recently diagnosed active TB or LTBI patients were administered the Short Form-36 (SF-36) and the Beck depression inventory (DI) at baseline, 3 months, and 6 months. Mixed-effect linear regression was used to compare the trajectory of HRQL over time in the two patient groups after adjusting for potential confounders. Ordinal logistic regression was used to determine the relationship between changes in HRQL of at least the minimal important difference. RESULTS: One hundred four active TB and 102 LTBI patients participated. At baseline, participants with active TB had significantly lower SF-36 mean domain and component scores (4 to 12 points lower, p < 0.03) and higher mean Beck DI scores (4 points higher, p < 0.0001) when compared to LBTI participants. In the responder analysis, those with active TB were associated with reporting improved scores at 6 months of at least the minimal important difference in vitality (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.3 to 5.6), role physical (OR, 3.1; 95% CI, 1.4 to 6.5), mental component score (OR, 3.2; 95% CI, 1.5 to 6.9), social functioning (OR, 11.1; 95% CI, 3.8 to 33), and role emotional (OR, 2.7; 95% CI, 1.2 to 6.0). CONCLUSIONS: Active TB patients had large improvements in most HRQL domains by 6 months. However, when compared to LTBI participants and US norms, HRQL was still low at completion of therapy.

Health state utilities in latent and active tuberculosis.

BACKGROUND: Tuberculosis (TB) remains a major public health threat worldwide. Numerous cost-effectiveness analyses of TB screening and treatment strategies have been recently published, but none have utilized quality-adjusted life-years as recommended because of the lack of utilities for TB health states. OBJECTIVE: To characterize and compare utility scores from either active TB or latent TB infection (LTBI) participants. METHODS: Consenting patients attending a population-based screening and treatment clinic were administered the Short Form 36 (SF-36), the Health Utilities Index 2/3 (HUI2/3), and a general health visual analog scale (VAS) along with demographic questions. SF-36 scores were converted to Short Form 6D (SF-6D) utility scores using an accepted algorithm. Utility results were compared across scales, and construct validity was assessed. RESULTS: A total of 162 TB patients (78 LTBI and 84 active TB) with available SF-36 and all four utility scores (Health Utilities Index 2, Health Utilities Index 3, SF-6D and VAS) were included in the analysis. Those with active TB had significantly lower SF-36 and utility scores than those with LTBI. Although all appeared to exhibit construct validity, the HUI2/3 and the VAS appeared to have significant ceiling effects, whereas the SF-6D had significant floor effects. CONCLUSIONS: Health state utility values for active TB and LTBI have been determined using different instruments. The three measures did not generate identical utility scores. The HUI2/3 was limited by ceiling effects, whereas the SF-6D appeared to display floor effects.

Cost-effectiveness of LTBI treatment for TB contacts in British Columbia.

BACKGROUND: Contacts of patients with active tuberculosis ("TB contacts") with a tuberculin skin test (TST) size > or = 5 mm are currently recommended treatment for latent TB infection (LTBI). Knowing the cost-effectiveness of LTBI therapy for specific TB contact subpopulations may improve the use of limited resources by reducing the treatment of persons at low TB risk. OBJECTIVE: To evaluate the cost-effectiveness of LTBI therapy for different TB contact populations defined by important risk factors, and to propose an optimal policy based on different recommendation for each subgroup of contacts. METHODS: A 6-year Markov decision analytic model simulating the quality-adjusted life years (QALYs), number of active TB cases prevented, and costs for hypothetical cohorts of Canadian TB contacts defined by TST size, age group (< 10 y/o or above), ethnicity, closeness of contact, and Bacillus Calmette-Guérin (BCG) vaccination status. RESULTS: For the majority of subgroups, the current policy of preventive therapy in those with positive TST was the most cost-effective. Nevertheless, our analysis determined that LTBI treatment is not cost-effective in nonhousehold Canadian-born (nonaboriginal) or foreign-born contacts age > or = 10 y/o. On the other hand, empirical treatment without screening of all non-BCG-vaccinated household contacts age < 10 y/o appeared cost-effective. Such an optimal approach would result in an incremental net monetary benefit of $25 for each contact investigated for a willingness-to-pay of $50,000/QALY. Results were robust to several alternative assumptions considered in sensitivity analyses. CONCLUSIONS: The current practice of LTBI treatment for TB contacts with a TST size > or = 5 mm is cost-effective. A customized approach based on excluding low risk groups from screening and providing treatment to high risk contacts without screening could improve the performance of the program.

The prevalence and predictors of tuberculin positivity in subjects screened for reasons other than contact investigation.

BACKGROUND: No previous studies have estimated the rates of tuberculin positivity (TP) in noncontact populations within the same community, which is important for prioritizing and implementing preventive measures. OBJECTIVES: To estimate the prevalence and predictors of TP in noncontact populations. METHODS: A retrospective analysis of tuberculin results of noncontact populations screened in British Columbia from 1990 to 2002 was conducted. RESULTS: The period prevalence of TP in 59,791 screened subjects was 12.7% (95% CI 12.4% to 13.0%), 30.4% (95% CI 28.2% to 32.7%) and 60.9% (95% CI 60.3% to 61.6%) for Canadian-born non-Aboriginals (CBNAs), Canadian-born Aboriginals (CBAs) and foreign born (FB), respectively. After controlling for age and sex, independent predictors of TP included Bacille Calmette-Guérin (BCG) vaccination (OR 19.6, 95% CI 17.9 to 21.5), country of birth (CBA: OR 2.87, 95% CI 2.44 to 3.37; FB: OR 3.67, 95% CI 3.34 to 4.03) and the following populations: correctional centre residents (OR 4.14, 95% CI 1.87 to 9.15), residents of long-term care and community care facilities (OR 1.79, 95% CI 1.44 to 2.23), immigrants (OR 1.75, 95 % CI 1.50 to 2.04), health centre employees (OR 1.71, 95 % CI 1.56 to 1.88), volunteers (OR 1.38, 95% CI 1.14 to 1.68), self-referred healthy subjects (OR 1.30, 95% CI 1.15 to 1.48) and students (OR 1.27, 95% CI 1.19 to 1.35). CBAs, FB and male subjects were less likely to react to tuberculin than CBNAs and female subjects among those vaccinated with Bacille Calmette-Guérin (P<0.05). CONCLUSIONS: Rates of TP correlate with disease rates by sex and origin. The continuation of tuberculin screening programs is warranted in noncontact populations with high TP rates, where unknown exposure to active cases is more likely to occur. Further research is needed to determine the reasons why a higher response to tuberculin occurs in BCG-vaccinated women and CBNAs.

Cost-effectiveness of post-landing latent tuberculosis infection control strategies in new migrants to Canada.

BACKGROUND: The majority of tuberculosis in migrants to Canada occurs due to reactivation of latent TB infection. Risk of tuberculosis in those with latent tuberculosis infection can be significantly reduced with treatment. Presently, only 2.4% of new migrants are flagged for post-landing surveillance, which may include latent tuberculosis infection screening; no other migrants receive routine latent tuberculosis infection screening. To aid in reducing the tuberculosis burden in new migrants to Canada, we determined the cost-effectiveness of using different latent tuberculosis infection interventions in migrants under post-arrival surveillance and in all new migrants. METHODS: A discrete event simulation model was developed that focused on a Canadian permanent resident cohort after arrival in Canada, utilizing a ten-year time horizon, healthcare system perspective, and 1.5% discount rate. Latent tuberculosis infection interventions were evaluated in the population under surveillance (N = 6100) and the total cohort (N = 260,600). In all evaluations, six different screening and treatment combinations were compared to the base case of tuberculin skin test screening followed by isoniazid treatment only in the population under surveillance. Quality adjusted life years, incident tuberculosis cases, and costs were recorded for each intervention and incremental cost-effectiveness ratios were calculated in relation to the base case. RESULTS: In the population under surveillance (N = 6100), using an interferon-gamma release assay followed by rifampin was dominant compared to the base case, preventing 4.90 cases of tuberculosis, a 4.9% reduction, adding 4.0 quality adjusted life years, and saving $353,013 over the ensuing ten-years. Latent tuberculosis infection screening in the total population (N = 260,600) was not cost-effective when compared to the base case, however could potentially prevent 21.8% of incident tuberculosis cases. CONCLUSIONS: Screening new migrants under surveillance with an interferon-gamma release assay and treating with rifampin is cost saving, but will not significantly impact TB incidence. Universal latent tuberculosis infection screening and treatment is cost-prohibitive. Research into using risk factors to target screening post-landing may provide alternate solutions.

Levofloxacin treatment of active tuberculosis and the risk of adverse events.

BACKGROUND: Fluoroquinolones are commonly used in the treatment of tuberculosis (TB) for drug-sensitive patients who are intolerant to first-line antituberculous agents or who are infected with drug-resistant organisms. Despite increasing use of these agents, there is little information on their tolerance outside of clinical trial settings. OBJECTIVES: To compare overall rate of major adverse events associated with levofloxacin-containing regimen to standard therapy. METHODS: Cases (levofloxacin-containing regimen) were matched by age and sex to their control subjects (standard first-line TB drugs). Eligible patients were identified from the provincial TB database from 2001 to 2004. Drug safety was assessed by evaluation of the nature of the adverse event, the likelihood of association with the study medications, and severity. Only major side effects, that is, those who had a severe or moderate adverse event that was categorized to be definitely, probably, or possibly related to the TB medications, were considered for the analysis. RESULTS: During the 3-year study period, 102 patients received levofloxacin, and 358 patients received first-line agents for treatment of active TB. There were no significant differences between the two groups except for indication (82% of patients in the levofloxacin group had an antecedent adverse event to first-line TB drugs, whereas 18% received levofloxacin because of resistance) and concurrent use of first-line drugs (majority of patients in the levofloxacin arm were not receiving concurrent isoniazid or rifampin). The rate of any major adverse event was almost half among those using levofloxacin as among those on standard therapies (rate ratio, 0.60; 95% confidence interval [CI], 0.44 to 0.82). After adjustment for the differences in exposure of concomitant medications, the rate of any major adverse event was similar between the levofloxacin and control arms (adjusted rate ratio, 0.83; 95% CI, 0.66 to 1.03). Furthermore, there was no difference between the levofloxacin and control arms with respect to CNS (adjusted rate ratio, 0.94; 95% CI, 0.61 to 1.43), GI tract (adjusted rate ratio, 0.81; 95% CI, 0.58 to 1.13), skin (adjusted rate ratio, 0.65; 95% CI, 0.38 to 1.10), or musculoskeletal (MSK) [adjusted rate ratio, 0.87; 95% CI, 0.48 to 1.60] related adverse events when adjusted for concomitant drugs. The results of the secondary analysis for the rate of major adverse events within the first 100 days were similar to the primary analysis. The time to the first major adverse event was similar between the levofloxacin group and the control group (adjusted hazards ratio, 1.01; 95% CI, 0.76 to 1.34). CONCLUSIONS: Concomitant use of a levofloxacin-containing regimen resulted in a similar rate of adverse events compared with conventional first-line regimens when used for treatment of active TB, despite a history of adverse events.

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.

Incidence of pulmonary disease caused by mycobacteria other than tuberculosis in British Columbia.

CONTEXT: The incidence of pulmonary disease due to mycobacteria other than tuberculosis (TB) in Canada has not been documented. OBJECTIVE: To determine the incidence of pulmonary disease due to mycobacteria in the nonimmunocompromised population of British Columbia. DESIGN: A retrospective cohort study of 110 cases of mycobacteria infection other than TB identified from 1991 to 1995. SETTING: British Columbia Centre for Disease Control, Division of TB Control. RESULTS: The overall incidence rate of infection with mycobacteria other than TB was 0.63 10-5/year. This incidence rate was significantly higher among women (relative risk [RR]=2, P=0.0006) and in those aged 55 years or older (RR=8, P<0.00001). In contrast with TB, patients were more frequently born in Canada (P<0.00001) or in industrialized countries other than Canada (P<0.00001), and were less likely to be Aboriginal (P=0.0007) or foreign born from Asia (P<0.0001). The most common organism isolated in British Columbia was Mycobacterium avium-intracellulare (82.7%). Overall, 78 (71%) cases had underlying lung disease. Drug intolerance was very common (42%). After treatment, 55% and 41% of the patients were rendered smear negative or culture negative, respectively. Radiological improvement was noted in 55% of patients, and 60% of patients responded symptomatically to treatment. CONCLUSIONS: The overall incidence of pulmonary disease is low. It is a disease predominantly of women 55 years and older, and targets completely different ethnic groups than TB, suggesting a protective effect of infection with Mycobacterium tuberculosis. M avium-intracellulare was the most common pathogen isolated. Further investigation is required into the natural history of so-called 'colonizers'. Considerable morbidity may be prevented with earlier intervention.

Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population.

AIMS: TB is a serious global public health problem. Isoniazid, a key drug used to treat latent TB, can cause hepatotoxicity in some patients. This pilot study investigated the effects of genetic variation in NAT2 and CYP2E1 on isoniazid-induced hepatotoxicity in TB contacts in British Columbia, Canada. MATERIALS & METHODS: DNA re-sequencing was used to establish the spectrum of genetic variation in the exons, promoter and conserved regions of NAT2 in all subjects. For CYP2E1, the CYP2E1*1C polymorphism was genotyped by PCR-RFLP. Association tests of NAT2 variants and haplotypes, as well acetylator types were performed. RESULTS: We enrolled 170 subjects on isoniazid treatment (23 cases and 147 controls). Systematic re-sequencing of NAT2 revealed 18 known and 10 novel variants. CONCLUSION: No single genetic variant of NAT2 and CYP2E1 showed a significant association with isoniazid-induced hepatotoxicity in this highly heterogeneous population. There was evidence of a trend for increasing hepatotoxicity risk across the rapid, intermediate and slow acetylator groups (p = 0.08).

Primary immune deficiencies presenting in adults: seven years of experience from Iran.

Primary immunodeficiencies (PIDs) are not solely diseases of childhood. We describe the clinical presentation and outcome for 55 adult patients with previously unrecognized PIDs. This series provides unique data regarding PIDs presenting in adulthood, and serves as a timely reminder that physicians must consider the diagnosis of PIDs in their adult patients. Using the experience gained from these patients, we outline key "warning signs" suggestive of an underlying PID. Only through increased physician awareness will patients with PIDs receive timely diagnosis and optimal management.

Predictors of clustering of tuberculosis in Greater Vancouver: a molecular epidemiologic study.

BACKGROUND: The understanding of how tuberculosis is transmitted can be improved by combining DNA fingerprinting of Mycobacterium tuberculosis with conventional epidemiologic methods. We used such techniques to determine the predictors of clustering of identical isolates from tuberculosis patients in Vancouver. METHODS: We used the restriction fragment length polymorphism (RFLP) technique and, if necessary, spoligotyping to determine DNA patterns of M. tuberculosis isolates from all patients with newly diagnosed tuberculosis in Greater Vancouver reported to the Division of Tuberculosis Control from January 1995 to March 1999. Isolates were considered to be part of a cluster if they had an identical DNA pattern. We also collected demographic and epidemiologic data. Predictors associated with being in a cluster were analyzed in a multivariate logistic regression model. RESULTS: Isolates from 793 patients (430 men) were identified; 137 (17.3%) were considered to be in clusters. After adjustment for multiple potential predictors, we found that the following patients were more likely to be part of a cluster: Canadian-born Aboriginals (v. foreign-born patients) (adjusted odds ratio [OR] 6.0, 95% confidence interval [CI] 3.0-11.7), Canadian-born non-Aboriginals (v. foreign-born patients) (adjusted OR 3.6, 95% CI 2.1-6.3), and injection drug users (v. patients who did not inject drugs) (adjusted OR 3.9, 95% CI 1.9-8.1). Patients with a prior history of tuberculosis were less likely to be part of a cluster than were patients with no history of tuberculosis (adjusted OR 0.3, 95% CI 0.1-0.8). INTERPRETATION: Our findings indicate the need to target groups at high risk of tuberculosis more aggressively to prevent transmission and to treat latent infection. DNA fingerprinting may be a useful adjunct to conventional epidemiologic methods to monitor the transmission of tuberculosis in an inner-city setting.