Mark N. Lobato

Treatment for latent TB in correctional facilities: a challenge for TB elimination.

BACKGROUND To eliminate tuberculosis (TB) in the United States, more information is needed on how to gain access to difficult-to-reach, high-risk populations to evaluate people who would benefit from treatment for latent TB infection (LTBI). METHODS A field study was conducted of people at risk for co-infection with TB and the human immunodeficiency virus (HIV) and to demonstrate that treating LTBI in inmates is feasible. Inmates were tested for LTBI using the Mantoux tuberculin skin test (TST). Outcomes measured were skin test results and the start and completion of treatment for LTBI. RESULTS In 49 correctional facilities in 12 states, 198102 inmates had a skin test read. The mean skin test positivity rate among inmates was 17.0%. Of those who had a known HIV test result, 14.5% tested HIV positive. Inmates with a positive TST were 4.2 times more likely than those with a negative TST to be HIV infected (95% confidence interval [CI]=3.9-4.4). Therapy for LTBI was completed in 55.9% of patients started on treatment. Patients who were HIV positive and started on a 12-month treatment regimen were less likely than HIV-negative patients (40.0% vs 68.1%, respectively) to complete treatment (odds ratio [OR]=0.24, 95% CI=0.20-0.28). Patients treated in jails were less likely than those treated in prisons (33.6% vs 57.7%, respectively) to complete treatment (OR=0.29, 95% CI=0.26-0.32). CONCLUSIONS Correctional facilities offer a venue for identifying and treating high-risk individuals for LTBI. However, completing treatment is more problematic in jails than in prisons.

Interferon-γ release assays: new diagnostic tests for Mycobacterium tuberculosis infection, and their use in children

Purpose of review The testing and treatment of children at risk for Mycobacterium tuberculosis infection represents an important public health priority in the United States. Until recently, diagnosis has relied upon the tuberculin skin test (TST). New interferon-γ release assays (IGRAs) offer improvements over TST, but these tests have not been studied in children until recently. Recent findings Evidence regarding IGRA performance in children is accumulating rapidly. Overall, the findings demonstrate performance of IGRAs equivalent or superior to that of the TST. However, IGRAs have biological limitations similar to TST and some technical problems of their own, and critical gaps in our knowledge remain. Summary Current evidence supports usage of IGRAs in children aged 5 years or older. IGRAs are preferred over TST when specificity is paramount or wherein patients might fail to return for TST reading. Evidence for use in children aged less than 5 years is insufficient at this time: the sensitivity is poorly defined, and TST is preferred for testing these children. Future IGRA research should focus on children aged less than 5 years for informing expanded usage in this vulnerable population.

Adverse Events and Treatment Completion for Latent Tuberculosis in Jail Inmates and Homeless Persons

BACKGROUND Recently, a short-course treatment using 60 daily doses of rifampin and pyrazinamide was recommended for latent tuberculosis (TB) infection (LTBI). STUDY OBJECTIVES To determine the acceptability, tolerability, and completion of treatment. DESIGN Observational cohort study. SETTING Five county jails and TB outreach clinics for homeless populations in three cities. PATIENTS Study staff enrolled 1,211 patients (844 inmates and 367 homeless persons). INTERVENTIONS Sites used 60 daily doses of rifampin and pyrazinamide, an approved treatment regimen for LTBI. MEASUREMENTS Types and frequency of drug-related adverse events and outcomes of treatment. RESULTS Prior to treatment, 25 of 1,178 patients (2.1%) had a serum aminotransferase measurement at least 2.5 times the upper limit of normal. Patients who reported excess alcohol use in the past 12 months were more likely than other patients to have an elevated pretreatment serum aminotransferase level (odds ratio, 2.1; 95% confidence interval, 1.1 to 6.1; p = 0.03). Treatment was stopped in 66 of 162 patients (13.4%) who had a drug-related adverse event. Among 715 patients who had serum aminotransferase measured during treatment, 43 patients (6.0%) had an elevation > 5 times the upper limits of normal, including one patient who died of liver failure attributed to treatment. In multivariate analyses, increasing age, an abnormal baseline aspartate aminotransferase level, and unemployment within the past 24 months were independent risk factors for hepatotoxicity. Completion rates were similar in jail inmates (47.5%) and homeless persons (43.6%). CONCLUSIONS This study detected the first treatment-associated fatality with the rifampin and pyrazinamide regimen, prompting surveillance that detected unacceptable levels of hepatotoxicity and retraction of recommendations for its routine use. Completion rates for LTBI treatment using a short-course regimen exceeds historical rates using isoniazid. Efforts to identify an effective short-course treatment for LTBI should be given a high priority.

Underuse of Effective Measures to Prevent and Manage Pediatric Tuberculosis in the United States

OBJECTIVE To characterize problems with prevention and management of pediatric tuberculosis (TB) and latent TB infection (LTBI). DESIGN A multisite, cross-sectional study using data from medical records and public health logs to categorize and define use of routine prevention practices in managing pediatric TB and LTBI. SETTING Four areas of the United States. PARTICIPANTS Children younger than 5 years diagnosed with TB from January 1, 2002, through December 31, 2004, and children with LTBI reported during a continuous 12-month period in 2003 to 2004. Main Exposure Mycobacterium tuberculosis. MAIN OUTCOME MEASURES Underuse or nonuse of standard medical and public health interventions. RESULTS Almost 40% of children had a TB risk factor related to their country of birth, parental origin, or travel to a country with a high incidence of TB. Children having LTBI were less likely than those having TB to complete treatment (53.7% vs 88.6%, respectively). Almost half (46.3%) of the children with TB came to medical attention late in their course when they already had symptoms. Among 63 adult source patients, 19 (30.2%) previously had LTBI but were not treated, and none of the 40 foreign-born source patients were known to have been evaluated for TB before entry into the United States. CONCLUSIONS Prevention efforts are unsatisfactory to prevent TB in children. Effective interventions such as treatment of LTBI and TB evaluation of adult immigrants remain less than optimal.

Old and new approaches to diagnosing and treating latent tuberculosis in children in low-incidence countries

Purpose of review The primary purpose is to review guidance on the testing and treatment of latent tuberculosis infection (LTBI) in children. Most children and adults with LTBI have positive tuberculin skin test (TST) or interferon gamma release assay (IGRA) results, normal examinations, and normal chest radiographs. Diagnosis of and treatment completion for LTBI are critical to diminish future cases of tuberculosis (TB) disease. Recent findings Children should be screened for TB risk factors, and only children with risk factors should be tested with either a TST or an IGRA. IGRAs measure interferon gamma production by lymphocytes after they are stimulated ex vivo by antigens that are primarily Mycobacterium tuberculosis-specific. The foundation of LTBI therapy in the United States has been 9 months of daily isoniazid, but shorter treatment regimens now exist, including a 12-dose regimen of weekly isoniazid and rifapentine. These shorter regimens are associated with higher completion rates. Summary There are two distinct modalities for LTBI diagnosis and several treatment regimens that can prevent TB disease in infected children. The selection of treatment regimen should take several factors into consideration, including adherence, drug susceptibility results of the presumed source case (if known), safety, cost, and patient preference.

Unintended consequences: mandatory tuberculin skin testing and severe isoniazid hepatotoxicity.

After mandatory school-enrollment tuberculin skin testing, a 4-year-old girl who was at low risk for Mycobacterium tuberculosis infection had severe isoniazid hepatotoxicity that was managed with a liver transplant. Although severe isoniazid hepatotoxicity is very uncommon in children, this case emphasizes the need to limit skin testing to persons who have a risk factor for infection and to educate parents on how to monitor for adverse effects during treatment.

Missed opportunities to prevent tuberculosis in foreign-born persons, Connecticut, 2005-2008.

SETTING Factors that influence testing for latent tuberculosis infection (LTBI) among foreign-born persons in Connecticut are not well understood. OBJECTIVE To identify predictors for LTBI testing and challenges related to accessing health care among the foreign-born population in Connecticut. DESIGN Foreign-born Connecticut residents with confirmed or suspected tuberculosis (TB) disease during June 2005-December 2008 were interviewed regarding health care access and immigration status. Predictors for self-reported testing for LTBI after US entry were determined. RESULTS Of 161 foreign-born persons interviewed, 48% experienced TB disease within 5 years after arrival. One third (51/156) reported having undergone post-arrival testing for LTBI. Although those with established health care providers were more likely to have reported testing (aOR 4.49, 95%CI 1.48-13.62), only 43% of such persons were tested. Undocumented persons, the majority of whom lacked a provider (53%), were less likely than documented persons to have reported testing (aOR 0.20, 95%CI 0.06-0.67). Hispanic permanent residents (immigrants and refugees) and visitors (persons admitted temporarily) were more likely than non-Hispanics in the respective groups to have reported testing (OR 5.25, 95%CI 1.51-18.31 and OR 7.08, 95%CI 1.30-38.44, respectively). CONCLUSIONS The self-reported rate of testing for LTBI among foreign-born persons in Connecticut with confirmed or suspected TB was low and differed significantly by ethnicity and immigration status. Strategies are needed to improve health care access for foreign-born persons and expand testing for LTBI, especially among non-Hispanic and undocumented populations.

Two tuberculosis genotyping clusters, one preventable outbreak.

In 2006, eight community tuberculosis (TB) cases and a ninth incarceration-related case were identified during an outbreak investigation, which included genotyping of all Mycobacterium tuberculosis isolates. In 1996, the source patient had pulmonary TB but completed only two weeks of treatment. From February 2005 to May 2006, the source patient lived in four different locations while contagious. The outbreak cases had matching isolate spoligotypes; however, the mycobacterial interspersed repetitive unit (MIRU) patterns from isolates from two secondary cases differed by one tandem repeat at a single MIRU locus. The source patients isolates showed a mixed mycobacterial population with both MIRU patterns. Traditional and molecular epidemiologic methods linked eight secondary TB cases to a single source patient whose incomplete initial treatment, incarceration, delayed diagnosis, and housing instability resulted in extensive transmission. Adequate treatment of the source patients initial TB or early diagnosis of recurrent TB could have prevented this outbreak.

Improved Program Activities Are Associated with Decreasing Tuberculosis Incidence in the United States

Objective. This study was conducted to determine whether improvements in tuberculosis (TB) program activities correlate with incident TB cases. Methods. National TB surveillance data and program data from patients with pulmonary and laryngeal TB and their contacts were collected. These data were analyzed using regression models to assess the association between changes in incident TB cases and indicators of program performance (a time series of percent changes in program indices). Results. A total of 1,361,113 contacts exposed to 150,668 TB patients were identified through contact investigations. From 1987 to 1992 (the period of TB resurgence and antedating increased funding), there was a decline in several measures used by TB programs for outcomes of contact investigations. From 1993 to 1998 (the period after increases in TB funds), there was an observable improvement in the program indices. Four program indices for contacts and two for TB cases (directly observed therapy and completion of therapy) were statistically associated (p≤0.01) with the decline in TB incident cases. Conclusions. These analyses suggest that expanded TB program activities resulted in the reduction in national TB cases and underscore the importance of treatment completion for TB disease and latent TB infection. Based on these results, we propose that further improvements in these activities will accelerate the decline of TB in the United States.

High Rate of Treatment Completion in Program Settings With 12-Dose Weekly Isoniazid and Rifapentine for Latent Mycobacterium tuberculosis Infection

Background Randomized controlled trials have demonstrated that the newest latent tuberculosis (LTBI) regimen, 12 weekly doses of directly observed isoniazid and rifapentine (3HP), is as efficacious as 9 months of isoniazid, with a greater completion rate (82% vs 69%); however, 3HP has not been assessed in routine healthcare settings. Methods Observational cohort of LTBI patients receiving 3HP through 16 US programs was used to assess treatment completion, adverse drug reactions, and factors associated with treatment discontinuation. Results Of 3288 patients eligible to complete 3HP, 2867 (87.2%) completed treatment. Children aged 2-17 years had the highest completion rate (94.5% [155/164]). Patients reporting homelessness had a completion rate of 81.2% (147/181). In univariable analyses, discontinuation was lowest among children (relative risk [RR], 0.44 [95% confidence interval {CI}, .23-.85]; P = .014), and highest in persons aged ≥65 years (RR, 1.72 [95% CI, 1.25-2.35]; P < .001). In multivariable analyses, discontinuation was lowest among contacts of patients with tuberculosis (TB) disease (adjusted RR [ARR], 0.68 [95% CI, .52-.89]; P = .005) and students (ARR, 0.45 [95% CI, .21-.98]; P = .044), and highest with incarceration (ARR, 1.43 [95% CI, 1.08-1.89]; P = .013) and homelessness (ARR, 1.72 [95% CI, 1.25-2.39]; P = .001). Adverse drug reactions were reported by 1174 (35.7%) patients, of whom 891 (76.0%) completed treatment. Conclusions Completion of 3HP in routine healthcare settings was greater overall than rates reported from clinical trials, and greater than historically observed using other regimens among reportedly nonadherent populations. Widespread use of 3HP for LTBI treatment could accelerate elimination of TB disease in the United States.