RATIONALE: From 1993-2010, annual U.S. tuberculosis (TB) rates declined by 58%. However, this decline has slowed and disproportionately occurred among U.S.-born (78%) vs. foreign-born persons (47%). Addressing the high burden of latent TB infection (LTBI) must be prioritized. OBJECTIVES: Only Tennessee has implemented a state-wide program for finding and treating people with LTBI. The program was designed to address high state-wide TB rates and growing burden among the foreign-born. We sought to assess the feasibility and yield of Tennessee's program. METHODS: Analyzing data from the 4.8-year period from program inception in March 2002 through December 2006, we quantified patients screened using a TB risk assessment tool, tuberculin skin tests (TST) placed and read, TST results, and patients initiating and completing LTBI treatment. We then estimated the number needed to screen to find and treat one person with LTBI and to prevent one case of TB. MEASUREMENTS AND MAIN RESULTS: Of 168,517 persons screened, 102,709 had a TST placed and read. Among 9,090 (9%) with a positive TST result, 53% initiated treatment, 54% of whom completed treatment. An estimated 195 TB cases were prevented over the 4.8 years analyzed, and program performance measures improved annually. The number of TSTs placed to prevent one TB case ranged from 150 for foreign-born persons to 9,834 for persons without TB risk. CONCLUSIONS: Targeted tuberculin testing and LTBI treatment is feasible and likely to reduce TB rates over time. Yield and cost-effectiveness are maximized by prioritizing foreign-born persons, a large population with high TB risk.

BACKGROUND: Multidrug-resistant tuberculosis programs in DOTS-Plus pilot sites in five countries. OBJECTIVES: To calculate sputum conversion time and its relationship to treatment outcome, document the frequency of culture reversions and examine concordance of smear and culture to assess the potential consequences of monitoring by smear microscopy alone. DESIGN: Retrospective cohort analysis of 1926 patients receiving individualized, second-line therapy. RESULTS: Among 1385 sputum culture-positive cases at baseline, 1146 (83%) experienced at least one culture conversion during treatment. Conversion, however, was not sustained in all patients: 201 (15%) experienced initial culture conversion and at least one subsequent culture reversion to positive; 1064 (77%) achieved sustainedculture conversion. Median time to culture conversion was 3 months. Among 206 patients whose final conversion occurred 7-18 months after the initiation of therapy, 71% were cured or had completed treatment. CONCLUSIONS: Prolonged treatment for patients with delayed conversion may be beneficial, as 71% of late converters still achieved cure or completed treatment. This has implications for programs with defined end points for treatment failure. The interval between first and final conversion among patients whose initial conversion is not sustained raises concern with respect to the ongoing debate regarding duration of treatment and the definition of cure. 2011 The Union.

BACKGROUND: In accordance with WHO guidelines, people with HIV infection in Botswana receive daily isoniazid preventive therapy against tuberculosis without obtaining a tuberculin skin test, but duration of prophylaxis is restricted to 6 months. We aimed to assess effectiveness of extended isoniazid therapy. METHODS: In our randomised, double-blind, placebo-controlled trial we enrolled adults infected with HIV aged 18 years or older at government HIV-care clinics in Botswana. Exclusion criteria included current illness such as cough and an abnormal chest radiograph without antecedent tuberculosis or pneumonia. Eligible individuals were randomly allocated (1:1) to receive 6 months' open-label isoniazid followed by 30 months' masked placebo (control group) or 6 months' open-label isoniazid followed by 30 months' masked isoniazid (continued isoniazid group) on the basis of a computer-generated randomisation list with permuted blocks of ten at each clinic. Antiretroviral therapy was provided if participants had CD4-positive lymphocyte counts of fewer than 200 cells per muL. We used Cox regression analysis and the log-rank test to compare incident tuberculosis in the groups. Cox regression models were used to estimate the effect of antiretroviral therapy. The trial is registered at ClinicalTrials.gov, number NCT00164281. FINDINGS: Between Nov 26, 2004, and July 3, 2009, we recorded 34 (3.4%) cases of incident tuberculosis in 989 participants allocated to the control group and 20 (2.0%) in 1006 allocated to the continued isoniazid group (incidence 1.26% per year vs 0.72%; hazard ratio 0.57, 95% CI 0.33-0.99, p=0.047). Tuberculosis incidence in those individuals receiving placebo escalated approximately 200 days after completion of open-label isoniazid. Participants who were tuberculin skin test positive (ie, ≥5 mm induration) at enrolment received a substantial benefit from continued isoniazid treatment (0.26, 0.09-0.80, p=0.02), whereas participants who were tuberculin skin test-negative received no significant benefit (0.75, 0.38-1.46, p=0.40). By study completion, 946 (47%) of 1995 participants had initiated antiretroviral therapy. Tuberculosis incidence was reduced by 50% in those receiving 360 days of antiretroviral therapy compared with participants receiving no antiretroviral therapy (adjusted hazard ratio 0.50, 95% CI 0.26-0.97). Severe adverse events and death were much the same in the control and continued isoniazid groups. INTERPRETATION: In a tuberculosis-endemic setting, 36 months' isoniazid prophylaxis was more effective for prevention of tuberculosis than was 6-month prophylaxis in individuals with HIV infection, and chiefly benefited those who were tuberculin skin test positive. FUNDING: US Centers for Disease Control and Prevention and US Agency for International Development.

BACKGROUND: Isoniazid preventive therapy (IPT) prevents tuberculosis (TB) in people living with HIV (human immunodeficiency virus, PLWH). Symptom screening without chest radiographs (CXRs) was established as the strategy for excluding TB disease among PLWH seeking IPT in Botswana's 2001 pilot project. This strategy was evaluated in 2004-2006 among candidates screened for an IPT clinical trial. METHODS: PLWH referred from clinics and HIV testing centers were screened for TB symptoms. All asymptomatic candidates received CXRs; those with abnormal CXRs were investigated further. RESULTS: Among 2732 asymptomatic candidates screened, 302 (11%) had abnormal CXRs potentially compatible with TB; TB disease was diagnosed in 43 of these 302 (14%), or 43 (1.6%) of the 2732 asymptomatic candidates. While not associated with CD4 lymphocyte counts < 200 cells/mm(3), TB was associated with a positive tuberculin skin test (relative risk 2.1, 95%CI 1.1-4.0). IPT was initiated in 113 (62%) of 182 asymptomatic PLWH with abnormal CXRs; 8/113 (7%) subsequently developed TB, and 7/8 (88%) successfully completed anti-tuberculosis treatment. CONCLUSIONS: The prevalences of abnormal CXRs and TB were respectively 2.6- and 8.9-fold higher among asymptomatic PLWH screened for the trial than in the pilot. A cost-effectiveness analysis is needed to determine whether the benefits of symptom screening alone are offset by the risk of inducing INH resistance by excluding CXRs during screening.

OBJECTIVES: To describe reasons for exclusion from isoniazid tuberculosis preventive therapy (IPT) and outcomes of persons living with HIV (PLWH) during 6 months of IPT. METHODS: In a clinical trial conducted in government clinics, first screening (screen 1) used National IPT Program guidelines and a second screening (screen 2) was trial specific. Adherence was defined as attending 6 monthly visits. RESULTS: Between 2004 and 2006, at 4018 screening visits, 2934 (73%) PLWH met screen 1 criteria; 1995 (68%) met screen 2 criteria and were enrolled. Major reasons for exclusion were illness (66%) at screen 1 and abnormal chest radiographs (36%) at screen 2. Tuberculin skin tests were ≥5 mm in 24% of those enrolled and 31% had CD4 lymphocyte counts <200 cells/mm. During the 6 months, 8 (0.40%) developed tuberculosis disease, 28 (1.4%) had severe adverse events (19/28 were hepatitis including one death probably isoniazid-associated), 20 others died, and 22% initiated antiretroviral therapy (ART). Although adherence was 86%, being on ART improved adherence: relative risk 1.41 (95% confidence limits 1.04-1.91). In multivariate analysis, ART was associated with a 4.38 greater odds of adherence to IPT. CONCLUSIONS: Six months of IPT was relatively safe and well-tolerated by PLWH. Adherence to IPT was significantly better among those receiving ART with IPT.

The HIV and multi-drug resistant tuberculosis (MDR-TB) epidemics are closely linked. In Thailand as part of a sentinel surveillance system, we collected data prospectively about pulmonary TB cases treated in public clinics. A subset of HIV-infected TB patients identified through this system had additional data collected for a research study. We conducted multivariate analysis to identify factors associated with MDR-TB. Of 10,428 TB patients, 2,376 (23%) were HIV-infected; 145 (1%) had MDR-TB. Of the MDR-TB cases, 52 (37%) were HIV-infected. Independent risk factors for MDR-TB included age 18-29 years old, male sex, and previous TB treatment, but not HIV infection. Among new patients, having an injection drug use history was a risk factor for MDR-TB. Of 539 HIV-infected TB patients in the research study, MDR-TB was diagnosed in 19 (4%); the only significant risk factors were previous TB treatment and previous hepatitis. In Thailand, HIV is common among MDR-TB patients, but is not an independent risk factor for MDR-TB. Populations at high risk for HIV-young adults, men, injection drug users - should be prioritized for drug susceptibility testing.