Translating tuberculosis research into practice: collaboration between academic researchers and public health departments in North Carolina.

Successful collaborations between academic researchers and local health departments are vital for public health research, but developing and maintaining such partnerships is often difficult. However, in the North Carolina Tuberculosis Control Program, such partnerships have flourished and have led to notable improvements in patient care.

Feasibility and willingness-to-pay for integrated community-based tuberculosis testing.

BACKGROUND: Community-based screening for TB, combined with HIV and syphilis testing, faces a number of barriers. One significant barrier is the value that target communities place on such screening. METHODS: Integrated testing for TB, HIV, and syphilis was performed in neighborhoods identified using geographic information systems-based disease mapping. TB testing included skin testing and interferon gamma release assays. Subjects completed a survey describing disease risk factors, healthcare access, healthcare utilization, and willingness to pay for integrated testing. RESULTS: Behavioral and social risk factors among the 113 subjects were prevalent (71% prior incarceration, 27% prior or current crack cocaine use, 35% homelessness), and only 38% had a regular healthcare provider. The initial 24 subjects reported that they would be willing to pay a median $20 (IQR: 0-100) for HIV testing and $10 (IQR: 0-100) for TB testing when the question was asked in an open-ended fashion, but when the question was changed to a multiple-choice format, the next 89 subjects reported that they would pay a median $5 for testing, and 23% reported that they would either not pay anything to get tested or would need to be paid $5 to get tested for TB, HIV, or syphilis. Among persons who received tuberculin skin testing, only 14/78 (18%) participants returned to have their skin tests read. Only 14/109 (13%) persons who underwent HIV testing returned to receive their HIV results. CONCLUSION: The relatively high-risk persons screened in this community outreach study placed low value on testing. Reported willingness to pay for such testing, while low, likely overestimated the true willingness to pay. Successful TB, HIV, and syphilis integrated testing programs in high risk populations will likely require one-visit diagnostic testing and incentives.

Factors associated with loss to follow-up in a large tuberculosis treatment trial (TBTC Study 22).

INTRODUCTION: Loss to follow-up in clinical trials compromises achievement of study goals. We evaluated factors associated with loss to follow-up after completion of treatment phase in a large tuberculosis treatment trial (TBTC/USPHS Study 22) in the U.S. and Canada. METHODS: Patients who were lost to follow-up were compared to those who reached a study end-point or successfully completed follow-up. A generalized estimating equation model was used to combine patient-specific and site-specific factors. RESULTS: Of 1075 patients enrolled, 965 (89.8%) reached a study end-point, died, or completed the 2 year post-treatment follow-up phase, and 110 (10.2%) did not. Multivariate analysis showed the following factors to be independently associated with loss to follow-up: birth outside USA/Canada (OR 2.07, 95% CI 1.25-3.40, p=0.005), history of homelessness (OR 1.94, 95% CI 1.00-3.80, p=0.05), enrollment at a health department (OR 2.71, 95% CI 1.27-5.79, p=0.010), and use of any kind of incentive (cash/cash equivalent) during treatment phase (OR 3.04, 95% CI 1.73-5.33 p=0.0001). CONCLUSIONS: Cultural or linguistic factors and lack of stable housing contribute to loss to follow-up. Attention to these factors could improve long-term retention in clinical trials. Enrollment at a health department and use of incentives during treatment phase may be markers for other factors leading to loss to follow-up.

Quality assurance in a large clinical trials consortium: the experience of the Tuberculosis Trials Consortium.

Quality assurance (QA) is essential for data accuracy and proper evaluation of study objectives in clinical trials. The Tuberculosis Trials Consortium (TBTC)-a collaboration of 28 clinical sites and the Centers for Disease Control and Prevention-has developed a comprehensive QA program that provides quantitative assessments of performance based on clearly defined standards that are communicated to data collectors through a feedback process. The Implementation and Quality Committee of the TBTC developed a Site Evaluation Report (SER) that assesses performance measures (PMs) critical to the accomplishment of study objectives. PMs are defined, quantified, and evaluated, and goals and minimum acceptable scores are specified. Sites not meeting a PM minimum must provide an explanation and develop a plan to meet the goal. Site-specific and system-wide problems can be readily identified through this process. The SER is used prospectively for all TBTC treatment trials, and a Web site has been developed to maximize the availability and usefulness of performance data. The TBTC's comprehensive QA program is an example of a successful method for ensuring high quality, evaluable data.

Geographic information system-based screening for TB, HIV, and syphilis (GIS-THIS): a cross-sectional study.

OBJECTIVE: To determine the feasibility and case detection rate of a geographic information systems (GIS)-based integrated community screening strategy for tuberculosis, syphilis, and human immunodeficiency virus (HIV). DESIGN: Prospective cross-sectional study of all participants presenting to geographic hot spot screenings in Wake County, North Carolina. METHODS: The residences of tuberculosis, HIV, and syphilis cases incident between 1/1/05-12/31/07 were mapped. Areas with high densities of all 3 diseases were designated "hot spots." Combined screening for tuberculosis, HIV, and syphilis were conducted at the hot spots; participants with positive tests were referred to the health department. RESULTS AND CONCLUSIONS: Participants (N = 247) reported high-risk characteristics: 67% previously incarcerated, 40% had lived in a homeless shelter, and 29% had a history of crack cocaine use. However, 34% reported never having been tested for HIV, and 41% did not recall prior tuberculin skin testing. Screening identified 3% (8/240) of participants with HIV infection, 1% (3/239) with untreated syphilis, and 15% (36/234) with latent tuberculosis infection. Of the eight persons with HIV, one was newly diagnosed and co-infected with latent tuberculosis; he was treated for latent TB and linked to an HIV provider. Two other HIV-positive persons had fallen out of care, and as a result of the study were linked back into HIV clinics. Of 27 persons with latent tuberculosis offered therapy, nine initiated and three completed treatment. GIS-based screening can effectively penetrate populations with high disease burden and poor healthcare access. Linkage to care remains challenging and will require creative interventions to impact morbidity.

Discriminating between latent and active tuberculosis with multiple biomarker responses.

We sought to identify biomarker responses to tuberculosis specific antigens which could 1) improve the diagnosis of tuberculosis infection and 2) allow the differentiation of active and latent infections. Seventy subjects with active tuberculosis (N = 12), latent tuberculosis (N = 32), or no evidence of tuberculosis infection (N = 26) were evaluated. We used the Luminex Multiplexed Bead Array platform to simultaneously evaluate 25 biomarkers in the supernatant of whole blood samples following overnight stimulation using the Quantiferon(®) Gold In-Tube kit. We defined the response to stimulation as the difference (within an individual patient) between the response to the pooled tuberculosis antigens and the negative control. IP-10 response was significantly higher in tuberculosis-infected (active or latent) subjects compared to the uninfected group (p < 0.0001). Among the 25 parameters, expression levels of IL-15 and MCP-1 were found to be significantly higher in the active tuberculosis group compared to the latent tuberculosis group (p = 0.0006 and 0.0030, respectively). When combined, IL-15 and MCP-1 accurately identified 83% of active and 88% of latent infections. The combination of IL-15 and MCP-1 responses was accurate in distinguishing persons with active tuberculosis from persons with latent tuberculosis in this study.

Effect of improving the quality of radiographic interpretation on the ability to predict pulmonary tuberculosis relapse.

RATIONALE AND OBJECTIVES: Chest radiographic findings are important for diagnosis and management of tuberculosis. The reliability of these findings is therefore of interest. We sought to describe interobserver reliability of chest radiographic findings in pulmonary tuberculosis, and to understand how the reliability of these findings might affect the utility of radiographic findings in predicting tuberculosis relapse. MATERIALS AND METHODS: Three blinded readers independently reviewed chest radiographs from a randomly selected group of 10% of HIV-seronegative subjects participating in a tuberculosis treatment trial. The three readers then arrived at a fourth, consensus radiographic interpretation. RESULTS: A total of 241 films obtained from 99 patients were reviewed. Agreement among the independent readers was very good for the findings of bilateral disease (kappa = 0.71-0.86 among readers) and cavitation (kappa = 0.66-0.73). The original interpretation was reasonably sensitive and specific (compared to the consensus interpretation) for bilateral disease, but the sensitivity for cavity decreased from 81% for the 2-month film to 47% at end of treatment (P = 0.013). Substituting the consensus interpretation for the original interpretation increased the odds ratio for the association between cavitation on early chest radiograph and subsequent tuberculosis relapse from 4.97 to 8.97. CONCLUSION: Radiographic findings were reasonably reliable between independent reviewers and the original interpretations. The original investigators, who knew the patient's clinical course, were less likely to identify cavitation on the end of treatment chest radiograph. Improving the reliability of these findings could improve the utility of chest radiographs for predicting tuberculosis relapse.

Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis.

RATIONALE: Moxifloxacin has promising preclinical activity against Mycobacterium tuberculosis, but has not been evaluated in multidrug treatment of tuberculosis in humans. OBJECTIVE: To compare the impact of moxifloxacin versus ethambutol, both in combination with isoniazid, rifampin, and pyrazinamide, on sputum culture conversion at 2 mo as a measure of the potential sterilizing activity of alternate induction regimens. METHODS: Adults with smear-positive pulmonary tuberculosis were randomized in a factorial design to receive moxifloxacin (400 mg) versus ethambutol given 5 d/wk versus 3 d/wk (after 2 wk of daily therapy). All doses were directly observed. MEASUREMENTS: The primary endpoint was sputum culture status at 2 mo of treatment. RESULTS: Of 336 patients enrolled, 277 (82%) were eligible for the efficacy analysis, 186 (67%) were male, 175 (63%) were enrolled at African sites, 206 (74%) had cavitation on chest radiograph, and 60 (22%) had HIV infection. Two-month cultures were negative in 71% of patients (99 of 139) treated with moxifloxacin versus 71% (98 of 138) treated with ethambutol (p = 0.97). Patients receiving moxifloxacin, however, more often had negative cultures after 4 wk of treatment. Patients treated with moxifloxacin more often reported nausea (22 vs. 9%, p = 0.002), but similar proportions completed study treatment (88 vs. 89%). Dosing frequency had little effect on 2-mo culture status or tolerability of therapy. CONCLUSIONS: The addition of moxifloxacin to isoniazid, rifampin, and pyrazinamide did not affect 2-mo sputum culture status but did show increased activity at earlier time points.

A prospective, randomized, double-blind study of the tolerability of rifapentine 600, 900, and 1,200 mg plus isoniazid in the continuation phase of tuberculosis treatment.

Once-weekly rifapentine 600 mg plus isoniazid (INH) during the continuation phase treatment of tuberculosis is associated with a relapse rate higher than that of twice-weekly rifampin plus INH. The safety and tolerability of higher rifapentine doses need to be determined. We conducted a prospective, randomized, double-blind trial of rifapentine at three doses (600, 900, and 1,200 mg) plus INH 15 mg/kg once weekly in the continuation phase treatment of culture-positive tuberculosis in 150 human immunodeficiency virus-seronegative adults. Outcome measures were discontinuation of therapy for any reason and adverse events on therapy. Treatment was discontinued in 3 of 52 (6%), 2 of 51 (4%), and 3 of 47 (6%) in the rifapentine 600-, 900-, and 1,200-mg treatment arms, respectively. Only one discontinuation, in the rifapentine 1,200-mg arm, was due to an adverse event possibly associated with study therapy. There was a trend toward more adverse events, possibly associated with study therapy, in the highest-dose arms (p = 0.051). Rifapentine 900-mg, once-weekly dosing appears to be safe and well tolerated and is being evaluated in Phase III efficacy trials of treatment of latent tuberculosis. Further evaluation of the safety and tolerability of rifapentine 1,200 mg is warranted.