Matthew Arentz

Diagnostic Accuracy and Reproducibility of WHO-Endorsed Phenotypic Drug Susceptibility Testing Methods for First-Line and Second-Line Antituberculosis Drugs

ABSTRACT In an effort to update and clarify policies on tuberculosis drug susceptibility testing (DST), the World Health Organization (WHO) commissioned a systematic review evaluating WHO-endorsed diagnostic tests. We report the results of this systematic review and meta-analysis of the diagnostic accuracy and reproducibility of phenotypic DST for first-line and second-line antituberculosis drugs. This review provides support for recommended critical concentrations for isoniazid and rifampin in commercial broth-based systems. Further studies are needed to evaluate critical concentrations for ethambutol and streptomycin that accurately detect susceptibility to these drugs. Evidence is limited on the performance of DST for pyrazinamide and second-line drugs.

Association between Smoking and Latent Tuberculosis in the U.S. Population: An Analysis of the National Health and Nutrition Examination Survey

Background Evidence of an association between cigarette smoking and latent tuberculosis infection (LTBI) is based on studies in special populations and/or from high prevalence settings. We sought to evaluate the association between LTBI and smoking in a low prevalence TB setting using population-based data from the National Health and Nutrition Examination Survey (NHANES). Methods In 1999–2000, NHANES assessed LTBI (defined as a tuberculin skin test measurement ≥10 mm) in participants, and those ≥20 years of age were queried regarding their tobacco use and serum cotinine was measured. We evaluated the association of LTBI with self-reported smoking history and smoking intensity in multivariable logistic regression models that adjusted for known confounders (gender, age, birthplace, race/ethnicity, poverty, education, history of BCG vaccination, and history of household exposure to tuberculosis disease). Results Estimated LTBI prevalence was 5.3% among those ≥20 years of age. The LTBI prevalence among never smokers, current smokers, and former smokers was 4.1%, 6.6%, and 6.2%, respectively. In a multivariable model, current smoking was associated with LTBI (OR 1.8; 95% CI, 1.1–2.9). The association between smoking and LTBI was strongest for Mexican-American and black individuals. In multivariate analysis stratified by race/ethnicity, cigarette packs per day among Mexican-American smokers and cotinine levels among black smokers, were significantly associated with LTBI. Conclusions In the large, representative, population-based NHANES sample, smoking was independently associated with significantly increased risks of LTBI. In certain populations, a greater risk of LTBI corresponded with increased smoking exposure.

Systematic Review of the Performance of Rapid Rifampicin Resistance Testing for Drug-Resistant Tuberculosis

Introduction Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB). However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection. Methods We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB. Results We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI) assay, Nitrate Reductase Assay (NRA) and MODS tests): for all tests, negative predictive values were high when rifampicin resistance prevalence was ≤ 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%. Limitations In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests. Discussion Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.

Use of anti-retroviral therapy in tuberculosis patients on second-line anti-TB regimens: a systematic review

Introduction Use of antiretroviral therapy (ART) during treatment of drug susceptible tuberculosis (TB) improves survival. However, data from HIV infected individuals with drug resistant TB are lacking. Second line TB drugs when combined with ART may increase drug interactions and lead to higher rates of toxicity and greater noncompliance. This systematic review sought to determine the benefit of ART in the setting of second line drug therapy for drug resistant TB. Methods We included individual patient data from studies that evaluated treatment of drug-resistant tuberculosis in HIV-1 infected individuals published between January 1980 and December of 2009. We evaluated the effect of ART on treatment outcomes, time to smear and culture conversion, and adverse events. Results Ten observational studies, including data from 217 subjects, were analyzed. Patients using ART during TB treatment had increased likelihood of cure (hazard ratio (HR) 3.4, 95% CI 1.6–7.4) and decreased likelihood of death (HR 0.4, 95% CI 0.3–0.6) during treatment for drug resistant TB. These associations remained significant in patients with a CD4 less than 200 cells/mm3 and less than 50 cells/mm3, and when correcting for drug resistance pattern. Limitations We identified only observational studies from which individual patient data could be drawn. Limitations in study design, and heterogeneity in a number of the outcomes of interest had the potential to introduce bias. Discussion While there are insufficient data to determine if ART use increases adverse drug interactions when used with second line TB drugs, ART use during treatment of drug resistant TB appears to improve cure rates and decrease risk of death. All individuals with HIV appear to benefit from ART use during treatment for TB.

Impact of smear microscopy results and observed therapy on tuberculosis treatment in Mombasa, Kenya.

SETTING Tuberculosis (TB) treatment center at Coast Provincial General Hospital in Mombasa, Kenya. OBJECTIVES To describe TB management practices in a facility in coastal Kenya and identify factors associated with poor treatment outcomes. DESIGN Retrospective review of patient treatment records from January 2008 to June 2009. Treatment outcomes of patients were classified as treatment success (cure or treatment completion) or poor treatment outcome (treatment failure, death or default). Relative risk regression was used to determine the association between exposures of interest and poor treatment outcomes. RESULTS Records were obtained from a total of 183 patients: 142 (78%) had pulmonary TB, 68 (37%) were human immunodeficiency virus (HIV) infected and 81 (44%) had acid-fast bacilli (AFB) positive smear micros- copy. Most treated individuals (86%) achieved a successful treatment outcome as defined by the World Health Organization. Of those with poor treatment outcomes, 64% defaulted, 32% died, and 4% failed treatment. Initial negative AFB smear and HIV co-infection were associated with poor treatment outcomes (RR 3.32, 95%CI 1.22-8.99 and RR 4.61, 95%CI 1.69- 12.59, respectively). CONCLUSION Strategies to accelerate accurate diagnosis of smear-negative TB and increase patient retention during treatment, especially in HIV co-infected individuals, are needed to reduce poor treatment outcomes in Kenya.