Tuberculosis (TB) is the leading cause of death for persons living with the human immunodeficiency virus (PLHIV). TB preventive therapy (TPT) works synergistically with, and independently of, antiretroviral therapy to reduce TB morbidity, mortality and incidence among PLHIV. However, although TPT is a crucial and cost-effective component of HIV care for adults and children and has been recommended as an international standard of care for over a decade, it remains highly underutilized. If we are to end the global TB epidemic, we must address the significant reservoir of tuberculous infection, especially in those, such as PLHIV, who are most likely to progress to TB disease. To do so, we must confront the pervasive perception that barriers to TPT scale-up are insurmountable in resource-limited settings. Here we review available evidence to address several commonly stated obstacles to TPT scale-up, including the need for the tuberculin skin test, limited diagnostic capacity to reliably exclude TB disease, concerns about creating drug resistance, suboptimal patient adherence to therapy, inability to monitor for and prevent adverse events, a 'one size fits all' option for TPT regimen and duration, and uncertainty about TPT use in children, adolescents, and pregnant women. We also discuss TPT delivery in the era of differentiated care for PLHIV, how best to tackle advanced planning for drug procurement and supply chain management, and how to create an enabling environment for TPT scale-up success.

SUMMARY SETTING-Multidrug-resistant tuberculosis (MDR-TB) treatment facility, Orel Oblast, Russian Federation.OBJECTIVES-To determine factors associated with poor outcome and to document status of patients after recording of TB outcomes. DESIGN-Retrospective review of prospective single cohort.RESULTS-Among 192 patients, factors significantly associated with poor outcome in multivariate analysis include three or more treatment interruptions during the intensive phase of therapy and alcohol or drug addiction (adjusted OR [aOR] 2.1, 95%CI 1.0-4.3 and aOR 1.9, 95%CI 1.0-3.7). Previous treatment was associated with poor outcome, but only among smearpositive patients (aOR 3.1,3). Ten patients (5%) developed extensively drugresistant TB (XDR-TB) during treatment; of 115 patients with at least 6 months of follow-up data after outcomes were recorded, 13 (11%) developed XDR-TB.CONCLUSION-Interventions focused on supporting patient adherence during the intensive phase of treatment; the management of drug and alcohol addiction should be developed and studied. A substantial proportion of patients developed XDR-TB during and after treatment. Longer term follow-up data of patients treated for MDR-TB are needed to better inform programmatic policy. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptTreatment outcomes for multidrug-resistant tuberculosis (MDR-TB), defined as TB caused by Mycobacterium tuberculosis strains resistant to both isoniazid (INH) and rifampin (RMP), are significantly worse than for drug-susceptible TB, but have varied widely. [1][2][3][4] Moreover, patients documented as having a good outcome do not always do well over time. [5][6][7][8] However, few reports have documented longer term follow-up of patients uniformly treated with second-line agents. Extensively drug-resistant TB (XDR-TB), defined as MDR-TB that is additionally resistant to a fluoroquinolone and an injectable second-line drug (SLD), is even more difficult to treat than MDR-TB; 9-13 however, relatively little has been documented about the risks of developing XDR-TB during and after the treatment of MDR-TB. 14 Political change and economic difficulties in Russia in the 1990s contributed to difficulties obtaining medications, which increased the incidence of MDR-TB. 15 By 2000, the prevalence of MDR-TB among newly treated patients in some oblasts exceeded 9%. 16 Treatment success, and risk factors associated with outcome, among patients in MDR-TB treatment programs in countries of the former Soviet Union have varied. 4,9,17,18 A better appreciation of these differences in treatment outcome may help elucidate reasons for treatment success or failure, and guide programmatic policy.The Orel Oblast DOTS-Plus Tuberculosis Treatment Project was one of the first Green Light Committee (GLC) approved programs in the Russian Federation specifically designed to treat MDR-TB with individualized regimens. The first cohort began enrollment in 2002, and the program has been active since.The purpose of this analysis...

Introduction Pyrazinamide (PZA) is essential in tuberculosis (TB) treatment. We describe the prevalence, trends and predictors of PZA resistance in Mycobacterium tuberculosis complex (MTBC) in the U.S. Methods We analyzed culture-positive MTBC cases with reported drug susceptibility tests (DST) for PZA in 38 jurisdictions routinely testing for PZA susceptibility from 1999-2009. National TB Genotyping Service data for 2004-2009 were used to distinguish Mycobacterium tuberculosis from Mycobacterium bovis and determine phylogenetic lineage. Results Overall 2.7% (2,167/79,321) of MTBC cases had PZA resistance, increasing annually from 2.0% to 3.3% during 1999-2009 (P<0.001), largely due to an increase in PZA monoresistance. PZA-monoresistant MTBC (versus drug-susceptible) was associated with age 0-24 years (adjusted prevalence ratio [aPR]=1.50, 95% CI 1.31-1.71), Hispanic ethnicity (aPR=3.52, 2.96-4.18), HIV infection (aPR=1.43, 1.15-1.77), extrapulmonary disease (aPR=3.02, 2.60-3.52), and normal chest radiograph (aPR=1.88, 1.63-2.16), and inversely associated with Asian (aPR=0.59, 0.47-0.73) and Black (aPR=0.37, 0.29-0.49) race. Among multidrug-resistant (MDR) cases 38.0% were PZA-resistant; PZA resistance in MDR MTBC was associated with female sex (aPR=1.25, 1.08-1.46) and previous TB diagnosis (aPR=1.37, 1.16-1.62). Of 28,080 cases with genotyping data, 925 (3.3%) had PZA resistance; 465/925 (50.3%) were M. bovis. In non-MDR M. tuberculosis cases, PZA resistance was higher in the Indo-Oceanic than the East Asian lineage (2.2% versus 0.9%; respectively; aPR=2.26, 1.53-3.36), but in MDR cases it was lower in the Indo-Oceanic lineage (22.0% versus 43.4%, respectively; aPR=0.54, 0.32-0.90). Conclusions Specific human and mycobacterial characteristics were associated with pyrazinamide-resistant MTBC, reflecting both specific subgroups of the population and phylogenetic lineages of the mycobacteria.

SummaryFollowing WHO's endorsement of the Xpert® MTB/RIF assay, which rapidly and simultaneously diagnoses tuberculosis (TB) and detects resistance to rifampin (RIF), the question arises to what extent RIF resistance is an adequate marker for multidrug-resistant (MDR) TB. A retrospective analysis of data from >81 countries and subnational settings demonstrated that >40% of RIF resistant isolates from new TB cases did not display resistance to isoniazid (INH) in settings with relatively low MDR-TB prevalence (1/3 of all countries and subnational settings). Results indicated the need for INH susceptibility testing in addition to RIF susceptibility testing.

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ObjectiveTo assess the performance of symptom-based screening for tuberculosis (TB), alone and with chest radiography among people living with HIV (PLHIV), including pregnant women, in Western Kenya.DesignProspective cohort studyMethodsPLHIV from 15 randomly-selected HIV clinics were screened with three clinical algorithms [World Health Organization (WHO), Ministry of Health (MOH), and “Improving Diagnosis of TB in HIV-infected persons” (ID-TB/HIV) study], underwent chest radiography (unless pregnant), and provided two or more sputum specimens for smear microscopy, liquid culture, and Xpert MTB/RIF. Performance of clinical screening was compared to laboratory results, controlling for the complex design of the survey.ResultsOverall, 738 (85.6%) of 862 PLHIV enrolled were included in the analysis. Estimated TB prevalence was 11.2% (95% CI, 9.9–12.7). Sensitivity of the three screening algorithms was similar [WHO, 74.1% (95% CI, 64.1–82.2); MOH, 77.5% (95% CI, 68.6–84.5); and ID-TB/HIV, 72.5% (95% CI, 60.9–81.7)]. Sensitivity of the WHO algorithm was significantly lower among HIV-infected pregnant women [28.2% (95% CI, 14.9–46.7)] compared to non-pregnant women [78.3% (95% CI, 67.3–86.4)] and men [77.2% (95% CI, 68.3–84.2)]. Chest radiography increased WHO algorithm sensitivity and negative predictive value to 90.9% (95% CI, 86.4–93.9) and 96.1% (95% CI, 94.4–97.3), respectively, among asymptomatic men and non-pregnant women.ConclusionsClinical screening missed approximately 25% of laboratory-confirmed TB cases among all PLHIV and more than 70% among HIV-infected pregnant women. National HIV programs should evaluate the feasibility of laboratory-based screening for TB, such as a single Xpert MTB/RIF test for all PLHIV, especially pregnant women, at enrollment in HIV services.

Children, foreign-born persons, Hispanics, and females are disproportionately affected by M. bovis, which was independently associated with extrapulmonary disease. Targeted prevention efforts aimed at Hispanic mothers and caregivers are warranted.

Based on data from 14 Supranational Tuberculosis (TB) Reference Laboratories worldwide, the proportion of rifampicin-resistant isolates that were isoniazid-susceptible by phenotypic drugsusceptibility tests varied widely (0.5%-11.6%). Rifampicin-resistant isolates that were isoniazidsusceptible had significantly lower rates of resistance to other first-line and second-line anti-TB drugs (except rifabutin) compared to multidrug-resistant isolates. Rifampicin resistance is not always a good proxy for a presumptive diagnosis of multidrug-resistant tuberculosis, which has implications for use of molecular assays that identify only rifampicin resistance-associated DNA mutations.