Christine Ho

Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Use of Whole Genome Sequencing to Determine the Microevolution of Mycobacterium tuberculosis during an Outbreak

Rationale Current tools available to study the molecular epidemiology of tuberculosis do not provide information about the directionality and sequence of transmission for tuberculosis cases occurring over a short period of time, such as during an outbreak. Recently, whole genome sequencing has been used to study molecular epidemiology of Mycobacterium tuberculosis over short time periods. Objective To describe the microevolution of M. tuberculosis during an outbreak caused by one drug-susceptible strain. Method and Measurements We included 9 patients with tuberculosis diagnosed during a period of 22 months, from a population-based study of the molecular epidemiology in San Francisco. Whole genome sequencing was performed using Illumina’s sequencing by synthesis technology. A custom program written in Python was used to determine single nucleotide polymorphisms which were confirmed by PCR product Sanger sequencing. Main results We obtained an average of 95.7% (94.1–96.9%) coverage for each isolate and an average fold read depth of 73 (1 to 250). We found 7 single nucleotide polymorphisms among the 9 isolates. The single nucleotide polymorphisms data confirmed all except one known epidemiological link. The outbreak strain resulted in 5 bacterial variants originating from the index case A1 with 0–2 mutations per transmission event that resulted in a secondary case. Conclusions Whole genome sequencing analysis from a recent outbreak of tuberculosis enabled us to identify microevolutionary events observable during transmission, to determine 0–2 single nucleotide polymorphisms per transmission event that resulted in a secondary case, and to identify new epidemiologic links in the chain of transmission.

Evaluation of Quantitative IFN-γ Response for Risk Stratification of Active Tuberculosis Suspects

RATIONALE The contribution of interferon-gamma release assays (IGRAs) to appropriate risk stratification of active tuberculosis suspects has not been studied. OBJECTIVES To determine whether the addition of quantitative IGRA results to a prediction model incorporating clinical criteria improves risk stratification of smear-negative-tuberculosis suspects. METHODS Clinical data from tuberculosis suspects evaluated by the San Francisco Department of Public Health Tuberculosis Control Clinic from March 2005 to February 2008 were reviewed. We excluded tuberculosis suspects who were acid fast-bacilli smear-positive, HIV-infected, or under 10 years of age. We developed a clinical prediction model for culture-positive disease and examined the benefit of adding quantitative interferon (IFN)-gamma results measured by QuantiFERON-TB Gold (Cellestis, Carnegie, Australia). MEASUREMENTS AND MAIN RESULTS Of 660 patients meeting eligibility criteria, 65 (10%) had culture-proven tuberculosis. The odds of active tuberculosis increased by 7% (95% confidence interval [CI], 3-11%) for each doubling of IFN-gamma level. The addition of quantitative IFN-gamma results to objective clinical data significantly improved model performance (c-statistic 0.71 vs. 0.78; P < 0.001) and correctly reclassified 32% of tuberculosis suspects (95% CI,11-52%; P < 0.001) into higher-risk or lower-risk categories. However, quantitative IFN-gamma results did not significantly improve appropriate risk reclassification beyond that provided by clinician assessment of risk (4%; 95% CI, -7 to +22%; P = 0.14). CONCLUSIONS Higher quantitative IFN-gamma results were associated with active tuberculosis, and added clinical value to a prediction model incorporating conventional risk factors. Although this benefit may be attenuated within highly experienced centers, the predictive accuracy of quantitative IFN-gamma levels should be evaluated in other settings.

Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study

BACKGROUND Weekly rifapentine plus isoniazid for 3 months (3HP) is as effective as daily isoniazid for 9 months (9H) for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome. METHODS We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT Tuberculosis study. RESULTS Among 7552 persons who received ≥ 1 dose of study drug, 153 had a SDR: 138/3893 (3.5%) with 3HP vs 15/3659 (0.4%) with 9H (P < .001). In the 3HP arm, 87 (63%) had flu-like syndrome and 23 (17%) had cutaneous reactions; 13/3893 (0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (adjusted odds ratio [aOR] 9.4; 95% confidence interval [CI], 5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3; 95% CI, 2.3, 4.7), female sex (aOR 2.0; 95% CI, 1.4, 2.9), age ≥ 35 years (aOR 2.0; 95% CI, 1.4, 2.9), and lower body mass index (body mass index [BMI]; P = .009). In a separate multivariate analysis among persons who received 3HP, severe SDR were associated with white non-Hispanic race/ethnicity (aOR 5.4; 95% CI, 1.8, 16.3), and receipt of concomitant non-study medications (aOR 5.9; 95% CI, 1.3, 27.1). CONCLUSIONS SDR were more common with 3HP, and mostly flu-like. Persons of white race, female sex, older age, and lower BMI were at increased risk. Severe reactions were rare and associated with 3HP, concomitant medication, and white race. The underlying mechanism is unclear. CLINICAL TRIALS REGISTRATION NCT00023452.

Programmatic impact of using QuantiFERON®-TB Gold in routine contact investigation activities.

OBJECTIVES To retrospectively assess the proportion of contacts tested with QuantiFERON ® -TB Gold (QFT-G) compared to the tuberculin skin test (TST) who were successfully evaluated and treated for latent tuberculosis infection (LTBI), and to assess the correlation of positive test results with measures of TB exposure. METHODS Contacts of culture-confirmed pulmonary TB cases reported to the San Francisco Department of Public Health between 1 March 2005 and 31 December 2007 were included. RESULTS Of 1291 contacts meeting the eligibility criteria, 641 (50%) were tested with QFT-G and 650 (50%) with TST. Contacts tested with QFT-G were more likely to complete evaluation (64% vs. 56%, OR(adj ) = 1.52, 95%CI 1.12-2.06). Infected contacts started (89% vs. 72%, OR(adj) = 5.18, 95%CI 2.10-14.18) and completed (70% vs. 53%, OR(adj) = 3.37, 95%CI 1.78-6.56) LTBI treatment more often in the group tested with QFT-G. Positive QFT-G results, but not positive TST results, correlated with the intensity, proximity and duration of TB exposure in foreign-born subjects. CONCLUSION More contacts were successfully evaluated and treated for LTBI when screened with QFT-G compared to TST. Measures of exposure correlated better with QFT-G-positive results and, therefore, appropriately identified high-risk contacts for TB prevention.

Impact of GeneXpert MTB/RIF on Patients and Tuberculosis Programs in a Low-Burden Setting. A Hypothetical Trial

RATIONALE Guidelines recommend routine nucleic-acid amplification testing in patients with presumed tuberculosis (TB), but these tests have not been widely adopted. GeneXpert MTB/RIF (Xpert), a novel, semiautomated TB nucleic-acid amplification test, has renewed interest in this technology, but data from low-burden countries are limited. OBJECTIVES We sought to estimate Xperts potential clinical and public health impact on empiric treatment, contact investigation, and housing in patients undergoing TB evaluation. METHODS We performed a prospective, cross-sectional study with 2-month follow-up comparing Xpert with standard strategies for evaluating outpatients for active pulmonary TB at the San Francisco Department of Public Health TB Clinic between May 2010 and June 2011. We calculated the diagnostic accuracy of standard algorithms for initial empiric TB treatment, contact investigation, and housing in reference to three Mycobacterium tuberculosis sputum cultures, as compared with that of a single sputum Xpert test. We estimated the incremental diagnostic value of Xpert, and the hypothetical reductions in unnecessary treatment, contact investigation, and housing if Xpert were adopted to guide management decisions. MEASUREMENTS AND MAIN RESULTS A total of 156 patients underwent Xpert testing. Fifty-nine (38%) received empiric TB treatment. Thirteen (8%) had culture-positive TB. Xpert-guided management would have hypothetically decreased overtreatment by 94%, eliminating a median of 44 overtreatment days (interquartile range, 43-47) per patient and 2,169 total overtreatment days (95% confidence interval, 1,938-2,400) annually, without reducing early detection of TB patients. We projected similar benefits for contact investigation and housing. CONCLUSIONS Xpert could greatly reduce the frequency and impact of unnecessary empiric treatment, contact investigation, and housing, providing substantial patient and programmatic benefits if used in management decisions.

Interferon-Gamma Release Assays and Pediatric Public Health Tuberculosis Screening: The San Francisco Program Experience 2005 to 2008

BACKGROUND Interferon-gamma release assay utilization in pediatric tuberculosis (TB) screening is limited by a paucity of longitudinal experience, particularly in low-TB burden populations. METHODS We conducted a retrospective review of QuantiFERON (QFT)-TB Gold results in San Francisco children from 2005 to 2008. Concordance with the tuberculin skin test (TST) was analyzed for a subset of children. Progression to active disease was determined through San Francisco and California TB registry matches. RESULTS Of 1092 children <15 years of age, 853 (78%) were foreign-born, and 136 (12%) were exposed to active TB cases (contacts). QuantiFERON tests were positive in 72 of 1092 (7%) children; 15 of 136 (11%) recent contacts; 53 of 807 (7%) foreign-born noncontacts; and 4 of 149 (3%) US-born noncontacts. QuantiFERON-negative/TST-positive discordance was seen more often in foreign-born/bacille Calmette-Guerin (BCG)-vaccinated children <5 years of age (52 of 56, 93%) compared to those ≥ 5 years of age (90 of 123, 73%; P = .003). Foreign-born, BCG-vaccinated children were more than twice as likely to have a discordant (79%) result as US-born, non-BCG-vaccinated children (37%; P < .0001). During 5587 person-years of follow-up of untreated children, including 146 TST-positive/QFT-negative children, no cases of active TB were identified, consistent with a negative predictive value of 100%. CONCLUSIONS Our experience supports the use of QFT to evaluate latent TB infection in children, particularly young BCG-vaccinated children. The proportion of QFT-positive results correlated with risk of exposure, and none of the untreated QFT-negative children developed TB. The low QFT-positive rate highlights the need for more selective testing based on current epidemiology and TB exposure risk.

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.

Tuberculosis Elimination Efforts in the United States in the Era of Insurance Expansion and the Affordable Care Act

The Patient Protection and Affordable Care Act can enhance ongoing efforts to control tuberculosis (TB) in the United States by bringing millions of currently uninsured Americans into the health-care system. However, much of the legislative and financial framework that provides essential public health services necessary for effective TB control is outside the scope of the law. We identified three key issues that will still need to be addressed after full implementation of the Affordable Care Act: (1) essential TB-related public health functions will still be needed and will remain the responsibility of federal, state, and local health departments; (2) testing and treatment for latent TB infection (LTBI) is not covered explicitly as a recommended preventive service without cost sharing or copayment; and (3) remaining uninsured populations will disproportionately include groups at high risk for TB. To improve and continue TB control efforts, it is important that all populations at risk be tested and treated for LTBI and TB; that testing and treatment services be accessible and affordable; that essential federal, state, and local public health functions be maintained; that private-sector medical/public health linkages for diagnosis and treatment be developed; and that health-care providers be trained in conducting appropriate LTBI and TB clinical care.

Tuberculosis in Jails and Prisons: United States, 2002−2013

OBJECTIVES To describe cases and estimate the annual incidence of tuberculosis in correctional facilities. METHODS We analyzed 2002 to 2013 National Tuberculosis Surveillance System case reports to characterize individuals who were employed or incarcerated in correctional facilities at time they were diagnosed with tuberculosis. Incidence was estimated with Bureau of Justice Statistics denominators. RESULTS Among 299 correctional employees with tuberculosis, 171 (57%) were US-born and 82 (27%) were female. Among 5579 persons incarcerated at the time of their tuberculosis diagnosis, 2520 (45%) were US-born and 495 (9%) were female. Median estimated annual tuberculosis incidence rates were 29 cases per 100 000 local jail inmates, 8 per 100 000 state prisoners, and 25 per 100 000 federal prisoners. The foreign-born proportion of incarcerated men 18 to 64 years old increased steadily from 33% in 2002 to 56% in 2013. Between 2009 and 2013, tuberculosis screenings were reported as leading to 10% of diagnoses among correctional employees, 47% among female inmates, and 42% among male inmates. CONCLUSIONS Systematic screening and treatment of tuberculosis infection and disease among correctional employees and incarcerated individuals remain essential to tuberculosis prevention and control.