Evidence Synthesis Number 142 Screening for Latent Tuberculosis Infection in Adults: An Evidence Review for the U.S. Preventive Services Task Force Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 5600 Fishers Lane Rockville, MD 20857 www.ahrq.gov Contract No. HHSA-290-2012-00015-I, Task Order No. 4 Prepared by: RTI International–University of North Carolina Evidence-based Practice Center Research Triangle Park, NC Investigators: Leila C. Kahwati, MD, MPH Cynthia Feltner, MD, MPH Michael Halpern, MD, PhD, MPH Carol L. Woodell, BSPH Erin Boland, BA Halle R. Amick, MSPH Rachel Palmieri Weber, PhD Daniel E. Jonas, MD, MPH AHRQ Publication No. 14-05212-EF-1 September 2016 This report is based on research conducted by the RTI International–University of North Carolina Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. HHSA-290-2012-00015-I, Task Order No. 4). The findings and conclusions in this document are those of the authors, who are responsible for its contents, and do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information (i.e., in the context of available resources and circumstances presented by individual patients). This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. This document is in the public domain and may be used and reprinted without permission except those copyrighted materials that are clearly noted in the document. Further reproduction of those copyrighted materials is prohibited without the specific permission of copyright holders. None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report. Acknowledgments The authors acknowledge the following individuals for their contributions to this project: Tina Fan, MD, MPH, AHRQ Medical Officer; Tracy Wolff, MD, MPH, Associate Scientific Director; current and former members of the U.S. Preventive Services Task Force who contributed to topic deliberations; Philip LoBue, MD, FACP, FCCP, and Christine Ho, MD, Centers for Disease Control and Prevention; expert reviewers John Bernardo, MD, Boston University School of Medicine, Dick Menzies, MD, MSc, McGill University, Neil Schluger, MD, Columbia University Medical Center, and Steven Teutsch, MD, MPH, Robert Wood Johnson Foundation; federal partner reviewers from the Centers for Disease Control and Prevention; Evelyn Whitlock, MD, MPH, Director, Kaiser Permanente Research Affiliates EPC; and RTI International– University of North Carolina EPC staff Meera Viswanathan, PhD, Russell Harris, MD, MPH, Molly Howard, PharmD, BCPS, CPP, Makda Majerette, BA, Roberta C. Wines, MPH, Christiane Voisin, MSLS, Rachael Posey, MSLS, Janice Handler, BA, Jennifer Drolet, MA, and Loraine Monroe. Screening for Latent Tuberculosis Infection ii RTI–UNC EPC Suggested Citation Kahwati LC, Feltner C, Halpern M, Woodell CL, Boland E, Amick HR, Weber RP, Jonas DE. Screening for Latent Tuberculosis Infection in Adults: An Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 142. AHRQ Publication No. 14-05212- EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2016. Screening for Latent Tuberculosis Infection iii RTI–UNC EPC Structured Abstract Purpose: To review evidence about targeted screening for and treatment of latent tuberculosis infection (LTBI) among adults in primary care settings. Data Sources: MEDLINE, the Cochrane Library, and trial registries through August 3, 2015; bibliographies from retrieved articles, outside experts, and reviewers, with surveillance of the literature through May 31, 2016. Study Selection: Two investigators independently selected studies using a priori inclusion and exclusion criteria. We selected studies that evaluated the tuberculin skin test (TST) using the Mantoux method or tests evaluating commercial interferon-gamma release assays (IGRAs). We selected trials of treatment that evaluated pharmacotherapy regimens that are currently recommended by the Centers for Disease Control and Prevention for the treatment of LTBI for synthesis of benefits and harms. We excluded studies of persons with underlying immunosuppression and for whom LTBI screening and treatment would be part of standard disease management by specialty care providers (e.g., persons with HIV, history of or planned organ transplant, or planned or active use of tumor necrosis factor-alpha inhibitors). We excluded poor-quality studies, studies assessing specificity in countries with a high tuberculosis (TB) burden, and studies assessing harms and benefits in developing countries. Data Extraction: One investigator extracted data and a second checked accuracy. Two reviewers independently rated quality for all included studies using predefined criteria. Data Synthesis: We did not identify any studies that compared screening with no screening. We included 72 studies of fair to good quality; 67 assessed test accuracy or reliability and five assessed benefits and harms of treatment. Pooled estimates for sensitivity of TST at both the 5- mm and 10-mm induration thresholds for positivity were 0.79; the pooled estimate at the 15-mm threshold was 0.52. Pooled estimates for sensitivity of IGRA tests ranged from 0.77 to 0.90. Estimates for specificity of TST at the 5-mm threshold varied considerably by TB burden of the study setting (0.94 to 0.97 in low-burden countries and 0.30 in an intermediate-burden country). Pooled estimates for specificity at the 10-mm and 15-mm thresholds were 0.97 and 0.99, respectively. Pooled estimates for specificity of IGRA tests ranged from 0.95 to 0.98. We found evidence for at least moderate interrater reliability for both TST and IGRA tests. The best evidence on effectiveness of treatment of LTBI was from the International Union Against Tuberculosis (IUAT) trial, a large (N=27,830) good-quality randomized, controlled trial (RCT) that evaluated multiple treatment durations for daily isoniazid. It found a relative risk (RR) for progression to active TB at 5 years of 0.35 (95% confidence interval [CI], 0.24 to 0.52) for 24 weeks of isoniazid compared with placebo (N=13,955; number needed to treat, 112). Our sensitivity analyses adding four RCTs that did not meet all of our eligibility criteria (e.g., compared isoniazid with placebo using a longer duration of treatment or used different doses than currently recommended) found an RR of 0.31 (95% CI, 0.24 to 0.41; I2=0%; 5 RCTs, N=36,823). A head-to-head, open-label, noninferiority RCT that compared a combination of once-weekly rifapentine plus isoniazid for 3 months with daily isoniazid for 9 months found the combination therapy to be noninferior to isoniazid alone for preventing the development of Screening for Latent Tuberculosis Infection iv RTI–UNC EPC active TB. For harms, the IUAT trial reported an RR for hepatotoxicity of 4.59 (95% CI, 2.03 to 10.39; number needed to harm [NNH], 279) for 24 weeks of isoniazid compared with placebo. Sensitivity analyses pooling the IUAT with three RCTs that used a longer duration of isoniazid yielded a similar result (pooled RR, 5.04 [95% CI, 2.50 to 10.15]; I2=0%; 4 RCTs, N=35,161). The RR of treatment discontinuation because of adverse effects across all treatment duration arms in IUAT was 1.50 (95% CI, 1.18 to 1.89; N=27,830; NNH, 167). For isoniazid compared with rifampin, the pooled RR for hepatotoxicity was 3.29 (95% CI, 1.72 to 6.28; I2=0%; 3 RCTs, N=1,327) and the pooled RR for treatment discontinuation because of adverse events was 1.61 (95% CI, 0.57 to 4.57; I2=40.0%; 3 RCTs, N=1,327). Limitations: No test for the direct diagnosis of LTBI exists; thus, studies of test accuracy use subjects with confirmed active TB to establish sensitivity and healthy, low-risk subjects to establish specificity. Thus, applicability to other populations is uncertain. The single trial meeting all eligibility criteria that established the benefits of a currently recommended treatment (isoniazid 300 mg daily for 24 weeks) for preventing active TB was published more than 30 years ago and was conducted among subjects with pulmonary fibrotic lesions; whether it may overestimate the benefits of treatment for populations with lower risk for progression is not clear. No trials evaluated the effectiveness (compared with placebo) of regimens other than isoniazid. Contemporary treatment studies have not included placebo arms; when available, information on benefits and harms of newer treatments are derived from comparative studies (vs. isoniazid). The evidence on harms is limited by heterogeneous specification of outcomes across studies. This review is not applicable to persons with the highest risk, for whom testing and treatment is considered part of disease management or public health surveillance. Conclusions: We did not find any studies evaluating the direct benefits and harms of screening for LTBI in the adult populations and settings included in this review. Both types of currently available tests (TST and IGRA) are moderately sensitive and, within countries with a low TB burden, highly specific.