Robert Belknap, MD; David Holland, MD, MHS; Pei-Jean Feng, MPH; Joan-Pau Millet, MD, MPH; Joan A. Caylà, MD, PhD; Neil A. Martinson, MBBCh, MPH; Alicia Wright, BS; Michael P. Chen, PhD; Ruth N. Moro, MD, MPH; Nigel A. Scott, MS; Bert Arevalo, BS, CCRP; José M. Miró, MD, PhD; Margarita E. Villarino, MD, MPH; Marc Weiner, MD; Andrey S. Borisov, MD, MPH (*); for the TB Trials Consortium iAdhere Study Team (*)
Financial Support: By the Centers for Disease Control and Prevention's Tuberculosis Trials Consortium.
Disclosures: Dr. Belknap reports grants from the Centers for Disease Control and Prevention (CDC) during the conduct of the study. Dr. Martinson reports that his institution has been contracted to contribute samples to studies of novel tuberculosis assays by 3 companies. Ms. Wright reports grants from the CDC during the conduct of the study. Dr. Moro reports that Sanofi donated rifapentine and rifampin and since 2007 has donated over $2.9 million to the CDC Foundation to supplement available U.S. federal funding for rifapentine research; these funds included salary support for Dr. Moro while this study was conducted. Mr. Scott reports that Sanofi donated rifapentine and since 2007 has donated over $2.9 million to the CDC Foundation to supplement available U.S. federal funding for rifapentine research; in the past, these funds included salary support for Mr. Scott. Dr. Miró reports grants and personal fees from AbbVie, Angelini, Bristol-Myers Squibb, Genentech, Gilead Sciences, Medtronic, Merck/MSD, Novartis, and ViiV Healthcare outside the submitted work. Dr. Weiner reports grants from Veterans Administration during the conduct of the study. Dr. Borisov reports that Sanofi, manufacturer of Priftin (rifapentine) evaluated in this research, donated study drugs to this clinical trial. Also, since 2007 Sanofi has donated over $2.9 million to the CDC Foundation (nongovernment organization) to supplement available U.S. federal funding for CDC's rifapentine research; in the past, these funds included salary support for the Foundation's contractors working at the CDC. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-1150.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: Available in the Supplement. Statistical code and data set: Not available.
Requests for Single Reprints: Robert Belknap, MD, 605 Bannock Street, Denver, CO 80204; e-mail, email@example.com.
Current Author Addresses: Dr. Belknap: Denver Public Health, 605 Bannock Street, Denver, CO 80204.
Dr. Holland: Emory Healthcare, Department of Medicine, Division of Infectious Diseases, 49 Jesse Hill Jr. Drive SE, Atlanta, GA 30303.
Ms. Feng; Drs. Chen, Moro, Villarino, and Borisov; and Mr. Scott: U.S. Centers for Disease Control and Prevention, Mailstop E-10, 1600 Clifton Road, Atlanta, GA 30329.
Dr. Millet: Public Health Agency of Barcelona, Epidemiology Service, Passatge de les Delícies, 5, Sant Cugat del Vallès (Les Planes), Barcelona 08196, Spain.
Dr. Caylà: Public Health Agency of Barcelona, Epidemiology Service, M. Xirgu, 50 àtic-2a, Badalona 08911, Spain.
Dr. Martinson: Perinatal HIV Research Unit, PO Box 144, Diepkloof 1864, South Africa.
Ms. Wright: Metro (Nashville/Davidson County) Public Health Department, Vanderbilt University's Tuberculosis Trials Consortium Unit, 2500 Charlotte Avenue, Nashville, TN 37209.
Mr. Arevalo: WESTAT, 237 SE 3rd Terrace, Dania Beach, FL 33004.
Dr. Miró: Hospital Clinic—IDIBAPS, University of Barcelona, Paseo de San Juan, 104, 5°–2a, Barcelona 08037, Spain.
Dr. Weiner: South Texas Veterans Health Care System, Medicine/Infectious Diseases (111F), 7400 Merton Minter Boulevard, San Antonio, TX 78229.
Author Contributions: Conception and design: R. Belknap, D. Holland, J.P. Millet, J.A. Caylà, A. Wright, M.P. Chen, J.M. Miró, M.E. Villarino, A.S. Borisov.
Analysis and interpretation of the data: R. Belknap, D. Holland, P.J. Feng, J.P. Millet, J.A. Caylà, M.P. Chen, R.N. Moro, N.A. Scott, J.M. Miró, M.E. Villarino, A.S. Borisov.
Drafting of the article: R. Belknap, D. Holland, J.P. Millet, J.A. Caylà, A. Wright, A.S. Borisov.
Critical revision of the article for important intellectual content: R. Belknap, D. Holland, J.P. Millet, J.A. Caylà, A. Wright, M.P. Chen, R.N. Moro, J.M. Miró, M.E. Villarino, A.S. Borisov.
Final approval of the article: R. Belknap, D. Holland, P.J. Feng, J.P. Millet, J.A. Caylà, N.A. Martinson, A. Wright, M.P. Chen, R.N. Moro, N.A. Scott, B. Arevalo, J.M. Miró, M.E. Villarino, M. Weiner, A.S. Borisov.
Provision of study materials or patients: R. Belknap, J.P. Millet, J.A. Caylà, N.A. Martinson, A. Wright, J.M. Miró, M. Weiner.
Statistical expertise: J.P. Millet, J.A. Caylà, M.P. Chen, R.N. Moro.
Obtaining of funding: M.E. Villarino.
Administrative, technical, or logistic support: D. Holland, J.A. Caylà, B. Arevalo, A.S. Borisov.
Collection and assembly of data: R. Belknap, D. Holland, P.J. Feng, J.P. Millet, J.A. Caylà, N.A. Martinson, A. Wright, R.N. Moro, N.A. Scott, J.M. Miró, M. Weiner, A.S. Borisov.
Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation.
To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self-administration versus direct observation.
An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711)
Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa.
1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection.
Participants received once-weekly isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring.
The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event–monitoring devices for self-administration. The main secondary outcome was adverse events.
Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration–with–reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met noninferiority criteria. A few drug-related adverse events occurred and were similar across groups.
Persons with latent tuberculosis infection enrolled in South Africa would not routinely be treated programmatically.
These results support using self-administered, once-weekly isoniazid and rifapentine to treat latent tuberculosis infection in the United States, and such treatment could be considered in similar settings when direct observation is not feasible.
Centers for Disease Control and Prevention.
Robert Belknap, David Holland, Pei-Jean Feng, Joan-Pau Millet, Joan A. Caylà, Neil A. Martinson, et al. Self-administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine Treatment of Latent Tuberculosis Infection: A Randomized Trial. Ann Intern Med. 2017;167:689–697. doi: 10.7326/M17-1150
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Published: Ann Intern Med. 2017;167(10):689-697.
Published at www.annals.org on 7 November 2017
Infectious Disease, Mycobacterial Infections.
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