Wirelessly observed therapy compared to directly observed therapy to confirm and support tuberculosis treatment adherence: A randomized controlled trial

Autoři: Sara H. Browne aff001;  Anya Umlauf aff001;  Amanda J. Tucker aff001;  Julie Low aff002;  Kathleen Moser aff003;  Jonathan Gonzalez Garcia aff001;  Charles A. Peloquin aff004;  Terrence Blaschke aff005;  Florin Vaida aff001;  Constance A. Benson aff001
Působiště autorů: University of California San Diego, La Jolla, California, United States of America aff001;  Orange County Health Care Agency, Santa Ana, California, United States of America aff002;  Health and Human Services Agency, San Diego, California, United States of America aff003;  University of Florida, Gainesville, Florida, United States of America aff004;  Stanford University, Stanford, California, United States of America aff005
Vyšlo v časopise: Wirelessly observed therapy compared to directly observed therapy to confirm and support tuberculosis treatment adherence: A randomized controlled trial. PLoS Med 16(10): e32767. doi:10.1371/journal.pmed.1002891
Kategorie: Research Article
doi: 10.1371/journal.pmed.1002891



Excellent adherence to tuberculosis (TB) treatment is critical to cure TB and avoid the emergence of resistance. Wirelessly observed therapy (WOT) is a novel patient self-management system consisting of an edible ingestion sensor (IS), external wearable patch, and paired mobile device that can detect and digitally record medication ingestions. Our study determined the accuracy of ingestion detection in clinical and home settings using WOT and subsequently compared, in a randomized control trial (RCT), confirmed daily adherence to medication in persons using WOT or directly observed therapy (DOT) during TB treatment.

Methods and findings

We evaluated WOT in persons with active Mycobacterium tuberculosis complex disease using IS-enabled combination isoniazid 150 mg/rifampin 300 mg (IS-Rifamate). Seventy-seven participants with drug-susceptible TB in the continuation phase of treatment, prescribed daily isoniazid 300 mg and rifampin 600 mg, used IS-Rifamate. The primary endpoints of the trial were determination of the positive detection accuracy (PDA) of WOT, defined as the percentage of ingestions detected by WOT administered under direct observation, and subsequently the proportion of prescribed doses confirmed by WOT compared to DOT. Initially participants received DOT and WOT simultaneously for 2–3 weeks to allow calculation of WOT PDA, and the 95% confidence interval (CI) was estimated using the bootstrap method with 10,000 samples. Sixty-one participants subsequently participated in an RCT to compare the proportion of prescribed doses confirmed by WOT and DOT. Participants were randomized 2:1 to receive WOT or maximal in-person DOT. In the WOT arm, if ingestions were not remotely confirmed, the participant was contacted within 24 hours by text or cell phone to provide support. The number of doses confirmed was collected, and nonparametric methods were used for group and individual comparisons to estimate the proportions of confirmed doses in each randomized arm with 95% CIs. Sensitivity analyses, not prespecified in the trial registration, were also performed, removing all nonworking (weekend and public holiday) and held-dose days. Participants, recruited from San Diego (SD) and Orange County (OC) Divisions of TB Control and Refugee Health, were 43.1 (range 18–80) years old, 57% male, 42% Asian, and 39% white with 49% Hispanic ethnicity. The PDA of WOT was 99.3% (CI 98.1; 100). Intent-to-treat (ITT) analysis within the RCT showed WOT confirmed 93% versus 63% DOT (p < 0.001) of daily doses prescribed. Secondary analysis removing all nonworking days (weekends and public holidays) and held doses from each arm showed WOT confirmed 95.6% versus 92.7% (p = 0.31); WOT was non-inferior to DOT (difference 2.8% CI [−1.8%, 9.1%]). One hundred percent of participants preferred using WOT. WOT associated adverse events were <10%, consisting of minor skin rash and pruritus associated with the patch. WOT provided longitudinal digital reporting in near real time, supporting patient self-management and allowing rapid remote identification of those who needed more support to maintain adherence. This study was conducted during the continuation phase of TB treatment, limiting its generalizability to the entire TB treatment course.


In terms of accuracy, WOT was equivalent to DOT. WOT was superior to DOT in supporting confirmed daily adherence to TB medications during the continuation phase of TB treatment and was overwhelmingly preferred by participants. WOT should be tested in high-burden TB settings, where it may substantially support low- and middle-income country (LMIC) TB programs.

Trial registration

ClinicalTrials.gov NCT01960257.

Klíčová slova:

Adverse events – Drug therapy – Ingestion – Patients – Public and occupational health – Tuberculosis – Isoniazid


1. Global TB Report WHO. 2018 [cited 2018 August 28]. Available from: http://www.who.int/tb/publications/global_report/en/.

2. Albert H, et al. Development, roll-out and impact of Xpert MTB/RIF for tuberculosis: what lessons have we learnt and how can we do better? Eur Respir J. 2016;48(2): 516–25. doi: 10.1183/13993003.00543-2016 27418550

3. Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). 2018. [cited 2018 Aug]. Available from: [http://www.who.int/tb/publications/2018/rapid_communications_MDR/en/.

4. D'Ambrosio L, et al. New anti-tuberculosis drugs and regimens: 2015 update. ERJ Open Res. 2015;1(1): 00010–2015. doi: 10.1183/23120541.00010-2015 27730131

5. Alipanah N, et al. Adherence interventions and outcomes of tuberculosis treatment: A systematic review and meta-analysis of trials and observational studies. PLoS Med. 2018;15(7): e1002595. doi: 10.1371/journal.pmed.1002595 29969463

6. Vijay S, et al. Risk factors associated with default among new smear positive TB patients treated under DOTS in India. PLoS ONE. 2010;5(4): e10043. doi: 10.1371/journal.pone.0010043 20386611

7. Chandrasekaran V, et al. Status of re-registered patients for tuberculosis treatment under DOTS programme. Indian J Tuberc. 2007;54(1): 12–16. 17455418

8. Thomas A, et al. Predictors of relapse among pulmonary tuberculosis patients treated in a DOTS programme in South India. Int J Tuberc Lung Dis. 2005;9(5): 556–61. 15875929

9. Marx FM, et al. The temporal dynamics of relapse and reinfection tuberculosis after successful treatment: a retrospective cohort study. Clin Infect Dis. 2014;58(12): 1676–83. doi: 10.1093/cid/ciu186 24647020

10. Cox H, et al. Tuberculosis recurrence and mortality after successful treatment: impact of drug resistance. PLoS Med. 2006;3(10): e384. doi: 10.1371/journal.pmed.0030384 17020405

11. den Boon S, et al. High prevalence of tuberculosis in previously treated patients, Cape Town, South Africa. Emerg Infect Dis. 2007;13(8): 1189–94. doi: 10.3201/eid1308.051327 17953090

12. Cadosch D., et al. The Role of Adherence and Retreatment in De Novo Emergence of MDR-TB. PLoS Comput Biol. 2016;12(3): e1004749. doi: 10.1371/journal.pcbi.1004749 26967493

13. Imperial MZ, et al. A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis. Nat Med. 2018 Nov;24(11):1708–1715. doi: 10.1038/s41591-018-0224-2 30397355

14. Chang K.C., et al., Dosing schedules of 6-month regimens and relapse for pulmonary tuberculosis. Am J Respir Crit Care Med. 2006;174(10): 1153–8. doi: 10.1164/rccm.200605-637OC 16908866

15. Vernon A.A., Iademarco MF. In the treatment of tuberculosis, you get what you pay for. Am J Respir Crit Care Med. 2004;170(10): 1040–2. doi: 10.1164/rccm.2409005 15533952

16. Vashishtha R., et al. Efficacy and safety of thrice weekly DOTS in tuberculosis patients with and without HIV co-infection: an observational study. BMC Infect Dis. 2013;13: 468. doi: 10.1186/1471-2334-13-468 24099345

17. Drusano GL, Sgambi N, Eichas A, Brown D, Kulawy R, Louie A. Effect of Administration of Moxifloxacin plus Rifampin against Mycobacterium tuberculosis for 7 of 7 Days versus 5 of 7 Days in an In Vitro Pharmacodynamic System. mBio. 2011;2(4): e00108–11. doi: 10.1128/mBio.00108-11 21750119

18. Chuck C, et al., Enhancing management of tuberculosis treatment with video directly observed therapy in New York City. Int J Tuberc Lung Dis. 2016;20(5): 588–93. doi: 10.5588/ijtld.15.0738 27084810

19. Weis SE, et al. Treatment costs of directly observed therapy and traditional therapy for Mycobacterium tuberculosis: a comparative analysis. Int J Tuberc Lung Dis. 1999;3(11): 976–84. 10587319

20. Maher D, Floyd K, Sharma BV, Jaramillo E, Nkhoma W, Nyarko E, et al. Community contribution to TB care: practice and policy: review of experience of community contribution to TB care and recommendations to national TB programs. Geneva: WHO/CDS/TB 2003.312. Available from: http://www.stoptb.org/assets/documents/countries/acsm/community%20contribution%20to%20tb%20care.pdf.

21. Walley J, et al. Tuberculosis patient adherence to direct observation: results of a social study in Pakistan. Health Policy and Planning. 2005;20(6): 354–365. doi: 10.1093/heapol/czi047 16183735

22. Egelund EF, Alsultan A, Peloquin CA. Optimizing the clinical pharmacology of tuberculosis medications. Clin Pharmacol Ther. 2015 Oct;98(4):387–93. doi: 10.1002/cpt.180 26138226

23. Tam CM., et al. Rifapentine and isoniazid in the continuation phase of a 6-month regimen. Final report at 5 years: prognostic value of various measures. Int J Tuberc Lung Dis. 2002;6(1): 3–10. 11931398

24. Controlled trial of 2, 4, and 6 months of pyrazinamide in 6-month, three-times-weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, and pyrazinamide. Results at 30 months. Hong Kong Chest Service/British Medical Research Council. Am Rev Respir Dis. 1991;143(4 Pt 1): 700–6.

25. Castelo A., et al. Comparison of daily and twice-weekly regimens to treat pulmonary tuberculosis. Lancet. 1989;2(8673): 1173–6. doi: 10.1016/s0140-6736(89)91788-1 2572899

26. Fox W. Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Third report. East African-British Medical Research Councils. Lancet. 1974;2(7875): 237–40. 4135686

27. Hafezi H, et al. An ingestible sensor for measuring medication adherence. IEEE Trans Biomed Eng. 2015;62(1): 99–109. doi: 10.1109/TBME.2014.2341272 25069107

28. Au-Yeung K.Y., et al., Early clinical experience with networked system for promoting patient self-management. Am J Manag Care. 2011;17(7): e277–87. 21819175

29. Browne SH, Behzadi Y, Littlewort G. Let Visuals Tell the Story: Medication Adherence in Patients with Type II Diabetes Captured by a Novel Ingestion Sensor Platform. JMIR Mhealth Uhealth. 2015;3(4): e108. doi: 10.2196/mhealth.4292 26721413

30. DiCarlo L, et al. A digital health solution for using and managing medications: wirelessly observed therapy. IEEE Pulse. 2012;3(5): 23–6. doi: 10.1109/MPUL.2012.2205777 23014703

31. Eisenberger U, et al. Medication adherence assessment: high accuracy of the new Ingestible Sensor System in kidney transplants. Transplantation. 2013;96(3): 245–50. doi: 10.1097/TP.0b013e31829b7571 23823651

32. Belknap R, et al. Feasibility of an ingestible sensor-based system for monitoring adherence to tuberculosis therapy. PLoS ONE. 2013;8(1): e53373. doi: 10.1371/journal.pone.0053373 23308203

33. Scholl L, Seth P, Karissa M, Wilson N, Baldwin G. Drug and Opioid-Involved Overdose Deaths—United States, 2013–2017. MMWR Morb Mortal Wkly Rep. 2018;67(5152): 1419–1427. doi: 10.15585/mmwr.mm675152e1 30605448

34. Browne SH., et al. Digitizing Medicines for Remote Capture of Oral Medication Adherence Using Co-encapsulation. Clin Pharmacol Ther. 2018;103(3): 502–510. doi: 10.1002/cpt.760 28597911

35. Peters-Strickland T, et al. Usability of a novel digital medicine system in adults with schizophrenia treated with sensor-embedded tablets of aripiprazole. Neuropsychiatr Dis Treat, 2016. 12: p. 2587–2594. doi: 10.2147/NDT.S116029 27785036

36. Marx FM., et al. The rate of sputum smear-positive tuberculosis after treatment default in a high-burden setting: a retrospective cohort study. PLoS ONE. 2012;7(9): e45724. doi: 10.1371/journal.pone.0045724 23049846

37. Davison AC, Hinkley D. Bootstrap Methods and Their Application. Cambridge, UK: Cambridge University Press; 1997.

38. FDA. FDA approves pill with sensor that digitally tracks if patients have ingested their medication [Internet]. [cited 2017 Nov 13]. Available from: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm584933.htm.

39. Cicero TJ., et al. The Changing Face of Heroin Use in the United States: A Retrospective Analysis of the Past 50 YearsChanging Face of Heroin Use in the United StatesChanging Face of Heroin Use in the United States. JAMA Psychiatry. 2014;71(7): 821–826. doi: 10.1001/jamapsychiatry.2014.366 24871348

40. Abstracts of the Society of General Internal Medicine 33rd Annual Meeting. Minneapolis, Minnesota, USA. April 28–May 1, 2010. J Gen Intern Med. 2010;25 Suppl. 3:S205–567.

41. Falvo DR, editor. Effective Patient Education: A Guide to Increased Adherence. 4th ed. Burlington MA: Jones and Bartlett; 2011.

42. Welfare IDoHa. Case Management. In: Welfare IDoHa, editor. 2007.

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