The Arcady Group founder, Bruce Thomas, led the Stop TB Partnership's Focus Group Workshop On Digital Adherence Technologies. At this meeting, innovators such as Everwell Health (99DOTS), Wisepill Technologies (evriMED medication monitor), Keheala (SMS-based behavioral counseling) and SureAdhere Mobile Technology (V-DOT) were connected with representatives of key NGO implementers and country programs (including Zimbabwe, Philippines, Moldova, and South Africa) to discuss opportunities for experimentation and uptake of digital adherence technologies through TB REACH Wave 6 grants. Bruce and Ram Subbaraman shared new evidence and insights about the importance of treatment adherence to avoid TB relapse.

1. ADHERENCE AND TB: BACKGROUND AND CONTEXT
Bruce V. Thomas, Founder & Managing Director, The Arcady Group, LLC
Ramnath Subbaraman, MD, MSc, FACP, Assistant Professor, Tufts University School of Medicine
1

2. 2
ADHERENCE TAXONOMY
Taxonomy Definition
Adherence To Medications The process by which patients take their medications as prescribed, composed of initiation,
implementation and discontinuation.
Discontinuation Occurs when the patient stops taking the prescribed medication.
Forgiveness The extent to which a medication’s post-dose duration of beneficial action exceeds the prescribed dosing
interval. When the duration of action greatly exceeds the dose interval, then the drug is considered forgiving.
Initiation Occurs wen the patient takes the first dose of a prescribed medication.
Implementation The extent to which a patient's actual dosing corresponds to the prescribed dosing regimen, from initiation until
the last dose.
Persistence The length of time between initiation and the last dose, which immediately precedes discontinuation.
Management Of Adherence The process of monitoring and supporting patients' adherence to medications by health care systems,
providers, patients, and their social networks.
“Pill-in-hand”
Technologies
Technologies designed to (i) electronically validate that the patient has accessed his/her daily dose (an activity
or event typically strongly correlated with actual medication ingestion), and (ii) compile detailed dosing histories
based on such electronic validation.
Initiate Implement Persist time

3. Key Insights
Adherence is a multi-factorial
behavioral issue . . . that
changes over time.
---
Medication-taking behavior is
extremely complex and
individual, requiring numerous
multifactorial strategies to
improve adherence
---
Adherence challenges are
exacerbated in the case of co-
morbidity and associated poly-
pharmacy.
TB Presents Myriad and
Significant Adherence
Challenges
BARRIERS RELATED TO ADHERENCE GENERALLY
3
• Type of disease
• Severity of symptoms
• Level of disability
• Rate of progression and
severity of disease
• Availability of effective
treatments
• Complexity and magnitude of
medical regimen/ behavioral
changes
• Drug effectiveness and
tolerability
• Route of administration
• Duration of treatment
• Previous treatment failures
• Frequent changes in treatment
• Poor patient-provider relationship,
e.g., time spent, follow-up
• Inadequate reimbursements (incl.
co-payment/ out-of-pocket payment)
• Poor medication distribution systems
• Barrier to care by providers
• Lack of effective social support network
• Demographics like age, race and sex of
patient
• Income status
• Cultures and beliefs about illness or
treatment
• Forgetfulness
• Inadequate knowledge of disease and
treatment
• Patient motivation, attitude and behavioral type
• Perceptions of diagnosis
• Misunderstanding of treatment instructions
and follow-up routine

4. 4
ILLUSTRATING THE DOSING CONFUSION PROBLEM
Self-Administering Patients Rely Solely On Verbal Instructions Given
At Dispensing – Even For Complicated MDR Poly-Pharmacy

5. YES! Poor medication adherence may
have the following impacts on health
outcomes:
§ Lower treatment completion and
higher loss to follow-up
Ø Low adherence associated with
discontinuation of therapy in hypertension1
Ø Low adherence associated with higher loss to
follow-up for TB patients2
5
DOES ADHERENCE REALLY MATTER IN TB?
Source: Vrijens et al, BMJ. 2008;336 (7653):1114-7.1
In patients taking medications for high blood
pressure, poor adherence is associated with
increased rates of discontinuation of treatment.

6. YES! Poor medication adherence may
have the following impact on health
outcomes:
§ Lower treatment completion and
higher loss to follow-up
§ Increased disease relapse
Ø Low adherence increased TB relapse in
recent clinical trials3
6
DOES ADHERENCE REALLY MATTER IN TB?
Source: TB ReFLECT Consortium, unpublished data3
TB patients taking HRZE with <90%
adherence had 5.6 times increased risk of
TB recurrence in a meta-analysis of the
OFLOTUB, REMox, and Rifaquin trials.

7. YES! Poor medication adherence may have
the following impact on health outcomes:
§ Lower treatment completion and
higher loss to follow-up
§ Increased disease relapse
Ø Low adherence increased relapse in routine
programmatic care in India4
Ø Relapse rates are high in TB programs in
South Africa (17%),5 India (15-18%),4,6 and
for MDR TB patients in Uzbekistan (44%)7
7
DOES ADHERENCE REALLY MATTER IN TB?
Study of 534 smear + patients in India found a
strong relationship between adherence and
post-treatment TB recurrence.
Severity of non-
adherence
TB recurrence
rate, 18 months
after completing
treatment
“Regular”
adherence
9%
“Irregular”
adherence
15%
“Very irregular”
adherence
25%
Source: Thomas et al. Int J TB Lung Dis 2005; 9(5): 556-614

8. YES! Poor medication adherence may have
the following impact on health outcomes:
§ Lower treatment completion and
higher loss to follow-up
§ Increased disease relapse
§ Increased acquired drug resistance
Ø Modeling study found adherence to be the
strongest predictor for the emergence of MDR TB
in retreatment patients8
8
DOES ADHERENCE REALLY MATTER IN TB?
“[P]robably the cheapest and most effective
way to ensure a positive treatment outcome
while minimizing the risk for the emergence of
MDR-TB is to maintain proper patient
compliance with the treatment.”8
Source: Cadosch et al. Plos Comp Bio 2016;12:e10047498

9. 9
TB ADHERENCE: HIGH LEVEL POTENTIAL IMPACT9
Conservatively Assuming A Post-treatment Relapse Rate Of 10% . . .

10. 10
RECENT WHO ACTION ON ADHERENCEPOLICY RECOMMENDATIONS
Link to download WHO guidelines9: http://bit.ly/2pRx8yu
burdensome on patients, providers and health systems.6
• DOT is often inadequately implemented, with patient self-administration increasingly becoming the norm in both the
private and public sectors.7,8
WHO recommends the use of additional adherence interventions to ensure good treatment outcomes.
Recommendation 2.1.4 c.: “Video observed treatment (VOT) can replace DOT when the video communication technology is
available and it can be appropriately organized and operated by health care providers and patients (Conditional recommendation,
very low certainty in the evidence).”9
As treatment
supervision alone
is not likely to be
suf�icient to ensure
good TB treatment
outcomes, additional
treatment adherence
interventions need to
be provided.”
“
WHO DS-TB
Guidelines, 2017
Footnotes / De�inition of Terms9:

11. 11
SPECIFIC ACTION ON ADHERENCE TECHNOLOGIES
POLICY RECOMMENDATIONS
Link to download WHO guidelines9: http://bit.ly/2pRx8yu
also has limitations:
• Facility-based DOT, still the most common model in many countries, is expensive, resource-intensive and highly
burdensome on patients, providers and health systems.6
• DOT is often inadequately implemented, with patient self-administration increasingly becoming the norm in both the
private and public sectors.7,8
WHO recommends the use of additional adherence interventions to ensure good treatment outcomes.
Recommendation 2.1.4 c.: “Video observed treatment (VOT) can replace DOT when the video communication technology is
available and it can be appropriately organized and operated by health care providers and patients (Conditional recommendation,
very low certainty in the evidence).”9
As treatment
supervision alone
is not likely to be
suf�icient to ensure
good TB treatment
outcomes, additional
treatment adherence
interventions need to
be provided.”
“
WHO DS-TB
Guidelines, 2017
POLICY RECOMMENDATIONS
Link to download WHO guidelines9: http://bit.ly/2pRx8yu
improvements in TB treatment outcomes.4,5 Despite its success, DOT as implemented currently in resource-limited settings
also has limitations:
• Facility-based DOT, still the most common model in many countries, is expensive, resource-intensive and highly
burdensome on patients, providers and health systems.6
• DOT is often inadequately implemented, with patient self-administration increasingly becoming the norm in both the
private and public sectors.7,8
WHO recommends the use of additional adherence interventions to ensure good treatment outcomes.
Recommendation 2.1.4 c.: “Video observed treatment (VOT) can replace DOT when the video communication technology is
available and it can be appropriately organized and operated by health care providers and patients (Conditional recommendation,
As treatment
supervision alone
is not likely to be
suf�icient to ensure
good TB treatment
outcomes, additional
treatment adherence
interventions need to
be provided.”
“
WHO DS-TB
Guidelines, 2017

12. § Systematic reviews: compared to self-administered
therapy, DOT may not improve treatment completion,
microbiological cure, disease relapse rates, and rates
of acquired drug resistance11-13
§ Ethical questions: loss of patient confidentiality, loss
of autonomy, fear of stigma14-16
§ Facility-based DOT: health facility visits may result in
loss of income and employment14-16
§ Real-world implementation is limited:
Ø In China only 14% of TB patients in 3 provinces actually
taking medications under direct observation17
Ø India currently shifting away from DOT towards either
99DOTS or self-administered therapy
© Bill & Melinda Gates Foundation | 12
ANOTHER DRIVER: MORE PATIENT-CENTERED CARE
“He comes to TB hospital by morning 9.30 and
by the time he reaches his house it will be
afternoon 2’o clock. He will not have any time to
go to work. If he does not go for his treatment,
he will die and if he does not go for work, his
children will die.”
-An Indian TB patient15
“I didn't finish the treatment because I had to
work to get food ... and to get food I had to work.
I didn't have money for transport to come to the
clinic and I couldn't walk always because I
would be too late by the time I arrived at the
clinic.”
-An Ethiopian TB patient16

13. • We know that TB medication adherence is important for patient outcomes
• We know that there are myriad challenges to proper TB medication adherence
• We know that some DOT models place substantial burdens upon patients
• We know that patients are self-administering their medications in many locations
• The WHO is supportive, encouraging adherence interventions enabled by digital
technologies
• In this context, what options, approaches, and alternatives are available?
13
THE CHALLENGE/THE OPPORTUNITY

14. 14
THE VISION: TRANSFORMING TB PATIENT MANAGEMENT
1
2
4
3
More Patients Properly Adhering And Retained In Care.
Enhanced Health System Efficiency.
• Fewer Dosing Errors: Helping
patients with issues of dosing
confusion: helping them understand
when and how to dose
• Patient-Centered Observation:
Observing patients and compiling
dosing histories in a highly
affordable, patient-centered way
• Enhanced Adherence Counseling:
Using dosing histories to enhance
patient counseling and support
• Differentiated Care: Continuously
“triaging” highest risk patients based
on their levels and patterns of non-
adherence

15. THE ROLE OF ADHERENCE MONITORING TECHNOLOGIES
• Help with dosing confusion: pictograms
of other graphical cues
• Reminder: via SMS, ringing / glowing light
on electronic pillboxes
• Verification: via video observation, SMS
response, unique phone number, opening/
closing of pillbox
• Dosing history compilation: usually to a
website or smartphone interface
• Healthcare provider interface: direct
video communication with patients, phone
calls to patients, etc.
• Triage: into high- or low-risk patients
• Differentiated care: unique screening and
intervention approaches for patients with
different levels of risk
15

16. 16
Research Priority Existing studies
Feasibility
• Cell- or smart-phone availability and literacy
• Cellular service coverage
• Battery life for electronic pillboxes
• Durability of electronic pillboxes
• Video DOT18
• Ingestible sensors19
Acceptability
• Perceived usefulness
• Ease of use
• Evaluate acceptance for both patients and
healthcare providers
• Zindagi SMS20
• 99DOTS (in progress)
• Medication Event Reminder Monitor
(MERM)21
• Video DOT18

17. 17
Research Priority Existing studies
Accuracy
• Over-reporting adherence (false-positives)
• Under-reporting adherence (false-negatives)
• Changes in accuracy throughout TB therapy
(due to “technology fatigue”)
• 99DOTS (in progress)
• MERM22
• Video DOT23
• Ingestible sensor19
Treatment outcomes
• Medication adherence
• Treatment completion
• TB recurrence-free survival
• Zindagi SMS (no impact)24
• MERM (medication adherence)25
• MERM (relapse-free survival)—in
progress

18. Accuracy of some adherence monitoring technologies may decline throughout TB therapy
Source: Mohammed et al. PLoS One 2016;11(11):e0162944.23

19. 19
Research Priority Existing studies
Costs and Cost-effectiveness
• Costs of the technology / implementation
• Time saved or lost by healthcare providers
• Cost-effectiveness:
(Additional resources saved)
----------------------------------------------------------
(Additional improvement in health outcomes)
• Video DOT26
• MERM – in progress
Provision of Differentiated Care
• Novel counseling strategies using dosing histories
• Linking triage to targeted screening and
intervention strategies to address causes of non-
adherence (depression, substance use, poor
treatment literacy, poverty and structural barriers)
Critical information needed,
especially in low- and
middle-income countries

20. 1. Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug
treatments: longitudinal study of electronically compiled dosing histories. BMJ 2008; 336(7653): 1114-7.
2. Vijay S, Kumar P, Chauhan LS, Vollepore BH, Kizhakkethil UP, Rao SG. Risk factors associated with
default among new smear positive TB patients treated under DOTS in India. PLoS One 2010; 5(4):
e10043.
3. TB ReFLECT Consortium, unpublished data (courtesy of Rada Savic).
4. Thomas A, Gopi PG, Santha T, 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.
5. Marx FM, Dunbar R, Enarson DA, et al. The temporal dynamics of relapse and reinfection tuberculosis
after successful treatment: a retrospective cohort study. Clin Inf Dis 2014; 58(12): 1676-83.
6. Sadacharam K, Gopi PG, Chandrasekaran V, et al. Status of smear-positive TB patients at 2-3 years after
initiation of treatment under a DOTS programme. Indian J Tuberc 2007; 54(4): 199-203.
7. Cox H, Kebede Y, Allamuratova S, et al. Tuberculosis recurrence and mortality after successful treatment:
Impact of drug resistance. PLoS Medicine 2006; 3(10): 1836-43.
8. Cadosch D, Abel Zur Wiesch P, Kouyos R, Bonhoeffer S. The Role of Adherence and Retreatment in De
Novo Emergence of MDR-TB. PLoS Computational biology 2016; 12(3): e1004749.
© Bill & Melinda Gates Foundation | 20
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