INT J TUBERC LUNG DIS 22(7):731–740

Q 2018 The Union

http://dx.doi.org/10.5588/ijtld.17.0596

Interventions to improve adherence to tuberculosis treatment:

systematic review and meta-analysis

A. M. Müller,*† C. S. Osório,* D. R. Silva,*†‡ G. Sbruzzi,*† P. de Tarso Roth Dalcin*†‡

*Universidade Federal do Rio Grande do Sul (UFRGS), †Programa de Pós Graduação em Ciências Pneumológicas,
UFRGS, Porto Alegre, Rio Grande do Sul, ‡Hospital de Clı́nicas de Porto Alegre, Porto Alegre, Rio Grande do Sul,
Brazil

SUMMARY

S E T T I N G : One of the most serious problems in tuber-
culosis (TB) control is non-adherence to treatment.
Several strategies have been developed to improve
adherence and increase the cure rate.
O B J E C T I V E : To systematically review interventions to
improve adherence to anti-tuberculosis treatment.
D E S I G N : We performed a systematic review and meta-
analysis of 22 randomised clinical trials (RCTs) to
ascertain whether providing directly observed treatment,
short-course (DOTS), financial incentives, food incen-
tives and/or patient education/counselling improved
adherence to anti-tuberculosis treatment. The primary
outcome was cure rate; secondary outcomes were
default and mortality rates. Sources used were Medline
(accessed via PubMed), Cochrane Central, LILACS
(Literatura Latino Americana em Ciências da Saúde,
Latin American and Caribbean Health Sciences Litera-
ture) and Embase from inception to October 2015.
R E S U LT S : A significant increase in cure rates, by 18%
with DOTS and by 16% with patient education and
counselling, was observed. In addition, the default rate
decreased by 49% with DOTS, by 26% with financial
incentives and by 13% with patient education and
counselling. There was no statistically significant
reduction in mortality rates with these interventions.
C O N C L U S I O N : Use of DOTS and patient education/
counselling significantly improved cure rates; DOTS,
patient education/counselling and financial incentives
led to a reduction in the default rate.
K E Y W O R D S : tuberculosis; adherence; intervention;
review

TUBERCULOSIS (TB) is the leading cause of death
due to an infectious disease worldwide. In 2014, an
estimated 9.6 million people fell ill with TB and 1.5
million died from the disease. TB is the main cause of
death among people living with the human immu-
nodeficiency virus (HIV), with one in three deaths
among persons living with HIV due to TB in 2015. In
2014, an estimated 480 000 people worldwide
developed multidrug-resistant TB (MDR-TB, de-
fined as TB resistant to at least isoniazid and
rifampicin). Given that most deaths from TB are
preventable, the death toll from the disease remains
unacceptably high, and efforts to combat it must be
accelerated.1
Anti-tuberculosis treatment can cure most people
with TB using a combination of drugs in short-
course chemotherapy. One of the most difficult
problems in TB control, however, is non-adherence
to treatment, which is associated with the risk of
acquiring drug-resistant strains of Mycobacterium
tuberculosis, disease transmission and even
death.1,2 Several factors are associated with non-
adherence: financial, social, familial, personal and
psychological.2–8
Directly observed treatment, short-course (DOTS)
is the internationally recommended strategy to
improve adherence, reduce the risk of acquired drug
resistance and increase the possibility of cure.
However, the effectiveness of DOTS has been
questioned in some studies. Both self-administered
treatment (SAT) and treatment observed by a family
member have been proposed as acceptable alterna-
tives.9 Patient adherence to anti-tuberculosis treat-
ment could be achieved by combining several
strategies. Health professionals can develop and
adapt strategies such as DOTS, individualised treat-
ment regimens, nutritional support and social bene-
fits, according to local conditions.10
The aim of the present study was to review studies
that evaluated interventions to improve adherence to
anti-tuberculosis treatment. We therefore conducted
a systematic review of the literature and a meta-
analysis of randomised trials.

Correspondence to: Alice Mânica Müller, Hospital de Clı́nicas de Porto Alegre, Rua Ramiro Barcelos, 2350 – Santa Cecı́lia,
Serviço de Pneumologia – Sala 2050, CEP: 90035-903, Porto Alegre-RS, Brazil. e-mail: alicemm26@gmail.com
Article submitted 23 August 2017. Final version accepted 5 February 2018.
732 The International Journal of Tuberculosis and Lung Disease
MATERIALS AND METHODS
This systematic review and meta-analysis was report-
ed according to the PRISMA Statement and Cochrane
Collaboration guidelines. Ethical approval of the
study protocol was not required.
Eligibility criteria
We included randomised clinical trials (RCTs) that
compared several strategies for improving adherence,
such as DOTS, financial incentives, food incentives
and patient education/counselling vs. no education or
counselling, and evaluated any of the following
outcomes: cure, default (now more commonly referred
to as loss to follow-up) and mortality rates. Studies
that included paediatric populations and individuals
with latent tuberculous infection were excluded.
The primary outcome measure was the cure rate.
This was defined as the percentage of patients who
completed 6 months of treatment and had two
negative sputum examinations during treatment,
one of which was at treatment completion. Secondary
outcome measures were the default and mortality
rates. Default rate was defined as the percentage of
patients who interrupted their treatment for 72
consecutive months. Mortality rate was defined as the
percentage of patients who died for any reason during
the course of treatment.
Search strategy
We searched, independently and in duplicate, the
following electronic databases: PubMed, Cochrane
Central Register of Controlled Trials (Cochrane
Central), LILACS (Literatura Latino Americana em
Ciências da Saúde, Latin American and Caribbean
Health Sciences Literature) and Embase from incep-
tion to October 2015.
The search strategy was based on the following
terms: ‘tuberculosis’, ‘directly observed therapy’,
‘food incentives’, ‘financial incentives’, ‘reminder
systems’, ‘mobile phone’, ‘patient education’, ‘coun-
selling’ and ‘health education’.
Our search was not limited to a particular language
or time period. Strategies used to search PubMed are
described in Table 1; details of other strategies used
are given in the Appendix.*
Study selection and data extraction
Titles and abstracts of all articles identified by the
search strategy were independently evaluated by two
investigators (AMM and CSO) in duplicate. None of
the abstracts provided sufficient information regard-
ing the inclusion and exclusion criteria selected for
full-text evaluation. In the second phase, the same
*The appendix is available in the online version of this article, at
http://www.ingentaconnect.com/content/iuatld/ijtld/2018/
00000022/00000007/art00007
Table 1 Terms employed for the search strategy for PubMed
#1 ‘Tuberculosis’ OR ‘Kochs Disease’ OR ‘Disease, Kochs’ OR
‘Koch’s Disease’ OR ‘Disease, Koch’s’ OR ‘Koch Disease’
#2 ‘Directly observed therapy’[MeSH] OR ‘Directly observed t
herapy’ OR ‘Therapy, Directly Observed’ OR ‘Motivation’
[MeSH] or ‘Motivation’ OR ‘Disincentives’ OR
‘Disincentive’ OR ‘Incentives’ OR ‘Incentive’ OR
‘Financial support’[MeSH] OR ‘Financial Support’ OR
‘Financial supports’ OR ‘Support, Financial’ OR ‘Supports,
Financial’ OR ‘economic support’ OR ‘Monetary incentive’
OR ‘Reminder systems’[MeSH] OR ‘Reminder systems’ OR
‘Reminder system’ OR ‘System, Reminder’ OR ‘Systems,
Reminder’ OR ‘Cell Phones’[MeSH] OR ‘Cell phones’ OR
‘Mobile phones’ OR ‘Smart phones’ OR ‘Text
messaging’[MeSH] OR ‘Text messaging’ OR ‘Text
messages’ OR ‘Short Message Service’ OR
‘Counseling’[MeSH] OR ‘Counseling’ OR ‘Counselors’ OR
‘Counselor’ OR ‘Health education’[MeSH] OR ‘Health
education’ OR ‘Education, Health’ OR ‘Community Health
Education’ OR ‘Health Education, Community’ OR
‘Education, Community Health’ OR ‘Patient
Education’[MeSH] OR ‘Patient Education’ OR ‘Education
of patients’ OR ‘Education, Patient’ OR ‘Patient
Education’ OR ‘food baskets’ OR ‘food incentives’ OR
‘food packages’ OR ‘voucher’
#3 (randomized controlled trial[pt] OR controlled clinical
trial[pt] OR randomized controlled trials[mh] OR random
allocation[mh] OR double-blind method[mh] OR single-
blind method[mh] OR clinical trial[pt] OR clinical
trials[mh] OR (‘‘clinical trial"[tw]) OR ((singl*[tw] OR
doubl*[tw] OR trebl*[tw] OR tripl*[tw]) AND (mask*[tw]
OR blind*[tw])) OR (‘‘latinsquare"[tw]) OR placebos[mh]
OR placebo*[tw] ORrandom*[tw] OR research
design[mh:noexp] OR follow-up studies[mh] OR
prospective studies[mh] OR cross-over studies[mh] OR
control*[tw] OR prospectiv*[tw] OR volunteer*[tw]) NOT
(animal[mh] NOT human[mh])
#4 #1 AND #2 AND #3
reviewers independently evaluated all full-text arti-
cles and made their selection in accordance with the
eligibility criteria. Differences between reviewers
were resolved by consensus; if disagreement persisted,
the text was evaluated by a third reviewer (DRS).
Two reviewers (AMM and CSO) independently
extracted data using standardised forms; disagree-
ments were resolved by consensus or by a third
reviewer (DRS). The primary endpoint extracted was
cure rate. Default and mortality rates were analysed
individually as secondary endpoints. The structured
data collection form for the extraction of study
characteristics included the country where the study
had been conducted, date of enrolment, study design,
study setting and patient characteristics. Numerical
data extracted included the number of patients in each
study, number of patients in each group, as well as the
cure, default and mortality rates in each study group.
Assessment of risk of bias
Study quality was analysed descriptively according to
the method proposed by the Cochrane Collabora-
tion11 to assess whether the following conditions had
been met: adequate sequence generation, allocation
concealment, blinding of assessors to outcomes, use
of intention-to-treat analysis and description of losses
Table 2 Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria
Quality assessment Patients, n Effect
Studies Study Risk of Other Interventions Control Relative Absolute
n design bias Inconsistency Indirectness Imprecision considerations n/N (%) n/N (%) (95%CI) (95%CI) Quality Importance
Cure rate: DOTS vs. SAT
8 Randomised Serious* Serious* Not serious Not serious None 1485/1822 1201/1719 RR 1.18 126 more /1000 Low
trials (81.5) (69.9) (1.08–1.28) (from 56 more to 196 more)
Cure rate: community vs. health facility DOTS
2 Randomised Serious* Not serious Not serious Not serious None 338/481 419/628 RR 1.03 20 more /1000 Moderate
trials (70.3) (66.7) (0.97–1.10) (from 20 fewer to 67 more)
Cure rate: family vs. community DOTS
2 Randomised Not serious Very serious* Not serious Not serious None 759/1020 918/1213 RR 1.02 15 more /1000 Low
trials (74.4) (75.7) (0.94–1.11) (from 45 fewer to 83 more)
Cure rate: patient education and counselling vs. no education or counselling
2 Randomised Serious* Not serious Not serious Not serious None 281/548 250/558 RR 1.16 72 more /1000 Moderate
trials (51.3) (44.8) (1.05–1.29) (from 22 more to 130 more)
Cure rate: food incentives vs. no food incentives
3 Randomised Serious* Serious* Not serious Not serious None 181/220 170/214 RR 1.07 56 more /1000 Low
trials (82.3) (79.4) (0.95–1.21) (from 40 fewer to 167 more)
Cure rate: financial incentives vs. no financial incentives
2 Randomised Serious* Serious* Not serious Not serious None 727/2149 762/2065 RR 1.00 0 fewer /1000 Low
trials (33.8) (36.9) (0.81–1.23) (from 70 fewer to 85 more)
Default rate: DOTS vs. SAT
5 Randomised Serious* Very serious* Not serious Not serious None 114/1513 238/1484 RR 0.51 79 fewer /1000 Very low
trials (7.5) (16.0) (0.32–0.84) (from 26 fewer to 109 fewer)
Default rate: community vs. health facility DOTS
2 Randomised Serious* Very serious* Not serious Not serious None 92/481 84/628 RR 1.04 5 more /1000 Very low
trials (19.1) (13.4) (0.34–3.19) (from 88 fewer to 293 more)
Default rate: family vs. community DOTS
2 Randomised Serious* Not serious Not serious Not serious None 106/1020 116/1213 RR 0.98 2 fewer /1000 Moderate
trials (10.4) (9.6) (0.77–1.26) (from 22 fewer to 25 more)
Default rate: financial incentives vs. no financial incentives
2 Randomised Serious* Not serious Not serious Not serious None 164/2149 217/2065 RR 0.74 27 fewer /1000 Moderate
trials (7.6) (10.5) (0.61–0.90) (from 11 fewer to 41 fewer)
Default rate: patient education/counselling vs. no education/counselling
2 Randomised Serious* Not serious Not serious Not serious None 235/548 277/558 RR 0.87 65 fewer /1000 Moderate
trials (42.9) (49.6) (0.77–0.98) (from 10 fewer to 114 fewer)
Mortality rate: DOTS vs. SAT
4 Randomised Serious* Serious* Not serious Not serious None 40/1378 50/1360 RR 0.75 9 fewer /1000 Low
trials (2.9) (3.7) (0.37–1.53) (from 19 more to 23 fewer)
Mortality rate: community vs. health facility DOTS
2 Randomised Serious* Very serious* Not serious Not serious None 29/481 69/628 RR 0.36 70 fewer /1000 Very low
trials (6.0) (11.0) (0.06–2.33) (from 103 fewer to 146 more)
Mortality rate: family vs. community DOTS
2 Randomised Not serious Very serious* Not serious Not serious None 128/1020 138/1213 RR 0.88 14 fewer /1000 Low
trials (12.5) (11.4) (0.43–1.78) (from 65 fewer to 89 more)
Mortality rate: financial incentives vs. no financial incentives
Adherence to anti-tuberculosis treatment

2 Randomised Serious* Not serious Not serious Not serious None 153/2149 145/2065 RR 1.02 1 more /1000 Moderate
trials (7.1) (7.0) (0.82–1.27) (from 13 fewer to 19 more)
* No explanation provided.
733

CI ¼ confidence interval; DOTS ¼ directly observed treatment, short-course; SAT ¼self-administered treatment; RR ¼ risk ratio.
734 The International Journal of Tuberculosis and Lung Disease
Figure 1 Flow chart of study selection. LILACS ¼ Literatura Latino Americana em Ciências da
Saúde (Latin American and Caribbean Health Sciences Literature).
and exclusions. Studies without a clear description of
any of these aspects were considered not adequately
informed. Use of intention-to-treat analysis was
based on confirmation on study assessment that the
number of participants randomised and the number
analysed were identical. Quality assessment was
independently performed by two reviewers (AMM
and CSO).
Summary of evidence: GRADE criteria
The quality of the evidence was evaluated using the
Grading of Recommendations Assessment, Develop-
ment and Evaluation (GRADE) criteria, as recom-
mended in the Cochrane Handbook for Systematic
Reviews of Interventions.11 For each specific out-
come, the quality of evidence was assessed according
to five factors: risk of bias, inconsistency, indirect-
ness, imprecision and publication bias (Table 2). The
GRADE approach resulted in four levels of quality of
evidence: high, moderate, low and very low (http://
www.guidelinedevelopment.org/).
Statistical analysis
Summary risk ratios (RRs) and 95% confidence
intervals (CIs) were calculated using the Mantel-
Haenszel random-effect model based on the number
of events reported in the original studies or sub-studies
using intention-to-treat analysis. Statistical heteroge-
neity of the treatment effects among studies was
assessed using the inconsistency I2 test; values above
25% and 50% were considered to indicate moderate
and high heterogeneity, respectively. A meta-analysis
was performed for all outcomes and conducted using
Review Manager v5.3 (Cochrane Collaboration,
London, UK). Sensitivity analyses were carried out
based on the different types of interventions.
RESULTS
Study selection
Of a total of 5303 articles obtained from our search, 511
duplicates were identified and removed. After reading
the titles and abstracts (where available), we selected 60
articles for full-text review, including 22 RCTs. Studies
were from different countries and involved different
types of interventions. A flow diagram of the study
selection process is shown in Figure 1.
 Adherence to anti-tuberculosis treatment 735

Table 3 Risk of bias in included studies

Adequate sequence Allocation Blinding of Description of loss Intention-to-treat
Study, year, reference generation concealment outcome assessors and exclusions analysis
Clarke, 200511 Yes Yes No Yes Yes
Hsieh, 200812 Yes Yes Unclear Yes No
Kamolratanakul, 199913 Yes Yes Yes Yes Yes
Lwilla, 200319 Yes Yes Unclear Yes Yes
Newell, 200621 Yes Yes Yes Yes Yes
Sivaraj, 201414 Yes Yes Unclear Yes Yes
Tandon, 200215 Yes Yes Unclear Yes Yes
Thiam, 200716 Yes Yes Yes Yes Yes
Toyota, 200317 Yes Yes Unclear Yes Yes
Wandwalo, 200420 Yes Yes Unclear Yes Yes
Wright, 200422 Yes Yes Yes Yes No
Zwarenstein, 199818 Yes Yes Unclear Yes Yes
Baral, 201423 Yes No Unclear Yes Yes
Jahnavi, 201025 Yes Yes Unclear Yes Yes
Lutge, 201324 Yes Yes No Yes Yes
Martins, 200926 Yes Yes Yes Yes Yes
Sudarsanam, 201127 Yes Yes No Yes Yes
Alvarez Gordillo, 200328 Yes No Unclear Yes Yes
Liefooghe, 199929 Yes Yes Unclear Yes No

Study characteristics incentives and no financial incentives (n ¼ 4214; RR

Studies were organised in sections by type of
intervention: DOTS vs. SAT, community vs. health
facility DOTS, family vs. community DOTS, finan-
cial incentives vs. no financial incentives, food
incentives vs. no food incentives, patient education/
counselling vs. no education/counselling and other
types of interventions for improving treatment
adherence (Appendix Table A.4).11–32
Of the studies included, 100% presented adequate
sequence generation, 89% reported allocation con-
cealment, 26% had blinded assessment of outcomes,
100% described default/loss to follow-up and exclu-
sions and 84% used the intention-to-treat principle
for statistical analyses (Table 3).
Primary outcome
Nineteen articles evaluated cure rates (Figure 2); eight
articles (n ¼ 3541 cases) that evaluated DOTS vs. SAT
concluded that DOTS was superior to SAT (RR 1.18,
95%CI 1.08–1.28, I2 ¼ 68%).12–19 Two articles
comparing community DOTS vs. health facility
DOT (n ¼ 1109) reported no significant difference
(RR 1.03, 95%CI 0.97–1.10, I2 ¼ 0%).20,21 Two
studies comparing family and community DOTS (n ¼
2233) showed no significant difference between the
twos strategies in terms of cure rate (RR 1.02, 95%CI
0.94–1.11, I2 ¼ 71%).22,23 Two studies comparing
patient education/counselling with no education/
counselling (n ¼ 1106) showed that patient educa-
tion/counselling led to better cure rates (RR 1.16,
95%CI 1.05–1.29, P ¼ 0.004, I2 ¼ 0%).24,25 Three
studies comparing food incentives vs. no food
incentives found no significant difference in cure
rates (n ¼ 434; RR 1.07, 95%CI 0.95–1.21, P ¼ 0.27,
I2 ¼ 50%);26–28 two other studies on financial
incentives vs. no financial incentives showed no
significant difference between the use of financial
1.00, 95%CI 0.81–1.23, P ¼ 0.99, I2 ¼ 67%).29,30
Based on the GRADE approach, the quality of the
evidence for this outcome was considered low due to
risk of bias and inconsistent results (Table 3).
Secondary outcomes
Default rate
Default rate was evaluated by 13 articles (Figure 3).
The meta-analysis of the all five studies comparing
DOTS and SAT in terms of default rate showed that
DOTS was superior to SAT, reducing default by 49%
(RR 0.51, 95%CI 0.32–0.84, P ¼ 0.008).12,14,17–19
The default rate decreased by respectively 26% (RR
0.74, 95%CI 0.61–0.90, P ¼ 0.002, I2 ¼ 0%)29,30 and
13% (RR 0.87, 95%CI 0.77–0.98, P ¼ 0.03, I2 ¼
0%)24,25 in patients who received financial incentives
and patient education/counselling. Three studies
comparing community and health facility DOTS
reported no significant difference between the two
strategies (RR 1.04, 95%CI 0.34–3.19, P ¼ 0.95, I2 ¼
74%),20,21 and no significant difference was observed
between family and community DOTS in two studies
(RR 0.98, 95%CI 0.77–1.26, P ¼ 0.98, I2 ¼ 0%).22,23
Based on the GRADE approach, the quality of the
evidence for this outcome was considered low due to
the risk of bias and inconsistent results.
Mortality rate
Ten articles evaluated the mortality rate (Figure 4).
The RR of patient deaths during anti-tuberculosis
treatment was not significantly different across the
intervention subgroups: DOTS vs. SAT (RR 0.75,
95%CI 0.37–1.53, P ¼ 0.43);12,14,17,19 community vs.
health facility DOTS (RR 0.36, 95%CI 0.06–2.33, P ¼
0.29);20,21 family vs. community DOTS (RR 0.88,
95%CI 0.43–1.78, P ¼ 0.72);22,23 financial incentives
vs. no financial incentives (RR 1.2, 95%CI 0.82–1.27,
736 The International Journal of Tuberculosis and Lung Disease
Figure 2 Cure rate. M-H ¼ Mantel-Haenszel; CI ¼ confidence interval; DOTS ¼ directly observed treatment, short-course; SAT ¼self-
administered treatment; df ¼ degrees of freedom.
P ¼ 85).29,30 According to the GRADE approach, the
quality of the evidence for this outcome was low due to
the risk of bias and inconsistent results (Table 3).
Assessment of study quality and risk of bias
Based on GRADE criteria, the quality of the studies
included in the review ranged from very low to
moderate. Quality and risk of bias assessments are
given in Tables 2 and 3.
DISCUSSION
We performed a systematic review and meta-analysis
to assess the impact of several types of interventions
for improving adherence to anti-tuberculosis treat-
ment, and consequently to increase the cure rate and
reduce the default rate.
Our results showed a significant increase in the
cure rate, by 18% with DOTS and by 16% with

Figure 3 Default rate. M-H ¼ Mantel-Haenszel; CI ¼ confidence interval; DOTS ¼ directly observed treatment, short-course; SAT ¼
self-administered treatment; df ¼ degrees of freedom.
patient education and counselling. In addition, the
default rate decreased by respectively 49%, 26% and
13% with DOTS, financial incentives and patient
education and counselling. There was no significant
reduction in mortality rates with the use of these
interventions. Assuming an appropriate drug regimen
is prescribed, treatment success depends largely on
the patient’s adherence to the regimen. Without
adequate support, a significant proportion of patients
with TB discontinue treatment before the end of the
planned period or take medication irregularly.31
Our analysis showed that DOTS significantly
increased the cure rate (n ¼ 3541; RR 1.18, 95%CI
1.08–1.28, P , 0.0001) and reduced default (n ¼
2997; RR 0.51, 95%CI 0.32–0.84, P ¼ 0.008) when
compared with SAT. A meta-analysis by Karumbi and
Garner, which involved five trials comparing DOTS
vs. SAT, showed that the TB cure rate was lower with
SAT across all studies (range 41–67%), and that
DOTS did not substantially improve this rate (n ¼
Adherence to anti-tuberculosis treatment 737
1645; RR 1.08, 95%CI 0.91–1.27).32 Direct obser-
vation and regular home visits by health workers
appear to reduce the risk of treatment non-adher-
ence.5
A meta-analysis by Pasipanodya and Gumbo
involved 10 studies (five RCTs and five observational
studies) with the allocation of 8774 patients.33
Endpoints were microbiological failure, relapse and
acquired drug resistance in patients on either DOTS
or SAT. In contrast to our meta-analysis, DOTS did
not yield significantly better results than SAT in
preventing microbiological failure, relapse or ac-
quired drug resistance. A possible reason for these
contradictory findings was the inclusion of observa-
tional studies in Pasipanodya and Gumbo’s meta-
analysis, while we included only RCTs.
The meta-analysis by Zhang et al., which involved
eight RCTs comparing community-based vs. clinic-
based DOTS, showed that community-based DOTS
improved TB treatment outcomes, thereby promoting
738 The International Journal of Tuberculosis and Lung Disease
Figure 4 Mortality rate. M-H ¼ Mantel-Haenszel; CI ¼ confidence interval; DOTS ¼ directly observed treatment, short-course; SAT ¼
self-administered treatment; df ¼ degrees of freedom.
treatment success (RR 1.11, 95%CI 1.02–1.19).34
DOTS supervised by a family member or someone in
the community was effective and low cost.35 We did
not find a significant association between communi-
ty-based DOTS, clinic-based DOTS and cure rate,
possibly because of the heterogeneity between the
studies included in Zhang et al.’s meta-analysis,
which analysed not only RCTs, but also cohort
studies and different forms of DOTS.34
In our meta-analysis, patient education and coun-
selling led to an increase in the cure rate (n ¼ 1106;
RR 1.16, 95%CI 1.05–1.29, P ¼ 0.004) and a
reduction in the default rate (n ¼ 1106; RR 0.87,
95%CI 0.77–0.98, P ¼ 0.03). A meta-analysis by
M’Imunya and Volmink involved three RCTs (n ¼
1437 cases) and examined the effects of patient
education and counselling on treatment adherence.36
Overall, patient education or counselling can increase
the chance of successful treatment completion, but
the magnitude of the benefit is likely to vary
depending on the nature of the intervention and the
setting. In a four-arm trial, counselling by nurses via
telephone resulted in an increase in the proportion of
participants completing treatment from 65% to 94%,
while counselling by nurses through home visits
increased the completion rate to 95%. Both of these
interventions were superior to counselling by physi-
cians at the TB clinic. Several factors are associated
with non-adherence to TB treatment: social, familial,
personal and psychological, as well as knowledge
about TB and about anti-tuberculosis treatment.2–
8,37–39 Psychological counselling and health educa-
tion services can reduce the level of non-adherence
among TB patients, and is recommended in the case
of routine treatment. This could be best achieved if
these interventions are guided by behavioural theories
and incorporated into routine anti-tuberculosis treat-
ment strategies.40
Some studies have shown which incentives used
during anti-tuberculosis treatment help patients
adhere to and complete treatment. Financial incen-
tives and patient education/counselling led to a
decrease in the default rate (n ¼ 4214; RR 0.74,
95%CI 0.61–0.90, P ¼ 0.002) in our study. A meta-
analysis by Petry et al. involving 15 randomised
studies to evaluate reinforcement interventions for
medication adherence reported a significant improve-
ment in adherence in the intervention group com-

pared with controls, with an overall effect size of 0.77
(95%CI 0.70–0.84, P , 0.001).41 A meta-analysis by
Lutge et al. comparing different types of incentives
found that an immediate cash incentive may be more
effective than delaying the incentive until after
treatment completion (RR 1.11, 95%CI 0.98–
1.24).30 Cash incentives may be more effective than
non-cash incentives (RR 1.26, 95%CI 1.02–1.56),
and higher cash incentives may be more effective than
lower cash incentives (RR 1.08, 95%CI 1.01–1.16).42
As TB is related to poverty, poor living conditions,
malnutrition and limited access to good public
services, interventions involving financial incentives
for food and transport resulted in significant im-
provements in treatment adherence.
Our study had five main limitations. First, most of
the studies included in our systematic review may not
represent the current situation, as interventions
depend on the setting. Second, there was significant
heterogeneity among studies, which could not be fully
explained by subgroup analyses. Third, although we
performed a stratified analysis by different forms of
DOTS and other strategies, some of the studies did
not explicitly state whether DOTS was applied
throughout the full course of treatment or describe
exactly the type/quality of DOTS and other educa-
tional interventions. Fourth, an inherent limitation of
any systematic review is that some studies may be
missed during the search, particularly those that are
unpublished. Although we have carried out a
comprehensive search for published and unpublished
studies without language restrictions, some eligible
studies may have been missed, resulting in selection
bias. Fifth, the present meta-analyses were carried out
by collecting aggregate patient data. Meta-analyses
based on individual patient data offer several
advantages and constitute the standard against which
all other systematic reviews should be compared.
Most published meta-analyses are based on summary
or aggregate patient data. Reasons suggested for this
include the considerable resources, years of study and
often broad international cooperation required for
individual meta-analyses of patient data.43
In conclusion, several strategies may help improve
TB treatment outcomes. DOTS and patient educa-
tion/counselling significantly improved cure rates,
and DOTS, patient education/counselling and finan-
cial incentives led to a reduction in default rates.
Acknowledgements
The present study received financial support from the Hospital de
Clı́nicas de Porto Alegre Research Incentive Fund (FIPE-HCPA)
Porto Alegre, RS, Brazil. AMM was a recipient of a fellowship from
Coordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior
(CAPES), Brasilia, DF, Brazil. CSO received a fellowship from the
Programa Institucional de Bolsas de Iniciação Cientı́fica Universi-
dade Federal do Rio Grande do Sul, Conselho Nacional de
Desenvolvimento Cientı́fico e Tecnológico, Brasilia, DF, Brazil.
Conflicts of interest: none declared.
Adherence to anti-tuberculosis treatment 739
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 Adherence to anti-tuberculosis treatment i

APPENDIX

Search strategy
Terms sensitive for searches for randomised con-
trolled trials were used for this study. The strategies
used for each database are described below.

Table A.1 Search strategy for the EMBASE database

#1 ‘Tuberculosis’
#2 ’directly observed therapy’/exp OR ’motivation’/exp OR ’financial management’/exp OR ’reminder system’/exp OR
’mobile phone’/exp OR ’text messaging’/exp OR ’counseling’/exp OR ’health education’/exp OR ’patient
education’/exp OR incentives OR ’economic support’ OR ’monetary incentive’ OR ’smart phones’ OR ’short
message services’ OR ’food baskets’ OR ’food incentives’ OR ’food packaging’ OR voucher
#3 [randomised controlled trial]/lim OR [humans]/lim OR [embase]/lim OR ([controlled clinical trial]/lim OR [randomised
controlled trial]/lim)
#4 #1 AND #2 AND #3

Table A.2 Search strategy for the LILACS database

#1 ‘Tuberculose’
#2 Adolescente OR Adulto OU ‘Adulto Jovem’ OR Humanos
#3 ‘Ensaio Clı́nico’ OR ‘Ensaio Clı́nico Controlado’ OR ‘Ensaio Clı́nico Controlado Aleatório’
#4 #1 AND #2 AND #3
LILACS ¼ Latin American and Caribbean Health Sciences Literature.

Table A.3 Search strategy for the Cochrane database

#1 ‘Tuberculosis’
#2 ‘Directly Observed Therapy’ OR ‘Motivation’ OR ‘Financial Support’ OR ‘Reminder Systems’ OR ‘Cell Phones’ OR
‘Text messaging’ OR ‘Counseling’ OR ‘Health Education’ OR ‘Patient Education’
#3 ‘Trials’
#4 #1 AND #2 AND #3

Table A.4 Summary of included studies

Number of
patients
Author, year, refer- Study (intervention/
ence location controls) Intervention Controls
DOTS vs. SAT
Clarke, 200511 South Africa 76/89 DOT by LHW; the intervention team consisted of Self-supervision
an experienced clinic nurse and two LHW
trainers
Hsieh, 200812 Taiwan 32/32 DOT for the first 2 months, 7 days a week; the Routine ward care without
group moved to self-administration after the any additional
month 2 with one unscheduled home visit per intervention; one clinic
week by a case manager. The subjects in the follow-up visit with case
group were offered clinical medical care and manager once per month
nursing instructions according to the clinical
pathway for TB during hospitalisation
Kamolratanakul, Thailand 414/422 DOT group: drug intake supervised daily by Self-supervised group: no
199913 individual patient supervisors. Health Centre treatment supervision
staff visited the patient homes: twice per was offered between
month during the initial 2 months of treatment, follow-up visits
and once per month during the remaining 4
months
Sivaraj, 201414 India 50/50 DOTS No DOTS
Tandon, 200215 India 226/153 DOTS monitored by educated patient attendant, SAT
village school teacher, in association with
medical personnel
Thiam, 200716 Africa 778/744 Reinforced counselling through improved TB control programme
communication between health personnel and procedures remained
patients, decentralised treatment, choice of unchanged
DOT supporter by patient and reinforcement of
supervision activities
ii The International Journal of Tuberculosis and Lung Disease

Table A.4 (continued)

Number of
patients
Author, year, refer- Study (intervention/
ence location controls) Intervention Controls
Toyota, 200317 Japan 135/124 DOT SAT
Zwarenstein, South Africa 111/105 DOT by clinic nurses. Attendance by new patients Self-supervision: patients to
199818 was expected 5 days a week for 8 weeks and visit the clinic once a
for 12 weeks by retreatment patients, week, or to send a family
following which attendance was expected 3 member to collect drugs
days a week during the continuation phase
Community vs. health facility DOTS
Lwilla, 200319 Tanzania 221/301 Community-based DOT: a community member Institutional-based DOT: the
living in the same village as that of the patient patient had to visit the
observed daily drug intake during the first 2 health facility daily to be
months (intensive treatment phase) and the observed during drug
patient visited the health facility monthly intake (the first months)
and every month during
the 6-month continuation
phase
Wandwalo, Tanzania 260/327 Community-based DOT using guardians and Health facility-based DOT:
200420 former TB patients. A guardian was defined as patient to visit TB clinic
a family member or a close relative living with daily during the 2-month
the patient intensive phase for drug
intake to be observed by
health worker
Family vs. community DOTS
Newell, 200621 Nepal 358/549 Family-member DOTS: drug intake supervised Community DOTS: drug
daily by a household member selected by the intake supervised daily by
patient, with drugs provided to the patient’s a female community
supervisor every week. Government workers health volunteer or a
provided dedicated tracing village health worker,
with drugs provided to
the supervisor every
month
Wright, 200422 Swaziland 664/662 A family member or carer was nominated by the Community health workers
patient to become the treatment supporter. acted as treatment
This person was then trained in observing the supporters, with the
patient’s daily drug intake, reminding them if patient visiting them
they forgot, and recording adherence. Patients every day for direct
visited the community health worker on a observation of treatment.
weekly basis to check on side effects, The health worker was
adherence and for general health education trained in observing the
patient’s daily drug
intake, reminding them if
they forgot, and
recording adherence
Patients offered financial incentives vs. no financial incentives
Baral, 201423 Nepal 42/81 Combined counselling and financial support: Usual care (i.e., no support)
patients receiving counselling individually and
in small groups provided for every 2–3 weeks.
Patients receiving financial support were given
2000 Nepali rupees (US$28) per month to
cover local transport, food and rental costs, but
patients were free to use it as they chose
24
Lutge, 2013 South Africa 2107/1984 Patients offered monthly voucher of 120.00 Usual TB care
South African rand (’US$15) by nurses until
treatment completion. Vouchers could be
redeemed at local shops for foodstuff
Patients offered food incentive vs. no food incentives
Jahnavi, 201025 India 36/36 Nutritional supplement group: current dietary No supplement group: only
intake estimated from a 24-h food recall, with given general advice and
advice about the dietary, dietary plan, food instructed to increase
supplements their food intake
Martins, 200926 Timor-Leste 136/129 Supplementary food: patients in the intervention Nutritional advice: verbal
group asked to attend the clinic at mid-day. and written advice
They received food every time they attended concerning the types of
the clinic. During the intensive phase, they locally available food that
were provided daily with one bowl of would constitute a
‘feijoada’, a locally popular meat, red kidney balanced diet likely to
beans and vegetable stew with rice at the assist TB cure
clinic. During the continuation phase, patients
given food parcel containing unprepared food
to take home
 Adherence to anti-tuberculosis treatment iii

Table A.4 (continued)

Number of
patients
Author, year, refer- Study (intervention/
ence location controls) Intervention Controls
Sudarsanam, India 48/49 Nutritional supplement plus standard of care Standard of care alone
201127
Patients given education and counselling vs. no education or counselling
Alvarez Gordillo, Mexico 44/43 Educational strategies Control group
200328
Liefooghe, 199929 Pakistan 504/515 Counselling— ambulatory patients: received No counselling: patients
individual counselling from a counsellor each given usual explanations
time they attended for follow-up assessment; about their disease and
admitted patients: received weekly counselling treatment by the medical
in the TB ward staff
Other studies
Kunawararak, Thailand 19/19 DOTS with a daily phone call reminder to take DOTS only
201130 their medication using a mobile phone
Mohan, 200331 Iraq 240/240 Patients received visits at home from a local No visits, conventional DOT
volunteer in order to motivate them to attend
the health centre daily
Walley, 200132 Pakistan 165/170 DOTS by family members DOTS by health workers
DOT/DOTS ¼ directly observed treatment, short-course; SAT ¼self-administered treatment; LHW ¼ lay health workers; TB ¼ tuberculosis.
iv The International Journal of Tuberculosis and Lung Disease
C O N T E X T E : Un des problèmes les plus graves en
matière de lutte contre la tuberculose (TB) est la non
adhérence au traitement. De nombreuses stratégies ont
été élabor ées afin d’am éliorer l’adhérence et
d’augmenter le taux de guérison.
O B J E C T I F : Revoir de façon systématique les différentes
interventions visant à améliorer l’adhérence au
traitement de la TB.
S C H É M A : Nous avons réalisé une revue systématique et
une méta-analyse d’essais cliniques randomisés (RCT)
qui ont comparé les stratégies suivantes : traitement
court sous observation directe (DOTS), incitations
financières, soutien alimentaire et éducation/conseil
contre contr ôle afin d’améliorer l’adh érence au
traitement de TB. Le résultat principal a été le taux de
guérison ; le deuxième résultat a été le taux de pertes de
vue et de décès. Les sources ont été Medline (accès par
M A R C O D E R E F E R E N C I A: Uno de los problemas más
graves en el control de la tuberculosis (TB) es el
incumplimiento terapéutico. Se han elaborado muchas
estrategias con el propósito de mejorar el cumplimiento
y aumentar las tasas de curación.
O B J E T I V O: Analizar de manera sistemática las
diferentes intervenciones encaminadas a mejorar el
cumplimiento del tratamiento antituberculoso.
M É T O D O: Se llevó a cabo una revisión sistemática y un
metanálisis de los ensayos clı́nicos aleatorizados que
comparaban las siguientes estrategias: el tratamiento
breve con observación directa (DOTS), los incentivos
económicos, los incentivos alimentarios y la educación y
el asesoramiento, comparadas con el control, con el fin
de mejorar el cumplimiento del tratamiento de la TB. El
principal criterio de valoración fue la tasa de curación;
los criterios secundarios fueron el abandono y la tasa de
mortalidad. Las fuentes de información fueron las bases
de datos Medline (consultada en PubMed), Cochrane
R É S U M É
PubMed), Cochrane Central, LILACS (Literatura Latino
Americana em Ciências da Saúde) et Embase depuis le
démarrage jusqu’en octobre 2015.
R É S U L T A T S : Notre revue a inclus 22 études. Nos
résultats ont mis en évidence une augmentation
significative de 18% du taux de guérison avec le
DOTS et de 16% avec l’éducation et le conseil. De
plus, une réduction du taux de perdus de vue de 49%
avec le DOTS, de 26% avec les incitations financières et
de 13% avec l’éducation et le conseil. Il n’y a pas eu de
réduction statistiquement significative du taux de
mortalité grâce à ces interventions.
C O N C L U S I O N : Nous avons observé que le DOTS et
l’éducation/le conseil ont significativement amélioré le
taux de guérison ; le DOTS, l’éducation/le conseil et les
incitations financières ont réduit le taux de perdus de
vue.
RESUMEN
Central, LILACS (Literatura Latino Americana em
Ciências da Saúde) y Embase desde el inicio hasta
octubre del 2015.
R E S U LT A D O S: Se incluyeron en la revisión 22 estudios.
Los resultados pusieron en evidencia un aumento
significativo de 18% de la tasa de curación con el
DOTS y de 16% con la educación y el asesoramiento.
Además, se observó una disminución de 49% de la tasa
de abandonos con el DOTS, de 26% con los incentivos
económicos y de 13% con la educaci ón y el
asesoramiento. La reducción de la tasa de mortalidad
no fue estadı́sticamente significativa con estas
intervenciones.
C O N C L U S I Ó N: Se observó que el DOTS y la educación
con asesoramiento mejoran de manera considerable la
tasa de curación, en igual medida que el DOTS, la
educaci ón y el asesoramiento y los incentivos
económicos disminuyen la tasa de abandonos.