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EVIDENCE SYNTHESIS

Strategies to promote adherence to treatment by


pulmonary tuberculosis patients: a systematic review
Wongduan Suwankeeree MSN, RN and Wilawan Picheansathian DNurs, RN

Faculty of Nursing, Chiang Mai University, Chiangmai, Thailand

ABSTRACT

Objective: The objective of this study is to review and synthesise the best available research evidence that
investigates the effectiveness of strategies to promote adherence to treatment by patients with newly diagnosed
pulmonary tuberculosis (TB).
Methods: The search sought to find published and unpublished studies. The search covered articles published from
1990 to 2010 in English and Thai. The database search included Cumulative Index to Nursing and Allied Health
Literature (CINAHL), EMBASE, Cochrane Library, PubMed, Science Direct, Current Content Connect, Thai Nursing
Research Database, Thai thesis database, Digital Library of Thailand Research Fund, Research of National Research
Council of Thailand and Database of Office of Higher Education Commission. Studies were additionally identified from
reference lists of all studies retrieved. Eligible studies were randomised controlled trials that explored different
strategies to promote adherence to TB treatment of patients with newly diagnosed pulmonary TB and also included
quasiexperimental studies. Two of the investigators independently assessed the studies and then extracted and
summarised data from eligible studies. Extracted data were entered into Review Manager software and analysed.
Results: A total of 7972 newly diagnosed pulmonary TB patients participated in 10 randomised controlled trials and
eight quasiexperimental studies. The studies reported on the effectiveness of a number of specific interventions to
improve adherence to TB treatment among newly diagnosed pulmonary TB patients. These interventions included
directly observed treatment (DOT) coupled with alternative patient supervision options, case management with DOT,
short-course directly observed treatment, the intensive triad-model programme and an intervention package aimed
at improved counselling and communication, decentralisation of treatment, patient choice of a DOT supporter and
reinforcement of supervision activities.
Conclusion: This review found evidence of beneficial effects from the DOT with regard to the medication adherence
among TB patients in terms of cure rate and success rate. However, no beneficial effect was found from DOT
intervention with increasing completion rate. In addition, the combined interventions to improve adherence to
tuberculosis treatment included case management with directly observed treatment short-course program, the
intensive triad-model programme and intervention package. These interventions should be implemented by
healthcare providers and tailored to local contexts and circumstances, wherever appropriate.
Key words: promote, pulmonary tuberculosis, treatment adherence
Int J Evid Based Healthc 2014; 12:316.

Background treatment short-course (DOTS) programmes and to


successfully treat at least 85% of detected cases.1 The
T argets for global tuberculosis (TB) control launched
by the WHO in 2006 are designed to detect at least
70% of new smear-positive cases in directly observed
DOTS strategy has five operational components for
effective TB control, including political commitment;
diagnosis based on sputum smear microscopy; stand-
ardised short-course drug regimens; adequate and unin-
Correspondence: Wilawan Picheansathian, Faculty of Nursing,
Chiang Mai University, 110 Indhavarorose Road, Muang, Chiangmai
terrupted supply of drugs and other materials; close
50200, Thailand. Tel: +66 53 949007; fax: +66 53 894171; e-mail: monitoring, in which patients are directly observed daily
wilawan.p@nurse.cmu.ac.th to ensure that every dose of recommended treat-
DOI: 10.1097/01.XEB.0000444614.17658.46 ment regimen is taken; and standardised recording

International Journal of Evidence-Based Healthcare 2014 University of Adelaide, Joanna Briggs Institute 3

2014 University of Adelaide, Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited.
W Suwankeeree and W Picheansathian

and reporting with sufficient feedback.2,3 To complete clinical evidence available on the effectiveness of
treatment is usually an independent choice of patients strategies to promote adherence to treatment by
and described as adherence. Successful TB control is patients with pulmonary TB.
heavily dependent on effective treatment of patients,
requiring adherence throughout the full course of treat- Definitions
ment.4 However, approximately half of TB patients do Treatment completion rate is defined as the percentage
not complete the treatment course under routine prac- of patients who completed the required treatment
tice conditions.5 7 This low adherence to treatment by course but did not receive sputum examinations on at
TB patients has been associated with adverse outcomes, least two occasions for cure detection.
including increased transmission rates of tubercle bacilli, Cure rate is defined as the percentage of patients who
prolonged infectiousness, treatment failure and relapse, completed treatment and had two negative sputum
drug resistance, and increased cost of TB control pro- examinations during treatment, of which one was at
grammes.810 Therefore, early and accurate diagnosis the end of treatment.
and effective treatment leading to cure are the core Success rate is the percentage of patients who are
elements of TB control. cured and those who have completed treatment.
There have been five systematic reviews related to TB DOT is defined as ingestion of anti-TB medications
treatment. The result of a systematic review of random- that was directly supervised by a healthcare worker
ised controlled trials (RCTs) from 1966 to 1996 indicated (HCW), community member or lay health worker or
that reminder letters, monetary incentives, health edu- case manager, or family member who was trained to
cation, and intensive supervision of staff in TB clinics do this.
improve adherence to TB treatment. These should be The DOTS is the control strategy for TB promoted by
adopted in the health system, depending on their appro- the WHO. The DOTS strategy is made up of five oper-
priateness to practice circumstances.8 A meta-analysis of ational components, including political commitment,
13 studies, including three RCTs, nine casecontrol diagnosis based on sputum smear microscopy, stand-
studies, and one cohort analytic study in 1999, indicated ardised short-course drug regimens, adequate and unin-
that the directly observed treatment (DOT) and incen- terrupted supply of drugs and other materials, close
tives of food, clothing, books, and transportation were monitoring in which patients are directly observed daily
effective in reducing the incidence of TB.11 On the to ensure drugs are taken (DOT), recording and reporting
contrary, a systemic review of 11 randomised and with sufficient feedback.
quasi-RCTs from 1966 to 2007 found no rigorous evi- Self-administered treatment (SAT) is defined as
dence to support the conclusion that the use of DOT in unsupervised administration of anti-TB medications
low-income and middle-income countries improves cure by patients.
or treatment completion in people with TB.12 The results Self-supervision is defined as responsibility for treat-
of nine RCTs from 1945 to 2008 indicated that both ment adherence by patients without supervision by
reminder systems and late patient tracers, which rou- another person, which is the same meaning of SAT.
tinely remind patients to keep an appointment, showed
benefits of the intervention in increasing incidence of Objectives
TB.13 In addition, a systematic review of 19 studies, The specific aims of the review were to
including six RCTs, five prospective cohort studies, seven
retrospective cohort studies and one pilot programme in (1) identify the existing strategies to promote adher-
the United States and Canada published between 1997 ence to treatment by patients with pulmonary
and 2007, showed that adherence and completion rates TB and
of treating latent TB infection are suboptimal across (2) identify the best strategy to promote adherence to
high-risk groups, and no single intervention has shown TB treatment by patients with pulmonary TB.
consistent effectiveness.10 However, these systematic
reviews did not focus on new cases of pulmonary TB. Inclusion criteria
In addition, some studies were not included in these Types of participants
reviews.1418 This review considered all studies that included adults
It is critically important to clarify the effectiveness of age 15 years at least diagnosed with smear-positive and
strategies to promote adherence to treatment by smear-negative pulmonary TB (regardless of HIV infec-
patients with pulmonary TB in order to support evi- tion) in community settings who had never received
dence-based practice. This review has evaluated the anti-TB drugs or had taken them for less than 1 month.

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2014 University of Adelaide, Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited.
EVIDENCE SYNTHESIS

The focus was on new cases and excluded previously medication, intervention, therapy, DOT, DOTS, health
treated patients because of the increased likelihood of education, home visit, self-administrated, self-supervised,
drug resistance and adverse outcomes such as treatment financial incentives, counselling, lay health workers, treat-
failure in the re-treatment group, which could nullify a ment completion, completion rate and cure rate.
treatment effect irrespective of the quality of treatment The time period of the search covered articles pub-
supervision. lished from 1990 to 2010 in English and Thai languages.
The database search included CINAHL, EMBASE,
Types of interventions Cochrane Library, PubMed, Science Direct, Current Con-
Interventions of interest were those related to strategies tent Connect, Thai Nursing Research Database, Thai
to promote adherence to treatment, including DOT, thesis database, Digital Library of Thailand Research
DOTS, case management, intervention package, parti- Fund, Research of National Research Council of Thailand
cipatory in-service training, food incentives, and inten- and Database of Office of Higher Education Commission.
sive triad-model programme. In order to avoid publication bias, hand searching of
the most recent issues (January 1990 to December 2010)
Types of outcome measures of the following journals was undertaken for additional
The outcomes of interest were treatment completion references: International Journal of Tuberculosis and Lung
rate, cure rate, and success rate. Disease, American Journal of Infection Control, Journal
of Infection, Thai Journal of Tuberculosis Chest Disease
Types of studies
and Critical Care, Journal of Thai Medical Association and
This review considered any RCTs that examined the differ-
Journal of Health Science. The search for unpublished
ent strategies used to promote adherence to treatment by
studies included the following sources: dissertation
patients with pulmonary TB. Additionally, quasiexperi-
abstracts, proceedings of nursing and allied health con-
mental studies were considered for inclusion in the review
ferences held in Thailand and other countries and direct
to enable the identification of current best evidence for
communication with researchers.
promoting adherence to the TB management.
Methods of the review
Exclusion criteria Critical appraisal
This review excluded articles that were expert opinion
All studies that met the inclusion criteria were assessed
and literature reviews.
for methodological quality using standardised critical
appraisal tools from the Joanna Briggs Institute Meta-
Search strategy Analysis of Statistics Assessment and Review Instrument
The search strategy was designed to identify both pub-
(http://joannabriggs.org/SUMARI). Two reviewers inde-
lished and unpublished studies. Two reviewers inde-
pendently appraised each study. Discrepancies in critical
pendently searched for the articles. A detailed search
appraisal were resolved at a meeting between reviewers.
strategy was developed to identify studies for inclusion
Those studies had to meet the criteria to be included in
in this review as follows:
the review.
(1) An initial limited search included journal indexes
Data collection
from MEDLINE and the Cumulative Index to
Two reviewers independently extracted data, using the
Nursing and Allied Health Literature (CINAHL). An
standardised data extraction tool from the Joanna Briggs
analysis of the text contained in the title, abstracts
Institute Meta-Analysis of Statistics Assessment and
and subject descriptors of relevant articles was
Review Instrument (http://joannabriggs.org/SUMARI).
undertaken to identify additional keywords.
However, the reviewers were not blinded to the authors
(2) A second search using all identified keywords
of the studies under review.
and index terms was then undertaken across all
included databases.
Data synthesis
(3) Reference lists and bibliographies of all identified
If two or more comparable studies were identified, data
articles were also searched for additional relevant
were pooled in a statistical meta-analysis to determine
studies and source journals.
the effectiveness of the intervention by using the Review
Keywords included tuberculosis, pulmonary Manager software (RevMan v. 5.2; The Cochrane Collab-
tuberculosis, sputum-positive tuberculosis, adherence, oration, The Nordic Cochrane Center, Copenhagen,
compliance, concordance, treatment, anti-tuberculosis Denmark). Comparability of the studies was defined

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W Suwankeeree and W Picheansathian

by the population, interventions and outcome measures. review as their outcome was measured either as sputum
Double data entry was undertaken to minimise the risk conversion rate after receiving TB treatment for 2 or
of data entry errors. 3 months or as a percentage of the medication taken.
Heterogeneity between combined studies was tested The extent to which these intermediate outcomes cor-
using the standard x2 test and visual inspection of the relate with actual drugs taken is unknown. However,
graphic presentation of the results. Pooled statistics were clinical cases could have higher completion rates and
calculated using a fixed-effect model when there was no lower rates of failure related to misclassification from
statistically significant heterogeneity. If evidence of sig- overdiagnosis cases. This could influence the chance of
nificant heterogeneity was identified, a random-effects demonstrating a treatment effect. The stages of search-
approach to the analysis was used. Relative risk (RR) was ing, inclusion and exclusion of references for this review
used for categorical outcomes data and their 95% con- are shown in Fig. 1.
fidence intervals (CIs) were calculated for each study. If
statistical pooling of results was not appropriate, the Methodological quality of randomised
findings were summarised in narrative form. controlled trials
All trials were assessed using the JBI Critical Appraisal
Results tools. Only Lewin et al.18 and Kamolratanakul et al.23 met
Description of studies all 10 criteria for methodological quality. Owing to the
The initial search on the basis of keywords yielded a total nature of the intervention, it was not possible to conceal
of 1341 papers; however, a substantial number of these assignment to the participant in seven trials.17,19,21,22,2426
articles did not address the objective of this review. Of
these, 1292 publications were excluded. A second-stage
elimination, based on closer scrutiny of the article Potentially reIevant articles
abstract and keywords in relation to the inclusion criteria, identified by Iiterature search
(n = 1341)
resulted in 49 studies being deemed relevant for this
review. Following the reading of these full-text articles,
31 papers were excluded as they did not fulfil the
inclusion criteria. After detailed examination, 18 studies Articles excluded after abstract
evaluation (n = 1292)
qualified for inclusion based on methodological quality
assessment.
The 18 studies identified gave a combined total of
7972 patients who were newly diagnosed with pulmon- Articles retrieved for detailed examination (n = 49)
ary TB regardless of HIV infection and starting a new
course of TB treatment, or who had taken anti-TB drugs
for less than 4 weeks. The majority (7621) were sputum
smear-positive cases, 191 cases were sputum smear- Articles excluded after review of
negative15 and 160 cases of unknown status.19 All full article (n = 31)
- Measured inappropriate outcome
studies used daily treatment throughout, except the (n = 9)
study in India20 which used the three-times-a-week - Included patients who did not
treatment both in the intensive and in the continuation meet inclusion criteria (n = 14)
phases. Ten studies were RCTs15,1719,2126 and eight - NonRCTs or quasiexperimental
studies (n = 4)
used quasiexperimental designs.5,14,16,20,27 29 Of these, - Unknown patient age and illness
16 were published in English5,1427,30 and two in status (n = 3)
Thai.28,29 The number of participants in each study - Published in Spanish (n = 1)
ranged from 89 to 1522 patients aged 15 years at
least. Seventeen of the 18 trials were conducted in
low-income and middle-income countries including Articles included in the systematic review
India,20 Nepal,25 Pakistan,21 Taiwan,14 Tanzania,26 (n = 18)
Timor-Leste,15 Thailand16,23,27 30 and Africa.1719,22,24 - Randomized controlled trials (n = 10)
One trial was conducted in a high-income country, USA.5 - Quasiexperimental studies (n = 8)
The outcomes of interest in this review were direct
methods, including treatment completion rate, cure rate Figure 1. Flow chart for identification of trials for inclusion
and success rate. Many studies were excluded from this and exclusion.

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EVIDENCE SYNTHESIS

One trial22 did not conceal the treatment allocation Effect of interventions
because of the impossibility of concealing assignment The findings of this review are discussed according to the
results to the assessor at the study site. However, assessors specific interventions used in the identified research and
were not involved in the design and implementation of their comparison with different control groups. The
the intervention or in the final data analysis. A study by results are broadly categorised into studies that eval-
Lwilla et al.26 also did not conceal the allocation to treat- uated DOT/DOTS, case management, intervention pack-
ment groups from the allocator, and a study by Clarke age, participatory in-service training, food incentives and
et al.22 was unclear on this criteria. A study by Martins intensive triad-model programme.
et al.15 did not include the outcomes of participants who
withdrew from the study in the analysis. Directly observed treatment
All trials use appropriate statistical analysis. Power Directly observed treatment vs. self-
analysis on sample size calculations was reported in nine supervision
trials.15,1719,21,22,2426 Study groups were identically Cure rate
treated (apart from the interventions), and outcomes An RCT23 (836 participants) conducted in Thailand dem-
appeared to be measured reliably in all studies. In each onstrated that cure rates of newly diagnosed pulmonary
study, attempts were made to control confounding TB patients who received DOT by individual patient
factors and ensure that any positive outcomes detected supervisors (76%) were significantly higher than the
were the result of the intervention. All RCTs used suitable rates of those on self-supervision (67%). This result
randomisation methods such as cluster randomisation, was consistent with two quasiexperimental studies27,29
block randomisation, stratified randomisation and (438 participants) conducted in Thailand that reported
randomisation sequence generated by computer algor- cure rates were higher in the DOT group than in those on
ithm. self-supervision. When results from the two quasi-
experimental studies27,29 were combined, higher cure
Methodological quality of quasiexperimental rates among newly diagnosed pulmonary TB patients
studies who received DOT were statistically significant com-
All of the eight quasiexperimental studies met five of the pared with those on self-supervision (RR 1.17, 95% CI
10 criteria except blinding, and six studies5,16,20,27,29,30 1.051.30, P 0.005] (Fig. 2).
did not randomly assign participants to treatment
and control groups. These studies used convenience Completion rate
sampling or purposive sampling depending on the avail- An RCT23 (836 participants) demonstrated that the com-
ability of the patients who sought treatment at the study pletion rates of newly diagnosed pulmonary TB patients
site. Although randomisation methods were not used who received DOT (7.7%) were similar to the rates of
in quasiexperimental studies, their quality was ensured those on self-supervision (8.7%); the authors did not
through comparison groups. The outcomes were report results statistically. This result was consistent with
assessed using objective criteria and in a reliable manner two quasiexperimental studies27,29 (438 participants)
in all of the included studies. Appropriate statistical which demonstrated that the completion rates in the
analysis was employed in all included studies. DOT group were similar to those in the self-supervision

DOT SS Risk ratio Risk ratio


Study or subgroup Events Total Events Total Weight M-H, fixed, 95% CI M-H, fixed, 95% CI
Akkslip 1999 184 216 78 110 71.2% 1.20 [1.05, 1.37]

Kungsaworn 1997 42 51 46 61 28.8% 1.09 [0.90, 1.32]

Total (95% CI) 267 171 100.0% 1.17 [1.05, 1.30]

Total events 226 124

Heterogeneity: 2 = 0.65, df = 1 (P = 0.42); I2 = 0%


0.2 0.5 1 2 5
Test for overall effect: Z = 2.82 (P = 0.005)
Favours SS Favours DOT

Figure 2. Cure rate Forest plot comparison: directly observed treatment (DOT) vs. self-supervision (SS). CI, confidence
interval.

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W Suwankeeree and W Picheansathian

DOT SS Risk ratio Risk ratio


Study or subgroup Events Total Events Total Weight M-H, fixed, 95% CI M-H, fixed, 95% CI
Akkslip 1999 1 216 0 110 32.6% 1.53 [0.06, 37.36]

Kungsaworn 1997 0 51 1 61 67.4% 0.40 [0.02, 9.55]

Total (95% CI) 267 171 100.0% 0.77 [0.09, 6.47]

Total events 1 1

Heterogeneity: = 0.35, df = 1 (P = 0.56); I = 0%


2 2

0.001 0.1 1 10 1000


Test for overall effect: Z = 0.24 (P = 0.81)
Favours SS Favours DOT

Figure 3. Completion rate Forest plot comparison: directly observed treatment (DOT) vs. self-supervision (SS). CI, confidence
interval.

group. When results from the two quasiexperimental Subgroup analysis for outcomes
studies27,29 were combined, the completion rates of Directly observed treatment by healthcare
newly diagnosed pulmonary TB patients who received worker vs. self-supervision
DOT compared with the rates of those on self-super- Cure rate
vision were not statistically significant (RR 0.77, 95% CI The meta-analysis of two trials23,30 (778 participants)
0.096.47, P 0.81) (Fig. 3). demonstrated that there was no significant difference
in cure rates between newly diagnosed pulmonary
Success rate TB patients who received DOT by HCW and those on
An RCT23 (836 participants) found success rates of newly self-supervision (RR 1.06, 95% CI 0.931.22, P 0.37)
diagnosed pulmonary TB patients who received DOT (Table 1). But the meta-analysis from three quasi-
(84%) were significantly higher than the rates of those on experimental studies5,27,28 (675 participants) demon-
self-supervision (76%). This result was consistent with strated that there were statistically significant higher
two quasiexperimental studies27,29 (438 participants) cure rates among newly diagnosed pulmonary TB
which demonstrated that the success rates were higher patients who received DOT by HCW compared with
in the DOT group than in the self-supervision group. those on self-supervision, although the difference was
When results from the two quasiexperimental stud- small (RR 1.22, 95% CI 1.121.34, P < 0.0001) (Table 1).
ies27,29 were combined, newly diagnosed pulmonary
TB patients who received DOT had a small but statisti- Completion rate
cally significant higher success rates compared with The meta-analysis of two RCTs21,23 (778 participants)
those on self-supervision (RR 1.17, 95% CI 1.051.30, with a fixed model demonstrated that there was no
P 0.005) (Fig. 4). statistical difference in the completion rates among

DOT SS Risk ratio Risk ratio


Study or subgroup Events Total Events Total Weight M-H, fixed, 95% CI M-H, fixed, 95% CI
Akkslip 1999 185 216 78 110 70.7% 1.21 [1.06, 1.38]

Kungsaworn 1997 42 51 47 61 29.3% 1.07 [0.89, 1.29]

Total (95% CI) 267 171 100.0% 1.17 [1.05, 1.30]

Total events 227 125

Heterogeneity: 2 = 1.11, df = 1 (P = 0.29); I2 = 10%


0.5 0.7 1 1.5 2
Test for overall effect: Z = 2.80 (P = 0.005)
Favours SS Favours DOT

Figure 4. Success rate Forest plot comparison: directly observed treatment (DOT) vs. self-supervision (SS). CI, confidence
interval.

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EVIDENCE SYNTHESIS

Table 1. Subgroup meta-analysis for outcomes


Subgroups Included studies OR (95% CI) P Heterogeneity
DOT by HCW vs. SS
Cure rate
RCTs 20, 22 1.06 (0.931.22) 0.37 No
Quasiexperimental studies 5, 26, 27 1.22 (1.121.34) 0.0001 No
Completion rate
RCTs 0, 22 0.95 (0.382.36) 0.92 No
Quasiexperimental studies 5, 27 0.44 (0.028.81) 0.59 Yes (P 0.03)
Success rate
RCTs 19, 20, 22, 23 1.07 (0.961.20) 0.21 No
Quasiexperimental studies 5, 26, 27 1.19 (1.101.29) 0.00001 No
DOT by CM vs. SS
Success rate
RCTs 22, 23 1.32 (0.782.23) 0.30 Yes (P 0.01)
DOT by FM vs. SS
Cure rate
RCTs 22, 22 1.02 (0.801.31) 0.85 Yes (P 0.02)
Completion rate
RCTs 20, 22 1.07 (0.701.63) 0.76 No
Success rate
RCTs 0, 22 1.07 (1.001.15) 0.04 No
DOT by HCW vs. DOT by CM
Cure rate
RCTs 21, 22, 23 0.94 (0.821.08) 0.39 No
Quasiexperimental studies 26, 30 1.06 (0.951.20) 0.30 No
Completion rate
RCTs 21, 22 0.48 (0.161.45) 0.20 No
Success rate
RCTs 21, 22, 23 0.86 (0.661.12) 0.27 Yes (P 0.03)
Quasiexperimental studies 26, 30 0.99 (0.891.09) 0.82 No
DOT by FM vs. DOT by CM
Success rate
RCTs 22, 24 1.05 (1.001.11) 0.04 No
DOT by FM vs. DOT by HCW
Cure rate
RCTs 20, 22 0.89 (0.771.03) 0.12 No
Quasiexperimental studies 26, 29 0.62 (0.123.36) 0.58 Yes (P < 0.000)
Completion rate
RCTs 20, 22 1.80 (0.814.02) 0.15 No
Quasiexperimental studies 26, 29 1.65 (1.072.55) 0.02 No
Success rate
RCT 20, 22 0.95 (0.831.07) 0.38 No
Quasiexperimental studies 26, 29 0.92 (0.581.46) 0.72 Yes (P 0.02)

CI, confidence interval; CM, case manager; DOT, directly observed treatment; DOTS, directly observed treatment short-course; FM, family member; HCW, healthcare
worker; OR, odds ratio; RCT, randomised controlled trial; SS, self-supervision.

newly diagnosed pulmonary TB patients who received showed no statistically significant difference in comple-
DOT by HCW compared with those on self-supervision tion rates (RR 0.44, 95% CI 0.028.81, P 0.59) (Table 1).
(RR 0.95, 95% CI 0.382.36, P 0.92) (Table 1). The results
of three quasiexperimental studies5,27,28 were inconsist- Success rate
ent. The results of one study were not suitable for meta- The meta-analysis of the four RCTs19,21,23,24 (1001 partici-
analysis.27 The combined results of two studies5,28 pants) with a fixed model demonstrated that there was
(544 participants) showed that there was significant no significant difference in success rates among newly
heterogeneity between the studies for completion diagnosed pulmonary TB patients who received DOT
rates (x2 4.47; P 0.03). Meta-analyses of these two by HCW compared with those on self-supervision
studies,5,28 performed using random-effects models, (RR 1.07, 95% CI 0.961.20, P 0.21) (Table 1). However,

International Journal of Evidence-Based Healthcare 2014 University of Adelaide, Joanna Briggs Institute 9

2014 University of Adelaide, Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited.
W Suwankeeree and W Picheansathian

the meta-analysis from three quasiexperimental stud- Directly observed treatment by family member
ies5,27,28 (675 participants) demonstrated that there was vs. self-supervision
a statistically significant higher success rate among Cure rate
newly diagnosed pulmonary TB patients who received The meta-analysis of the two RCTs21,23 (1101 partici-
DOT by HCW compared with those on self-supervision pants) with significant heterogeneity was performed
(RR 1.19, 95% CI 1.101.29, P < 0.00001) (Table 1). using a random-effects model (x2 5.84, P 0.02). The
result indicated that there was no statistically significant
Directly observed treatment by case manager difference in the cure rates between groups (RR 1.02,
vs. self-supervision 95% CI 0.081.31, P 0.85) (Table 1). On the contrary, a
Cure rate quasiexperimental study by Akkslip et al.27 (304 partici-
An RCT in Thailand by Kamolratanakul et al.23 (466 pants) demonstrated that the cure rates among newly
participants) found that the cure rates among newly diagnosed pulmonary TB patients who received DOT by
diagnosis pulmonary TB patients who received DOT by family member (86%) were higher than the rates in those
case manager (73%) were higher than the rates in those on self-supervision (70%); the authors did not report
on self-supervision (67%); the authors did not report results statistically.
results statistically. This result was consistent with a
Completion rate
quasiexperimental study by Akkslip et al.27 who reported
The meta-analysis of the two RCTs21,23 (1101 partici-
only one newly diagnosed pulmonary TB patient who
pants) used a fixed model and demonstrated that there
received DOT by case manager and met the criteria of
was no statistically significant difference in completion
cure (100%). This rate was higher than the rate in those
rates among newly diagnosed pulmonary TB patients on
on self-supervision [70% (78/110)]; the authors did not
self-supervision compared with those who received DOT
report results statistically. As these two studies used
by family member (RR 1.07, 95% CI 0.701.63, P 0.76)
different methodology, it is inappropriate to pool their
(Table 1). This result was consistent with a quasi-
results in meta-analysis.
experimental study27 (304 participants) which reported
only one newly diagnosed pulmonary TB patient
Completion rate
who received DOT by family member and none on
An RCT in Thailand by Kamolratanakul et al.23 (466
self-supervision who met the criteria of treatment com-
participants) indicated that the completion rates among
pletion (1/149 and 0/110, respectively).
newly diagnosed pulmonary TB patients who received
DOT by case manager (5%) were lower than the rates in Success rate
those on self-supervision (8%); the authors did not report The meta-analysis of the two RCTs21,23 (1101 partici-
results statistically. However, a quasiexperimental study pants) used a fixed model and demonstrated that
by Akkslip et al.27 found that there were no newly there was statistically significant higher success rates
diagnosed pulmonary TB patients who received DOT among newly diagnosed pulmonary TB patients who
by case manager or on self-supervision who met the received DOT by family member compared with those
criteria of treatment completion (0/1 and 0/110, respect- on self-supervision (RR 1.07, 95% CI 1.001.15, P 0.04,
ively). I2 63.0%) (Table 1). This result was consistent with a
quasiexperimental study by Akkslip et al.27 (304 partici-
Success rate pants), which demonstrated the success rates among
The meta-analysis of two RCTs23,24 (516 participants) newly diagnosed pulmonary TB patients who received
with significant heterogeneity was performed using a DOT by family member (86%) were higher than the rates
random-effects model (x2 6.29, P 0.01). There was in those on self-supervision control group (70%); the
no statistically significant difference in success rates authors did not report results statistically.
among groups (RR 1.32, 95% CI 0.78 2.23, P 0.30)
(Table 1). This result was inconsistent with a quasi- Directly observed treatment by healthcare
experimental study in Thailand by Akkslip et al.27 who worker vs. directly observed treatment by case
reported that there was only one newly diagnosed manager
pulmonary TB patient who received DOT by case Cure rate
manager and met the criteria of success (100%). This The meta-analysis of three RCTs23,26,27 (669 participants)
rate was higher than the rate in those on self-super- used a fixed model and found no statistical difference
vision [70% (78/110)]; the authors did not report for cure rates among newly diagnosed pulmonary TB
results statistically. patients who received DOT by HCW compared with

10 International Journal of Evidence-Based Healthcare 2014 University of Adelaide, Joanna Briggs Institute

2014 University of Adelaide, Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited.
EVIDENCE SYNTHESIS

those who received DOT by case manager (RR 0.94, 95% However, a quasiexperimental study by Akkslip et al.27
CI 0.821.08, P 0.39) (Table 1). This result was consist- (195 participants) indicated that there was only
ent with the meta-analysis from two quasiexperimental one newly diagnosed pulmonary TB patient who
studies20,27 (639 participants) which demonstrated no received DOT by case manager and met the criteria of
significant difference for cure rates between newly diag- cure (100%). This rate was higher than the rate in those
nosed pulmonary TB patients who received DOT by HCW who received DOT by family member [(86% (167/194)];
and those received DOT by case manager (RR 1.06, 95% the authors did not report results statistically. As these
CI 0.951.20, P 0.30) (Table 1). two studies used different methodology, it is inappro-
priate to pool results in meta-analysis.
Completion rate
The meta-analysis of two RCTs22,23 (147 participants) Completion rate
used a fixed model and demonstrated no significant An RCT study by Kamolratanakul et al.23 (386 partici-
difference for completion rates between newly diag- pants) found no statistically significant difference in
nosed pulmonary TB patients who received DOT by completion rates among newly diagnosed pulmonary
HCW and those who received DOT by case manager TB patients who received DOT by family member (7%)
(RR 0.48, 95% CI 0.161.45, P 0.20) (Table 1). Two compared with the rates in those who received DOT by
quasiexperimental studies20,27 examined the effect of case manager (5%). This result was consistent with a
DOT by HCW on completion rates compared with DOT quasiexperimental study by Akkslip et al.27 (195 partici-
by case manager. A study by Singh et al.20 showed that pants) which reported that there was only one newly
the completion rates among newly diagnosed pulmon- diagnosed pulmonary TB patient who received DOT by
ary TB patients who received DOT by case manager (7%) family member and none who received DOT by case
was higher than those who received DOT by HCW (2%); manager who met the criteria of treatment completion
the authors did not report results statistically. However, a (1/194 and 0/1, respectively).
study by Akkslip et al.27 found that none of the newly
diagnosed pulmonary TB patients who received DOT by Success rate
HCW or those who received DOT by case manager The meta-analysis of the two RCTs23,25 (1293 partici-
met the criteria of treatment completion (0/21 and 0/1, pants) used a fixed model and demonstrated that there
respectively). was a statistically significant higher success rate among
newly diagnosed pulmonary TB patients who received
Success rate DOT by family member compared with those who
The meta-analysis of the three RCTs2224 (216 partici- received DOT by case manager (RR 1.05, 95% CI 1.00
pants) with significant heterogeneity was performed 1.11, P 0.04) (Table 1). However, a quasiexperimental
using a random-effects model (x2 6.86, P 0.03). The study by Akkslip et al.27 (195 participants) demonstrated
result demonstrated that the success rate was not stat- that there was only one newly diagnosed pulmonary TB
istically significant between the groups (RR 0.86, 95% CI patient who received DOT by case manager who met the
0.661.12, P 0.27) (Table 1). This result was consistent criteria of cure (100%). This rate was higher than the
with two quasiexperimental studies20,27 (639 partici- rate in those who received DOT by family member [86%
pants) which demonstrated no statistically significant (168/194)]; the authors did not report result statistically.
difference in success rates between newly diagnosed
pulmonary TB patients who received DOT by HCW and Directly observed treatment by family member
those who received DOT by case manager (RR 0.99, 95% vs. directly observed treatment by healthcare
CI 0.891.09, P 0.82) (Table 1). worker
Cure rate
Directly observed treatment by family member The meta-analysis of the two RCTs21,23 (711 participants)
vs. directly observed treatment by case used a fixed model and demonstrated that there was no
manager statistically significant difference in cure rates among
Cure rate newly diagnosed pulmonary TB patients who received
An RCT by Kamolratanakul et al.23 (386 participants) DOT by family member compared with those who
found no statistically significant difference in cure rates received DOT by HCW (RR 0.89, 95% CI 0.771.03,
among newly diagnosed pulmonary TB patients who P 0.12) (Table 1). Results of two quasiexperimental
received DOT by family member (76%) compared with studies27,30 (709 participants) were inconsistent. There
those who received DOT by case manager (73%). was significant heterogeneity (x2 21.78, P < 0.000)

International Journal of Evidence-Based Healthcare 2014 University of Adelaide, Joanna Briggs Institute 11

2014 University of Adelaide, Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited.
W Suwankeeree and W Picheansathian

when these two quasiexperimental studies27,30 were who received traditional case management, and those
pooled, so they were analysed through meta-analysis who did not receive any intervention (93.7 vs. 68.6 vs.
using the random-effects model. The result indicated 68.6%, P 0.023).
that the difference in cure rates was not statistically
significant between groups (RR 0.62, 95% CI 0.12 Food incentive
3.36, P 0.58) (Table 1). A study in Timor-Leste15 demonstrated that provision of
food had no significant beneficial or harmful impact on
Completion rate the completion of treatment (76 vs. 78%, P 0.7), but did
The meta-analysis of the two RCTs21,23 (711 participants) lead to improved weight gain at the end of treatment
used a fixed model and demonstrated that there was no (10.1 vs. 7.5% improvement, P 0.04).
statistically significant difference in completion rates
among newly diagnosed pulmonary TB patients who Intensive triad-model programme
received DOT by family member compared with those A study in Thailand16 found that the intensive triad-
who received DOT by HCW (RR 1.80, 95% CI 0.814.02, model programme can improve a patients adherence to
P 0.15) (Table 1). The results of two quasiexperimental a TB treatment regimen. The triad-model emphasises the
studies27,30 (709 participants) were inconsistent. The roles of three key persons (healthcare provider, TB
meta-analysis of the two quasiexperimental studies27,30 patient and treatment supporter) and provides compre-
used a fixed model and demonstrated that there were hensive health education about TB and the importance
statistically significant higher completion rates among of its treatment. The healthcare provider and treatment
newly diagnosed pulmonary TB patients who received supporter visited all patients at home once a month to
DOT by family member compared with those who encourage them to take medication regularly under the
received DOT by HCW (RR 1.65, 95% CI 1.072.55, supervision of the healthcare provider. The success
P 0.02) (Table 1). rate of treatment was higher in the patients receiving
the intensive triad-model programme than those in the
Success rate control group (96.0 vs. 84.9%, P 0.057). Moreover,
The meta-analysis of the two RCTs21,23 (711 participants) the confirmed cure rate was also significantly higher
used a fixed model and demonstrated that there was no in the experimental group than in the comparison group
statistically significant difference in success rates among (95.3 vs. 78.9%, P 0.02).
newly diagnosed pulmonary TB patients who received
DOT by family member compared with those who Intervention package
received DOT by HCW (RR 0.95, 95% CI 0.831.07, A study in Senegal, West Africa,17 demonstrated treat-
P 0.38) (Table 1). Results of two quasiexperimental ment success for 88% of the patients who received the
studies27,30 were inconsistent. Analyses were adjusted intervention package. The intervention included
to the random-effects model (n 709) because of reinforced counselling through improved communi-
heterogeneity of the studies (x2 5.89, P 0.02). The cation between health personnel and patients, decen-
meta-analysis of the two quasiexperimental studies27,30 tralisation of treatment, patient choice of a DOT
demonstrated that the difference in the success rates supporter and reinforcement of supervision activities
were not statistically significant between the groups (RR compared with 76% in the patients who received the
0.92, 95% CI 0.581.46, P 0.72) (Table 1). usual TB control programme [adjusted risk ratio (RR) 1.18,
95% CI 1.031.34]. In addition, this study found that
Case management choice of a DOT supporter among the patients family
A study in Taiwan14 found that the TB patients who members yielded better treatment outcomes than
received DOTS case management comprising hospital having other DOT supporters.
education, direct daily observation in the first 2 months
and one home visit per week by the case manager had Participatory in-service training vs. usual
better treatment completion rates than those who care (directly observed treatment short-
received traditional case management comprising in- course)
hospital education and one home visit per month, and Lewin et al.18 undertook a study in South Africa to assess
those who did not receive any intervention (96.9 vs. 68.6 the addition to the DOTS strategy of an experimental,
vs. 68.6%, P 0.007). In addition, the treatment success participatory in-service training programme for clinic
rate of the TB patients who received DOTS case manage- staff delivered by nurse facilitators and focused on
ment was significantly improved compared with those patient centeredness, critical reflection on practice and

12 International Journal of Evidence-Based Healthcare 2014 University of Adelaide, Joanna Briggs Institute

2014 University of Adelaide, Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited.
EVIDENCE SYNTHESIS

quality improvement. The results indicated that the cure burdens on patients, keep the impact of stigma to a
rates in the intervention clinics following the interven- minimum and give patients improved access to care. The
tion were 49.1% compared with 51% in the control variants of DOT differ in important ways in terms of who
clinics. In addition, the completion rate in the interven- is being observed, where the observation takes place
tion group was 17.4% compared with 15.9% in the and how often the observations occur.32 A variety of
control group. However, these differences were not supervision options have been explored, such as
statistically significant, and the findings of this trial supervision by family members, HCWs and community
are inconclusive. members.
There was no significant difference in cure rates,
Discussion completion rates, and success rates among pulmonary
Approximately half of the TB patients did not complete TB patients who received DOT by a community member
the treatment course under routine practice con- or family member or HCW. This finding is similar to the
ditions;5 7 however, the average adherence level to reviews conducted by Volmink and Garner,12 which
treatment among patients with HIV, infectious diseases indicated that there is no evidence showing that one
and pulmonary diseases was 88.35, 74.0 and 68.8%, form of direct observation is better than another. Never-
respectively. In addition, adherence to care for pulmon- theless, two RCTs23,25 found that the success rates of
ary conditions is significantly lower compared with other pulmonary TB patients who received DOT by a family
conditions (t 2.02, P 0.04).31 The effectiveness of member were significantly higher than the rates of those
strategies to promote adherence to treatment by TB who received DOT by a community member. This result
patients requires further research. was inconsistent with a quasiexperimental study by
Pooled results of RCTs and quasiexperimental studies Akkslip et al.,27 which demonstrated that the success
consistently indicate the evidence of beneficial effects rate among newly diagnosed pulmonary TB patients
from DOT with increased medication adherence among who received DOT by case manager were higher than
TB patients in terms of cure rate and success rate. the rates in those who received DOT by family member.
Although these effects were small, there are clinically However, this quasiexperimental study was conducted
significant differences in overall public health and health with a small sample size (195 participants). In addition,
system, including decreased transmission, shortened the findings of three studies24,25,27 showed that family
infectiousness, prevented treatment failure and relapse, member DOT and community DOT strategies can both
which induce drug resistance and mortality, and reach the WHO target for treatment success. This
decrease cost of TB treatment and control. However, strategy may be suitable for hard-to-access areas where
no beneficial effects were found from DOT intervention TB patient services are becoming increasingly over-
with increased completion rates. This finding is similar to loaded and there are many different health programmes
a review conducted by Parent,11 which indicated that requesting HCWs effort and time.
DOT was effective in promoting adherence to and com- As DOTS in a health facility is not always convenient
pletion of TB treatment. But the two reviews previously and accessible to TB patients, it is necessary to explore
published on adherence to treatment of latent TB infec- additional options. One option is to have a family mem-
tion differ from this review. A review of evidence in the ber supervise DOT. Using family observation, combined
United States and Canada demonstrated that no single with intensive supervision and home visits, has achieved
intervention has been consistently effective in improv- high cure rates; however, family members may not
ing adherence to treatment for latent TB infection, understand the need to provide consistent treatment.
including DOT.10 The second review by Volmink and Despite the best educational efforts of healthcare staff,
Garner12 found no assurance that the routine use of DOT there may be limited understanding of, or confidence in,
in low-income and middle-income countries improves the efficacy of prescribed medicines. If adherence to
cure or treatment completion in people requiring treat- treatment creates tension in the family, the simplest way
ment for clinically active TB or preventing active dis- to eliminate the source of tension is to discontinue
eases. This difference may be because of defining treatment observation. Therefore, family members can
different participants and outcome measures. However, potentially be effective treatment observers but only
it is essential that all implementation of DOT strategies within the restrictions that required close monitoring of
with patients in the communities must identify and all aspects of the treatment delivery system through
remove constraints of access to care. Therefore, DOT frequent home visits by health facility staff.27,33
should be modified to suit local situations.10 It is import- The most common accompanying interventions with
ant to devise treatment strategies that lessen financial DOT are improved accessibility of services, increased

International Journal of Evidence-Based Healthcare 2014 University of Adelaide, Joanna Briggs Institute 13

2014 University of Adelaide, Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited.
W Suwankeeree and W Picheansathian

availability of drugs, changes in drug regimens, patient possibly because of a range of health system barriers
incentives, tracing of patients who default and outreach that were not addressed by the training programme or
efforts.8 However, there have been problems with this because of other unknown or unmeasurable factors.
approach, most likely because of insufficient communi- Therefore, a training programme should combine with
cation between the centres and the various agents of the interventions to address other barriers to clinic and
primary healthcare structure. One study demonstrated organisational change (e.g. shortage of experienced
that the intervention package based on improved staff).
patient counselling and communication between health This review supports the results from previous sys-
personnel and patients, decentralisation of treatment, tematic reviews of qualitative research. The review
patient choice of DOT supporter and reinforcement of showed an absence of any evidence against DOT com-
supervision activities led to improvement in patients pared with people treating themselves at home.32 How-
successfully completing the 8-month course of treat- ever, this review indicated that self-supervision or SAT
ment.17 This result is consistent with a systematic review promoted adherence to treatment among TB patients to
conducted by Haynes et al.,34 which showed that the a lesser extent than DOT. Appropriately trained health-
interventions that were effective for long-term care were care providers will be able to anticipate patient adher-
complex, including combinations of more convenient ence and therefore those suitable for self-supervision or
care, information, reminders, self-monitoring, reinforce- SAT should be assigned. Educational programmes should
ment, counselling, family therapy, psychological therapy, be undertaken to educate private providers regarding
crisis intervention, manual telephone follow-up and suitable patients for SAT; all patients with newly diag-
supportive care. nosed TB should be evaluated by the public health
Food incentives did not result in a significant department for possible assignment to DOT.
improvement in adherence to treatment or successful
completion of treatment.15 This result was inconsistent Limitations of the review
with a review conducted by Parent,11 which indicated This review has some limitations. First, it is limited to
that DOT and incentive components such as food, cloth- evaluating outcomes within adult populations. Studies
ing, books and transportation were frequently found to with adolescents and children were not included as they
be the most effective factors in treatment completion for face significantly different issues in the context of treat-
pulmonary TB patients. The only outcome significantly ment adherence, particularly with parental involvement
associated with the intervention was weight gain. There- in adherence. Secondly, focus was on studies with new
fore, a food intervention may be worth considering in pulmonary TB patients in order to identify successful
patients with TB who are malnourished. For a variety strategies aimed at improving adherence among this
of patient populations, including alcoholic patients, sub- group of TB patients. Finally, many studies were
stance abuse patients, homeless persons and patients excluded from this review because they were not
infected with HIV, a combination of multiple incentives designed specifically to assess treatment completion
was found to be effective. rates, cure rates and success rates but rather to assess
TB case management combined with the imple- sputum smear conversion rates in the second or third
mentation of DOT in the first 2 months could effectively month of treatment.
improve the adherence of TB patients to treatment and
increase the patients completion and treatment success Conclusion
rates. Clinical nurses can make a significant contribution Several adherence interventions have been developed
to healthcare delivery by using this model to oversee and to improve treatment for TB infection. This review found
monitor TB patients medicine intake and medical care to evidence of benefits from a number of specific inter-
ensure their adherence and improve the patients treat- ventions to improve adherence to TB treatment among
ment completion rates. The model emphasises the newly diagnosed patients, including DOT with patient
participation of key persons, a comprehensive TB health choice of a DOT supporter, case management with DOT
education and visits to all patients at home once a month and the intensive triad-model programme. In addition,
as key to improving TB cure rates.16 the intervention package based on improved patient
Healthcare workers can play a key role in supporting counselling and communication, decentralisation of
adherence to treatment, justifying the training com- treatment, patient choice of a DOT supporter and
ponent of the tested strategy and promoting improved reinforcement of supervision activities could be gener-
counselling. But one study indicated that staff training alised in the context of TB control programmes in
did not seem to improve TB treatment outcomes,18 resource-poor countries. These should be implemented

14 International Journal of Evidence-Based Healthcare 2014 University of Adelaide, Joanna Briggs Institute

2014 University of Adelaide, Joanna Briggs Institute. Unauthorized reproduction of this article is prohibited.
EVIDENCE SYNTHESIS

by healthcare providers and tailored to local contexts Implications for research


and circumstances, wherever appropriate. Our review shows the need for further large-scale studies
on adherence to treatment by newly diagnosed pulmon-
Implications for practice ary TB patients. It may also be worth comparing DOT to
There is evidence supporting the use of DOT to improve other strategies aimed at improving adherence. Factors
adherence to TB treatment among newly diagnosed TB that determine its usefulness in various settings require
patients. A frequent objection to DOT is that daily further study.
observation of all patients by healthcare professionals Further strategies, especially those that are feasible in
is not a feasible approach for low-income countries, developing countries or countries with limited resources,
where the financial means to employ and train the should be evaluated in RCTs before being introduced
requisite staff are unavailable. This option cannot be into routine practice. Additionally, further research is
used by a large number of patients in rural areas who required that investigates DOT vs. self-supervision to
may live far away from the nearest health centre. Giving determine ongoing treatment success and re-treatment
patients alternative supervision options that are con- rates.
venient and accessible, such as community or family
members, may have contributed to the comparatively Acknowledgements
favourable results in improving adherence to treatment. The authors sincerely thank The Joanna Briggs Institute
Facilitation of the role of family or community members for supporting this review. The review received financial
in DOT involved training by HCWs and close supervision support from the Thailand Centre for Evidence-Based
through frequent home visits by health facility staff. In Nursing and Midwifery, Faculty of Nursing, Chiang Mai
areas in which patients live far from health centres, University, Thailand.
access to drugs would be improved through decentral- The author reports no conflicts of interest.
isation of treatment.17 Therefore, it would be beneficial
to shift the treatment of all TB patients to facilities within
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