Strategies to promote adherence to treatment by pulmonary tuberculosis patients: a systematic review.

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 Methods: The search sought to find published and unpublished studies.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; 12:3–16.

Background

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

Correspondence: Wilawan Picheansathian, Faculty of Nursing, Chiang Mai University, 110 Indhavarorose Road, Muang, Chiangmai 50200, Thailand. Tel: +66 53 949007; fax: +66 53 894171; e-mail: [email protected] DOI: 10.1097/01.XEB.0000444614.17658.46

treatment short-course (DOTS) programmes and to successfully treat at least 85% of detected cases.1 The DOTS strategy has five operational components for effective TB control, including political commitment; diagnosis based on sputum smear microscopy; standardised short-course drug regimens; adequate and uninterrupted supply of drugs and other materials; close monitoring, in which patients are directly observed daily to ensure that every dose of recommended treatment regimen is taken; and standardised recording

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

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©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 treatment is usually an independent choice of patients and described as adherence. Successful TB control is heavily dependent on effective treatment of patients, requiring adherence throughout the full course of treatment.4 However, approximately half of TB patients do not complete the treatment course under routine practice conditions.5 –7 This low adherence to treatment by TB patients has been associated with adverse outcomes, including increased transmission rates of tubercle bacilli, prolonged infectiousness, treatment failure and relapse, drug resistance, and increased cost of TB control programmes.8–10 Therefore, early and accurate diagnosis and effective treatment leading to cure are the core elements of TB control. There have been five systematic reviews related to TB treatment. The result of a systematic review of randomised controlled trials (RCTs) from 1966 to 1996 indicated that reminder letters, monetary incentives, health education, and intensive supervision of staff in TB clinics improve adherence to TB treatment. These should be adopted in the health system, depending on their appropriateness to practice circumstances.8 A meta-analysis of 13 studies, including three RCTs, nine case–control studies, and one cohort analytic study in 1999, indicated that the directly observed treatment (DOT) and incentives of food, clothing, books, and transportation were effective in reducing the incidence of TB.11 On the contrary, a systemic review of 11 randomised and quasi-RCTs from 1966 to 2007 found no rigorous evidence to support the conclusion that the use of DOT in low-income and middle-income countries improves cure or treatment completion in people with TB.12 The results of nine RCTs from 1945 to 2008 indicated that both reminder systems and late patient tracers, which routinely remind patients to keep an appointment, showed benefits of the intervention in increasing incidence of TB.13 In addition, a systematic review of 19 studies, including six RCTs, five prospective cohort studies, seven retrospective cohort studies and one pilot programme in the United States and Canada published between 1997 and 2007, showed that adherence and completion rates of treating latent TB infection are suboptimal across high-risk groups, and no single intervention has shown consistent effectiveness.10 However, these systematic reviews did not focus on new cases of pulmonary TB. In addition, some studies were not included in these reviews.14–18 It is critically important to clarify the effectiveness of strategies to promote adherence to treatment by patients with pulmonary TB in order to support evidence-based practice. This review has evaluated the 4

clinical evidence available on the effectiveness of strategies to promote adherence to treatment by patients with pulmonary TB.

Definitions Treatment completion rate is defined as the percentage of patients who completed the required treatment course but did not receive sputum examinations on at least two occasions for cure detection. Cure rate is defined as the percentage of patients who completed treatment and had two negative sputum examinations during treatment, of which one was at the end of treatment. Success rate is the percentage of patients who are cured and those who have completed treatment. DOT is defined as ingestion of anti-TB medications that was directly supervised by a healthcare worker (HCW), community member or lay health worker or case manager, or family member who was trained to do this. The DOTS is the control strategy for TB promoted by the WHO. The DOTS strategy is made up of five operational components, including political commitment, diagnosis based on sputum smear microscopy, standardised short-course drug regimens, adequate and uninterrupted supply of drugs and other materials, close monitoring in which patients are directly observed daily to ensure drugs are taken (DOT), recording and reporting with sufficient feedback. Self-administered treatment (SAT) is defined as unsupervised administration of anti-TB medications by patients. Self-supervision is defined as responsibility for treatment adherence by patients without supervision by another person, which is the same meaning of SAT.

Objectives The specific aims of the review were to (1) identify the existing strategies to promote adherence to treatment by patients with pulmonary TB and (2) identify the best strategy to promote adherence to TB treatment by patients with pulmonary TB.

Inclusion criteria Types of participants This review considered all studies that included adults age 15 years at least diagnosed with smear-positive and smear-negative pulmonary TB (regardless of HIV infection) in community settings who had never received anti-TB drugs or had taken them for less than 1 month.



EVIDENCE SYNTHESIS The focus was on new cases and excluded previously treated patients because of the increased likelihood of drug resistance and adverse outcomes such as treatment failure in the re-treatment group, which could nullify a treatment effect irrespective of the quality of treatment supervision.

Types of interventions Interventions of interest were those related to strategies to promote adherence to treatment, including DOT, DOTS, case management, intervention package, participatory in-service training, food incentives, and intensive triad-model programme. Types of outcome measures The outcomes of interest were treatment completion rate, cure rate, and success rate. Types of studies This review considered any RCTs that examined the different strategies used to promote adherence to treatment by patients with pulmonary TB. Additionally, quasiexperimental studies were considered for inclusion in the review to enable the identification of current best evidence for promoting adherence to the TB management.

Exclusion criteria This review excluded articles that were expert opinion and literature reviews.

Search strategy The search strategy was designed to identify both published and unpublished studies. Two reviewers independently searched for the articles. A detailed search strategy was developed to identify studies for inclusion in this review as follows: (1) An initial limited search included journal indexes from MEDLINE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). An analysis of the text contained in the title, abstracts and subject descriptors of relevant articles was undertaken to identify additional keywords. (2) A second search using all identified keywords and index terms was then undertaken across all included databases. (3) Reference lists and bibliographies of all identified articles were also searched for additional relevant studies and source journals. Keywords included tuberculosis, pulmonary tuberculosis, sputum-positive tuberculosis, adherence, compliance, concordance, treatment, anti-tuberculosis

medication, intervention, therapy, DOT, DOTS, health education, home visit, self-administrated, self-supervised, financial incentives, counselling, lay health workers, treatment completion, completion rate and cure rate. The time period of the search covered articles published from 1990 to 2010 in English and Thai languages. The database search included 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. In order to avoid publication bias, hand searching of the most recent issues (January 1990 to December 2010) of the following journals was undertaken for additional references: International Journal of Tuberculosis and Lung Disease, American Journal of Infection Control, Journal of Infection, Thai Journal of Tuberculosis Chest Disease and Critical Care, Journal of Thai Medical Association and Journal of Health Science. The search for unpublished studies included the following sources: dissertation abstracts, proceedings of nursing and allied health conferences held in Thailand and other countries and direct communication with researchers.

Methods of the review Critical appraisal All studies that met the inclusion criteria were assessed for methodological quality using standardised critical appraisal tools from the Joanna Briggs Institute MetaAnalysis of Statistics Assessment and Review Instrument (http://joannabriggs.org/SUMARI). Two reviewers independently appraised each study. Discrepancies in critical appraisal were resolved at a meeting between reviewers. Those studies had to meet the criteria to be included in the review. Data collection Two reviewers independently extracted data, using the standardised data extraction tool from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (http://joannabriggs.org/SUMARI). However, the reviewers were not blinded to the authors of the studies under review. Data synthesis If two or more comparable studies were identified, data were pooled in a statistical meta-analysis to determine the effectiveness of the intervention by using the Review Manager software (RevMan v. 5.2; The Cochrane Collaboration, The Nordic Cochrane Center, Copenhagen, Denmark). Comparability of the studies was defined


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by the population, interventions and outcome measures. Double data entry was undertaken to minimise the risk of data entry errors. Heterogeneity between combined studies was tested using the standard x2 test and visual inspection of the graphic presentation of the results. Pooled statistics were calculated using a fixed-effect model when there was no statistically significant heterogeneity. If evidence of significant heterogeneity was identified, a random-effects approach to the analysis was used. Relative risk (RR) was used for categorical outcomes data and their 95% confidence intervals (CIs) were calculated for each study. If statistical pooling of results was not appropriate, the findings were summarised in narrative form.

Results Description of studies The initial search on the basis of keywords yielded a total of 1341 papers; however, a substantial number of these 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 abstract and keywords in relation to the inclusion criteria, 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 qualified for inclusion based on methodological quality assessment. The 18 studies identified gave a combined total of 7972 patients who were newly diagnosed with pulmonary 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 smearnegative15 and 160 cases of unknown status.19 All studies used daily treatment throughout, except the study in India20 which used the three-times-a-week treatment both in the intensive and in the continuation phases. Ten studies were RCTs15,17–19,21–26 and eight used quasiexperimental designs.5,14,16,20,27 –29 Of these, 16 were published in English5,14–27,30 and two in Thai.28,29 The number of participants in each study 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 India,20 Nepal,25 Pakistan,21 Taiwan,14 Tanzania,26 Timor-Leste,15 Thailand16,23,27 –30 and Africa.17–19,22,24 One trial was conducted in a high-income country, USA.5 The outcomes of interest in this review were direct methods, including treatment completion rate, cure rate and success rate. Many studies were excluded from this 6

review as their outcome was measured either as sputum conversion rate after receiving TB treatment for 2 or 3 months or as a percentage of the medication taken. The extent to which these intermediate outcomes correlate with actual drugs taken is unknown. However, clinical cases could have higher completion rates and lower rates of failure related to misclassification from overdiagnosis cases. This could influence the chance of demonstrating a treatment effect. The stages of searching, inclusion and exclusion of references for this review are shown in Fig. 1.

Methodological quality of randomised controlled trials All trials were assessed using the JBI Critical Appraisal tools. Only Lewin et al.18 and Kamolratanakul et al.23 met all 10 criteria for methodological quality. Owing to the nature of the intervention, it was not possible to conceal assignment to the participant in seven trials.17,19,21,22,24–26

Potentially reIevant articles identified by Iiterature search (n = 1341)

Articles excluded after abstract evaluation (n = 1292)

Articles retrieved for detailed examination (n = 49)

Articles excluded after review of full article (n = 31) - Measured inappropriate outcome (n = 9) - Included patients who did not meet inclusion criteria (n = 14) - NonRCTs or quasiexperimental studies (n = 4) - Unknown patient age and illness status (n = 3) - Published in Spanish (n = 1)

Articles included in the systematic review (n = 18) - Randomized controlled trials (n = 10) - Quasiexperimental studies (n = 8)

Figure 1. Flow chart for identification of trials for inclusion and exclusion.



EVIDENCE SYNTHESIS One trial22 did not conceal the treatment allocation because of the impossibility of concealing assignment results to the assessor at the study site. However, assessors were not involved in the design and implementation of the intervention or in the final data analysis. A study by Lwilla et al.26 also did not conceal the allocation to treatment groups from the allocator, and a study by Clarke et al.22 was unclear on this criteria. A study by Martins et al.15 did not include the outcomes of participants who withdrew from the study in the analysis. All trials use appropriate statistical analysis. Power analysis on sample size calculations was reported in nine trials.15,17–19,21,22,24–26 Study groups were identically treated (apart from the interventions), and outcomes appeared to be measured reliably in all studies. In each study, attempts were made to control confounding factors and ensure that any positive outcomes detected were the result of the intervention. All RCTs used suitable randomisation methods such as cluster randomisation, block randomisation, stratified randomisation and randomisation sequence generated by computer algorithm.

Methodological quality of quasiexperimental studies All of the eight quasiexperimental studies met five of the 10 criteria except blinding, and six studies5,16,20,27,29,30 did not randomly assign participants to treatment and control groups. These studies used convenience sampling or purposive sampling depending on the availability of the patients who sought treatment at the study site. Although randomisation methods were not used in quasiexperimental studies, their quality was ensured through comparison groups. The outcomes were assessed using objective criteria and in a reliable manner in all of the included studies. Appropriate statistical analysis was employed in all included studies.

Study or subgroup Akkslip 1999 Kungsaworn 1997

SS DOT Events Total Events Total Weight

Directly observed treatment Directly observed treatment vs. selfsupervision Cure rate An RCT23 (836 participants) conducted in Thailand demonstrated that cure rates of newly diagnosed pulmonary TB patients who received DOT by individual patient supervisors (76%) were significantly higher than the rates of those on self-supervision (67%). This result was consistent with two quasiexperimental studies27,29 (438 participants) conducted in Thailand that reported cure rates were higher in the DOT group than in those on self-supervision. When results from the two quasiexperimental studies27,29 were combined, higher cure rates among newly diagnosed pulmonary TB patients who received DOT were statistically significant compared with those on self-supervision (RR 1.17, 95% CI 1.05–1.30, P ¼ 0.005] (Fig. 2). Completion rate An RCT23 (836 participants) demonstrated that the completion rates of newly diagnosed pulmonary TB patients who received DOT (7.7%) were similar to the rates of those on self-supervision (8.7%); the authors did not report results statistically. This result was consistent with two quasiexperimental studies27,29 (438 participants) which demonstrated that the completion rates in the DOT group were similar to those in the self-supervision Risk ratio M-H, fixed, 95% CI

184

216

78

110

71.2%

1.20 [1.05, 1.37]

42

51

46

61

28.8%

1.09 [0.90, 1.32]

171

100.0%

Total (95% CI) Total events

Effect of interventions The findings of this review are discussed according to the specific interventions used in the identified research and their comparison with different control groups. The results are broadly categorised into studies that evaluated DOT/DOTS, case management, intervention package, participatory in-service training, food incentives and intensive triad-model programme.

267 226

Risk ratio M-H, fixed, 95% CI

1.17 [1.05, 1.30]

124

Heterogeneity: χ2 = 0.65, df = 1 (P = 0.42); I2 = 0% Test for overall effect: Z = 2.82 (P = 0.005)

0.2

0.5

Favours SS

1

2

5

Favours DOT

Figure 2. Cure rate Forest plot comparison: directly observed treatment (DOT) vs. self-supervision (SS). CI, confidence interval. International Journal of Evidence-Based Healthcare ß 2014 University of Adelaide, Joanna Briggs Institute

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Study or subgroup



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]

171

100.0%

Total (95% CI)

267

Total events


0.77 [0.09, 6.47]

1

1

Heterogeneity: χ = 0.35, df = 1 (P = 0.56); I = 0% 2

2

0.001

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

0.1

1

Favours SS

10

1000

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 studies27,29 were combined, the completion rates of newly diagnosed pulmonary TB patients who received DOT compared with the rates of those on self-supervision were not statistically significant (RR 0.77, 95% CI 0.09–6.47, P ¼ 0.81) (Fig. 3).

Success rate An RCT23 (836 participants) found success rates of newly diagnosed pulmonary TB patients who received DOT (84%) were significantly higher than the rates of those on self-supervision (76%). This result was consistent with two quasiexperimental studies27,29 (438 participants) which demonstrated that the success rates were higher in the DOT group than in the self-supervision group. When results from the two quasiexperimental studies27,29 were combined, newly diagnosed pulmonary TB patients who received DOT had a small but statistically significant higher success rates compared with those on self-supervision (RR 1.17, 95% CI 1.05–1.30, P ¼ 0.005) (Fig. 4).

Study or subgroup Akkslip 1999 Kungsaworn 1997


Directly observed treatment by healthcare worker vs. self-supervision Cure rate The meta-analysis of two trials23,30 (778 participants) demonstrated that there was no significant difference in cure rates between newly diagnosed pulmonary TB patients who received DOT by HCW and those on self-supervision (RR 1.06, 95% CI 0.93–1.22, P ¼ 0.37) (Table 1). But the meta-analysis from three quasiexperimental studies5,27,28 (675 participants) demonstrated that there were statistically significant higher cure rates among newly diagnosed pulmonary TB patients who received DOT by HCW compared with those on self-supervision, although the difference was small (RR 1.22, 95% CI 1.12–1.34, P < 0.0001) (Table 1). Completion rate The meta-analysis of two RCTs21,23 (778 participants) with a fixed model demonstrated that there was no statistical difference in the completion rates among


185

216

78

110

70.7%

1.21 [1.06, 1.38]

42

51

47

61

29.3%

1.07 [0.89, 1.29]

171

100.0%

Total (95% CI) Total events

Subgroup analysis for outcomes

267 227


1.17 [1.05, 1.30]

125

Heterogeneity: χ2 = 1.11, df = 1 (P = 0.29); I2 = 10% Test for overall effect: Z = 2.80 (P = 0.005)

0.5

0.7

Favours SS

1

1.5

2

Favours DOT

Figure 4. Success rate Forest plot comparison: directly observed treatment (DOT) vs. self-supervision (SS). CI, confidence interval. 8



EVIDENCE SYNTHESIS Table 1. Subgroup meta-analysis for outcomes Subgroups DOT by HCW vs. SS Cure rate RCTs Quasiexperimental studies Completion rate RCTs Quasiexperimental studies Success rate RCTs Quasiexperimental studies DOT by CM vs. SS Success rate RCTs DOT by FM vs. SS Cure rate RCTs Completion rate RCTs Success rate RCTs DOT by HCW vs. DOT by CM Cure rate RCTs Quasiexperimental studies Completion rate RCTs Success rate RCTs Quasiexperimental studies DOT by FM vs. DOT by CM Success rate RCTs DOT by FM vs. DOT by HCW Cure rate RCTs Quasiexperimental studies Completion rate RCTs Quasiexperimental studies Success rate RCT Quasiexperimental studies

Included studies

OR (95% CI)

P

Heterogeneity

20, 22 5, 26, 27

1.06 (0.93–1.22) 1.22 (1.12–1.34)

0.37 0.0001

No No

0, 22 5, 27

0.95 (0.38–2.36) 0.44 (0.02–8.81)

0.92 0.59

No Yes (P ¼ 0.03)

19, 20, 22, 23 5, 26, 27

1.07 (0.96–1.20) 1.19 (1.10–1.29)

0.21 0.00001

No No

22, 23

1.32 (0.78–2.23)

0.30

Yes (P ¼ 0.01)

22, 22

1.02 (0.80–1.31)

0.85

Yes (P ¼ 0.02)

20, 22

1.07 (0.70–1.63)

0.76

No

0, 22

1.07 (1.00–1.15)

0.04

No

21, 22, 23 26, 30

0.94 (0.82–1.08) 1.06 (0.95–1.20)

0.39 0.30

No No

21, 22

0.48 (0.16–1.45)

0.20

No

21, 22, 23 26, 30

0.86 (0.66–1.12) 0.99 (0.89–1.09)

0.27 0.82

Yes (P ¼ 0.03) No

22, 24

1.05 (1.00–1.11)

0.04

No

20, 22 26, 29

0.89 (0.77–1.03) 0.62 (0.12–3.36)

0.12 0.58

No Yes (P < 0.000)

20, 22 26, 29

1.80 (0.81–4.02) 1.65 (1.07–2.55)

0.15 0.02

No No

20, 22 26, 29

0.95 (0.83–1.07) 0.92 (0.58–1.46)

0.38 0.72

No Yes (P ¼ 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 DOT by HCW compared with those on self-supervision (RR 0.95, 95% CI 0.38–2.36, P ¼ 0.92) (Table 1). The results of three quasiexperimental studies5,27,28 were inconsistent. The results of one study were not suitable for metaanalysis.27 The combined results of two studies5,28 (544 participants) showed that there was significant heterogeneity between the studies for completion rates (x2 ¼ 4.47; P ¼ 0.03). Meta-analyses of these two studies,5,28 performed using random-effects models,

showed no statistically significant difference in completion rates (RR 0.44, 95% CI 0.02–8.81, P ¼ 0.59) (Table 1).

Success rate The meta-analysis of the four RCTs19,21,23,24 (1001 participants) with a fixed model demonstrated that there was no significant difference in success rates among newly diagnosed pulmonary TB patients who received DOT by HCW compared with those on self-supervision (RR 1.07, 95% CI 0.96–1.20, P ¼ 0.21) (Table 1). However,


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the meta-analysis from three quasiexperimental studies5,27,28 (675 participants) demonstrated that there was a statistically significant higher success rate among newly diagnosed pulmonary TB patients who received DOT by HCW compared with those on self-supervision (RR 1.19, 95% CI 1.10–1.29, P < 0.00001) (Table 1).

Directly observed treatment by case manager vs. self-supervision Cure rate An RCT in Thailand by Kamolratanakul et al.23 (466 participants) found that the cure rates among newly diagnosis pulmonary TB patients who received DOT by case manager (73%) were higher than the rates in those on self-supervision (67%); the authors did not report results statistically. This result was consistent with a quasiexperimental study by Akkslip et al.27 who reported only one newly diagnosed pulmonary TB patient who received DOT by case manager and met the criteria of cure (100%). This rate was higher than the rate in those on self-supervision [70% (78/110)]; the authors did not report results statistically. As these two studies used different methodology, it is inappropriate to pool their results in meta-analysis. Completion rate An RCT in Thailand by Kamolratanakul et al.23 (466 participants) indicated that the completion rates among newly diagnosed pulmonary TB patients who received DOT by case manager (5%) were lower than the rates in those on self-supervision (8%); the authors did not report results statistically. However, a quasiexperimental study by Akkslip et al.27 found that there were no newly diagnosed pulmonary TB patients who received DOT by case manager or on self-supervision who met the criteria of treatment completion (0/1 and 0/110, respectively). Success rate The meta-analysis of two RCTs23,24 (516 participants) with significant heterogeneity was performed using a random-effects model (x2 ¼ 6.29, P ¼ 0.01). There was no statistically significant difference in success rates among groups (RR 1.32, 95% CI 0.78 –2.23, P ¼ 0.30) (Table 1). This result was inconsistent with a quasiexperimental study in Thailand by Akkslip et al.27 who reported that there was only one newly diagnosed pulmonary TB patient who received DOT by case manager and met the criteria of success (100%). This rate was higher than the rate in those on self-supervision [70% (78/110)]; the authors did not report results statistically. 10

Directly observed treatment by family member vs. self-supervision Cure rate The meta-analysis of the two RCTs21,23 (1101 participants) with significant heterogeneity was performed using a random-effects model (x2 ¼ 5.84, P ¼ 0.02). The result indicated that there was no statistically significant difference in the cure rates between groups (RR 1.02, 95% CI 0.08–1.31, P ¼ 0.85) (Table 1). On the contrary, a quasiexperimental study by Akkslip et al.27 (304 participants) demonstrated that the cure rates among newly diagnosed pulmonary TB patients who received DOT by family member (86%) were higher than the rates in those on self-supervision (70%); the authors did not report results statistically. Completion rate The meta-analysis of the two RCTs21,23 (1101 participants) used a fixed model and demonstrated that there was no statistically significant difference in completion rates among newly diagnosed pulmonary TB patients on self-supervision compared with those who received DOT by family member (RR 1.07, 95% CI 0.70–1.63, P ¼ 0.76) (Table 1). This result was consistent with a quasiexperimental study27 (304 participants) which reported only one newly diagnosed pulmonary TB patient who received DOT by family member and none on self-supervision who met the criteria of treatment completion (1/149 and 0/110, respectively). Success rate The meta-analysis of the two RCTs21,23 (1101 participants) used a fixed model and demonstrated that there was statistically significant higher success rates among newly diagnosed pulmonary TB patients who received DOT by family member compared with those on self-supervision (RR 1.07, 95% CI 1.00–1.15, P ¼ 0.04, I2 ¼ 63.0%) (Table 1). This result was consistent with a quasiexperimental study by Akkslip et al.27 (304 participants), which demonstrated the success rates among newly diagnosed pulmonary TB patients who received DOT by family member (86%) were higher than the rates in those on self-supervision control group (70%); the authors did not report results statistically. Directly observed treatment by healthcare worker vs. directly observed treatment by case manager Cure rate The meta-analysis of three RCTs23,26,27 (669 participants) used a fixed model and found no statistical difference for cure rates among newly diagnosed pulmonary TB patients who received DOT by HCW compared with



EVIDENCE SYNTHESIS those who received DOT by case manager (RR 0.94, 95% CI 0.82–1.08, P ¼ 0.39) (Table 1). This result was consistent with the meta-analysis from two quasiexperimental studies20,27 (639 participants) which demonstrated no significant difference for cure rates between newly diagnosed pulmonary TB patients who received DOT by HCW and those received DOT by case manager (RR 1.06, 95% CI 0.95–1.20, P ¼ 0.30) (Table 1).

Completion rate The meta-analysis of two RCTs22,23 (147 participants) used a fixed model and demonstrated no significant difference for completion rates between newly diagnosed pulmonary TB patients who received DOT by HCW and those who received DOT by case manager (RR 0.48, 95% CI 0.16–1.45, P ¼ 0.20) (Table 1). Two quasiexperimental studies20,27 examined the effect of DOT by HCW on completion rates compared with DOT by case manager. A study by Singh et al.20 showed that the completion rates among newly diagnosed pulmonary TB patients who received DOT by case manager (7%) was higher than those who received DOT by HCW (2%); the authors did not report results statistically. However, a study by Akkslip et al.27 found that none of the newly diagnosed pulmonary TB patients who received DOT by HCW or those who received DOT by case manager met the criteria of treatment completion (0/21 and 0/1, respectively). Success rate The meta-analysis of the three RCTs22–24 (216 participants) with significant heterogeneity was performed using a random-effects model (x2 ¼ 6.86, P ¼ 0.03). The result demonstrated that the success rate was not statistically significant between the groups (RR 0.86, 95% CI 0.66–1.12, P ¼ 0.27) (Table 1). This result was consistent with two quasiexperimental studies20,27 (639 participants) which demonstrated no statistically significant difference in success rates between newly diagnosed pulmonary TB patients who received DOT by HCW and those who received DOT by case manager (RR 0.99, 95% CI 0.89–1.09, P ¼ 0.82) (Table 1). Directly observed treatment by family member vs. directly observed treatment by case manager Cure rate An RCT by Kamolratanakul et al.23 (386 participants) found no statistically significant difference in cure rates among newly diagnosed pulmonary TB patients who received DOT by family member (76%) compared with those who received DOT by case manager (73%).

However, a quasiexperimental study by Akkslip et al.27 (195 participants) indicated that there was only one newly diagnosed pulmonary TB patient who received DOT by case manager and met the criteria of cure (100%). This rate was higher than the rate in those who received DOT by family member [(86% (167/194)]; the authors did not report results statistically. As these two studies used different methodology, it is inappropriate to pool results in meta-analysis.

Completion rate An RCT study by Kamolratanakul et al.23 (386 participants) found no statistically significant difference in completion rates among newly diagnosed pulmonary TB patients who received DOT by family member (7%) compared with the rates in those who received DOT by case manager (5%). This result was consistent with a quasiexperimental study by Akkslip et al.27 (195 participants) which reported that there was only one newly diagnosed pulmonary TB patient who received DOT by family member and none who received DOT by case manager who met the criteria of treatment completion (1/194 and 0/1, respectively). Success rate The meta-analysis of the two RCTs23,25 (1293 participants) used a fixed model and demonstrated that there was a statistically significant higher success rate among newly diagnosed pulmonary TB patients who received DOT by family member compared with those who received DOT by case manager (RR 1.05, 95% CI 1.00– 1.11, P ¼ 0.04) (Table 1). However, a quasiexperimental study by Akkslip et al.27 (195 participants) demonstrated that there was only one newly diagnosed pulmonary TB patient who received DOT by case manager who met the criteria of cure (100%). This rate was higher than the rate in those who received DOT by family member [86% (168/194)]; the authors did not report result statistically. Directly observed treatment by family member vs. directly observed treatment by healthcare worker Cure rate The meta-analysis of the two RCTs21,23 (711 participants) used a fixed model and demonstrated that there was no statistically significant difference in cure rates among newly diagnosed pulmonary TB patients who received DOT by family member compared with those who received DOT by HCW (RR 0.89, 95% CI 0.77–1.03, P ¼ 0.12) (Table 1). Results of two quasiexperimental studies27,30 (709 participants) were inconsistent. There was significant heterogeneity (x2 ¼ 21.78, P < 0.000)


11



when these two quasiexperimental studies27,30 were pooled, so they were analysed through meta-analysis using the random-effects model. The result indicated that the difference in cure rates was not statistically significant between groups (RR 0.62, 95% CI 0.12– 3.36, P ¼ 0.58) (Table 1).

Completion rate The meta-analysis of the two RCTs21,23 (711 participants) used a fixed model and demonstrated that there was no statistically significant difference in completion rates among newly diagnosed pulmonary TB patients who received DOT by family member compared with those who received DOT by HCW (RR 1.80, 95% CI 0.81–4.02, P ¼ 0.15) (Table 1). The results of two quasiexperimental studies27,30 (709 participants) were inconsistent. The meta-analysis of the two quasiexperimental studies27,30 used a fixed model and demonstrated that there were statistically significant higher completion rates among newly diagnosed pulmonary TB patients who received DOT by family member compared with those who received DOT by HCW (RR 1.65, 95% CI 1.07–2.55, P ¼ 0.02) (Table 1). Success rate The meta-analysis of the two RCTs21,23 (711 participants) used a fixed model and demonstrated that there was no statistically significant difference in success rates among newly diagnosed pulmonary TB patients who received DOT by family member compared with those who received DOT by HCW (RR 0.95, 95% CI 0.83–1.07, P ¼ 0.38) (Table 1). Results of two quasiexperimental studies27,30 were inconsistent. Analyses were adjusted to the random-effects model (n ¼ 709) because of heterogeneity of the studies (x2 ¼ 5.89, P ¼ 0.02). The meta-analysis of the two quasiexperimental studies27,30 demonstrated that the difference in the success rates were not statistically significant between the groups (RR 0.92, 95% CI 0.58–1.46, P ¼ 0.72) (Table 1).

Case management A study in Taiwan14 found that the TB patients who received DOTS case management comprising hospital education, direct daily observation in the first 2 months and one home visit per week by the case manager had better treatment completion rates than those who received traditional case management comprising inhospital education and one home visit per month, and those who did not receive any intervention (96.9 vs. 68.6 vs. 68.6%, P ¼ 0.007). In addition, the treatment success rate of the TB patients who received DOTS case management was significantly improved compared with those 12

who received traditional case management, and those who did not receive any intervention (93.7 vs. 68.6 vs. 68.6%, P ¼ 0.023).

Food incentive A study in Timor-Leste15 demonstrated that provision of food had no significant beneficial or harmful impact on the completion of treatment (76 vs. 78%, P ¼ 0.7), but did lead to improved weight gain at the end of treatment (10.1 vs. 7.5% improvement, P ¼ 0.04).

Intensive triad-model programme A study in Thailand16 found that the intensive triadmodel programme can improve a patient’s adherence to a TB treatment regimen. The triad-model emphasises the roles of three key persons (healthcare provider, TB patient and treatment supporter) and provides comprehensive health education about TB and the importance of its treatment. The healthcare provider and treatment supporter visited all patients at home once a month to encourage them to take medication regularly under the supervision of the healthcare provider. The success rate of treatment was higher in the patients receiving the intensive triad-model programme than those in the control group (96.0 vs. 84.9%, P ¼ 0.057). Moreover, the confirmed cure rate was also significantly higher in the experimental group than in the comparison group (95.3 vs. 78.9%, P ¼ 0.02).

Intervention package A study in Senegal, West Africa,17 demonstrated treatment success for 88% of the patients who received the intervention package. The intervention included reinforced counselling through improved communication between health personnel and patients, decentralisation of treatment, patient choice of a DOT supporter and reinforcement of supervision activities compared with 76% in the patients who received the usual TB control programme [adjusted risk ratio (RR) 1.18, 95% CI 1.03–1.34]. In addition, this study found that choice of a DOT supporter among the patients’ family members yielded better treatment outcomes than having other DOT supporters.

Participatory in-service training vs. usual care (directly observed treatment shortcourse) Lewin et al.18 undertook a study in South Africa to assess the addition to the DOTS strategy of an experimental, participatory in-service training programme for clinic staff delivered by nurse facilitators and focused on patient centeredness, critical reflection on practice and



EVIDENCE SYNTHESIS quality improvement. The results indicated that the cure rates in the intervention clinics following the intervention were 49.1% compared with 51% in the control clinics. In addition, the completion rate in the intervention group was 17.4% compared with 15.9% in the control group. However, these differences were not statistically significant, and the findings of this trial are inconclusive.

Discussion Approximately half of the TB patients did not complete the treatment course under routine practice conditions;5 –7 however, the average adherence level to treatment among patients with HIV, infectious diseases and pulmonary diseases was 88.35, 74.0 and 68.8%, respectively. In addition, adherence to care for pulmonary conditions is significantly lower compared with other conditions (t ¼ 2.02, P ¼ 0.04).31 The effectiveness of strategies to promote adherence to treatment by TB patients requires further research. Pooled results of RCTs and quasiexperimental studies consistently indicate the evidence of beneficial effects from DOT with increased medication adherence among TB patients in terms of cure rate and success rate. Although these effects were small, there are clinically significant differences in overall public health and health system, including decreased transmission, shortened infectiousness, prevented treatment failure and relapse, which induce drug resistance and mortality, and decrease cost of TB treatment and control. However, no beneficial effects were found from DOT intervention with increased completion rates. This finding is similar to a review conducted by Parent,11 which indicated that DOT was effective in promoting adherence to and completion of TB treatment. But the two reviews previously published on adherence to treatment of latent TB infection differ from this review. A review of evidence in the United States and Canada demonstrated that no single intervention has been consistently effective in improving adherence to treatment for latent TB infection, including DOT.10 The second review by Volmink and Garner12 found no assurance that the routine use of DOT in low-income and middle-income countries improves cure or treatment completion in people requiring treatment for clinically active TB or preventing active diseases. This difference may be because of defining different participants and outcome measures. However, it is essential that all implementation of DOT strategies with patients in the communities must identify and remove constraints of access to care. Therefore, DOT should be modified to suit local situations.10 It is important to devise treatment strategies that lessen financial

burdens on patients, keep the impact of stigma to a minimum and give patients improved access to care. The variants of DOT differ in important ways in terms of who is being observed, where the observation takes place and how often the observations occur.32 A variety of supervision options have been explored, such as supervision by family members, HCWs and community members. There was no significant difference in cure rates, completion rates, and success rates among pulmonary TB patients who received DOT by a community member or family member or HCW. This finding is similar to the reviews conducted by Volmink and Garner,12 which indicated that there is no evidence showing that one form of direct observation is better than another. Nevertheless, two RCTs23,25 found that the success rates of pulmonary TB patients who received DOT by a family member were significantly higher than the rates of those who received DOT by a community member. This result was inconsistent with a quasiexperimental study by Akkslip et al.,27 which demonstrated that the success rate among newly diagnosed pulmonary TB patients who received DOT by case manager were higher than the rates in those who received DOT by family member. However, this quasiexperimental study was conducted with a small sample size (195 participants). In addition, the findings of three studies24,25,27 showed that family member DOT and community DOT strategies can both reach the WHO target for treatment success. This strategy may be suitable for hard-to-access areas where TB patient services are becoming increasingly overloaded and there are many different health programmes requesting HCWs’ effort and time. As DOTS in a health facility is not always convenient and accessible to TB patients, it is necessary to explore additional options. One option is to have a family member supervise DOT. Using family observation, combined with intensive supervision and home visits, has achieved high cure rates; however, family members may not understand the need to provide consistent treatment. Despite the best educational efforts of healthcare staff, there may be limited understanding of, or confidence in, the efficacy of prescribed medicines. If adherence to treatment creates tension in the family, the simplest way to eliminate the source of tension is to discontinue treatment observation. Therefore, family members can potentially be effective treatment observers but only within the restrictions that required close monitoring of all aspects of the treatment delivery system through frequent home visits by health facility staff.27,33 The most common accompanying interventions with DOT are improved accessibility of services, increased


13



availability of drugs, changes in drug regimens, patient incentives, tracing of patients who default and outreach efforts.8 However, there have been problems with this approach, most likely because of insufficient communication between the centres and the various agents of the primary healthcare structure. One study demonstrated that the intervention package based on improved patient counselling and communication between health personnel and patients, decentralisation of treatment, patient choice of DOT supporter and reinforcement of supervision activities led to improvement in patients successfully completing the 8-month course of treatment.17 This result is consistent with a systematic review conducted by Haynes et al.,34 which showed that the interventions that were effective for long-term care were complex, including combinations of more convenient care, information, reminders, self-monitoring, reinforcement, counselling, family therapy, psychological therapy, crisis intervention, manual telephone follow-up and supportive care. Food incentives did not result in a significant improvement in adherence to treatment or successful completion of treatment.15 This result was inconsistent with a review conducted by Parent,11 which indicated that DOT and incentive components such as food, clothing, books and transportation were frequently found to be the most effective factors in treatment completion for pulmonary TB patients. The only outcome significantly associated with the intervention was weight gain. Therefore, a food intervention may be worth considering in patients with TB who are malnourished. For a variety of patient populations, including alcoholic patients, substance abuse patients, homeless persons and patients infected with HIV, a combination of multiple incentives was found to be effective. TB case management combined with the implementation of DOT in the first 2 months could effectively improve the adherence of TB patients to treatment and increase the patients’ completion and treatment success rates. Clinical nurses can make a significant contribution to healthcare delivery by using this model to oversee and monitor TB patients’ medicine intake and medical care to ensure their adherence and improve the patients’ treatment completion rates. The model emphasises the participation of key persons, a comprehensive TB health education and visits to all patients at home once a month as key to improving TB cure rates.16 Healthcare workers can play a key role in supporting adherence to treatment, justifying the training component of the tested strategy and promoting improved counselling. But one study indicated that staff training did not seem to improve TB treatment outcomes,18 14

possibly because of a range of health system barriers that were not addressed by the training programme or because of other unknown or unmeasurable factors. Therefore, a training programme should combine with interventions to address other barriers to clinic and organisational change (e.g. shortage of experienced staff). This review supports the results from previous systematic reviews of qualitative research. The review showed an absence of any evidence against DOT compared with people treating themselves at home.32 However, this review indicated that self-supervision or SAT promoted adherence to treatment among TB patients to a lesser extent than DOT. Appropriately trained healthcare providers will be able to anticipate patient adherence and therefore those suitable for self-supervision or SAT should be assigned. Educational programmes should be undertaken to educate private providers regarding suitable patients for SAT; all patients with newly diagnosed TB should be evaluated by the public health department for possible assignment to DOT.

Limitations of the review This review has some limitations. First, it is limited to evaluating outcomes within adult populations. Studies with adolescents and children were not included as they face significantly different issues in the context of treatment adherence, particularly with parental involvement in adherence. Secondly, focus was on studies with new pulmonary TB patients in order to identify successful strategies aimed at improving adherence among this group of TB patients. Finally, many studies were excluded from this review because they were not designed specifically to assess treatment completion rates, cure rates and success rates but rather to assess sputum smear conversion rates in the second or third month of treatment.

Conclusion Several adherence interventions have been developed to improve treatment for TB infection. This review found evidence of benefits from a number of specific interventions to improve adherence to TB treatment among newly diagnosed patients, including DOT with patient choice of a DOT supporter, case management with DOT and the intensive triad-model programme. In addition, the intervention package based on improved patient counselling and communication, decentralisation of treatment, patient choice of a DOT supporter and reinforcement of supervision activities could be generalised in the context of TB control programmes in resource-poor countries. These should be implemented



EVIDENCE SYNTHESIS by healthcare providers and tailored to local contexts and circumstances, wherever appropriate.

Implications for practice There is evidence supporting the use of DOT to improve adherence to TB treatment among newly diagnosed TB patients. A frequent objection to DOT is that daily observation of all patients by healthcare professionals is not a feasible approach for low-income countries, where the financial means to employ and train the requisite staff are unavailable. This option cannot be used by a large number of patients in rural areas who may live far away from the nearest health centre. Giving patients alternative supervision options that are convenient and accessible, such as community or family members, may have contributed to the comparatively favourable results in improving adherence to treatment. Facilitation of the role of family or community members in DOT involved training by HCWs and close supervision through frequent home visits by health facility staff. In areas in which patients live far from health centres, access to drugs would be improved through decentralisation of treatment.17 Therefore, it would be beneficial to shift the treatment of all TB patients to facilities within the primary healthcare structure. However, this would need to be well planned and tailored to local contexts and circumstances. However, DOT alone may be ineffective in the fight against TB. Multiple components might account for the success of DOT programmes. DOT coupled with food incentives may be worth considering in patients with TB who are malnourished at diagnosis. Case management combined with DOTS should be used for improving adherence to treatment among newly diagnosed TB patients. This approach should be implemented in the first 2 months as the adherences of subjects declined with time. A TB case management team should be set up at the hospital and in community settings. The keys elements of case management should include the facilitation of treatment plans comprising education, direct daily observation in the first 2 months and one home visit per week by the case manager. Patients need to understand how their treatment is to be organised. Therefore, it is essential that formalised educational programmes should be integrated into TB prevention and treatment programmes. To implement comprehensive health education about TB and the importance of treating it, the participation of key persons including a healthcare provider, TB patient and treatment supporter (the intensive triad-model programme) could be helpful in improving TB cure rates.

Implications for research Our review shows the need for further large-scale studies on adherence to treatment by newly diagnosed pulmonary TB patients. It may also be worth comparing DOT to other strategies aimed at improving adherence. Factors that determine its usefulness in various settings require further study. Further strategies, especially those that are feasible in developing countries or countries with limited resources, should be evaluated in RCTs before being introduced into routine practice. Additionally, further research is required that investigates DOT vs. self-supervision to determine ongoing treatment success and re-treatment rates.

Acknowledgements The authors sincerely thank The Joanna Briggs Institute for supporting this review. The review received financial support from the Thailand Centre for Evidence-Based Nursing and Midwifery, Faculty of Nursing, Chiang Mai University, Thailand. The author reports no conflicts of interest.

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