Effectiveness of directly observed treatment of tuberculosis: a systematic review of controlled studies.

INT J TUBERC LUNG DIS 18(9):1092–1098 Q 2014 The Union http://dx.doi.org/10.5588/ijtld.13.0867

Effectiveness of directly observed treatment of tuberculosis: a systematic review of controlled studies J-H. Tian,* Z-X. Lu,† M. O. Bachmann,‡ F-J. Song‡ *Evidence-Based Medicine Centre, Lanzhou University, Lanzhou, Gansu, †Department of Social Medicine and Health Management, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; ‡Norwich Medical School, University of East Anglia, Norwich, UK SUMMARY BACKGROUND:

There is controversy about the effectiveness of directly observed treatment (DOT) for antituberculosis treatment. This systematic review aimed to synthesise evidence from studies that compared DOT and self-administered treatment (SAT) or different types of DOT for anti-tuberculosis treatment. M E T H O D S : Multiple databases were searched by two independent reviewers to identify relevant randomised (RCTs) and non-randomised studies. The risk of bias was independently assessed by two reviewers, and studies at high risk of bias were excluded. Data extraction was conducted by one reviewer and checked by a second reviewer. Primary outcome measures were cure and treatment success. R E S U L T S : We included eight RCTs and 15 non-

randomised studies that were predominantly conducted in low- and middle-income countries. There was no convincing evidence that clinic DOT was more effective than SAT. Evidence from both RCTs and non-randomised studies suggested that community DOT was more effective than SAT. Community DOT was as effective as, or more effective than, clinic DOT. There was no statistically significant difference in results between family and non-family community DOT. C O N C L U S I O N S : Community DOT by non-family members might be the best option if it is more convenient to patients and less costly to health services than clinic DOT. K E Y W O R D S : directly observed treatment; self-administered treatment; tuberculosis; community-based DOT

THE MAIN PILLAR of global tuberculosis (TB) control is the diagnosis and treatment of persons with active disease. To this end, the World Health Organization (WHO) recommended directly observed treatment (DOT) in 1993, and then the DOTS strategy in 1997. The DOTS strategy contains five major elements: political commitment, improved laboratory testing, adequate and free supply of antituberculosis drugs, a reporting system to document progress and DOT. Considerable progress has been made towards global TB control since the recommendation of the DOTS strategy.1 A complete course of anti-tuberculosis treatment usually lasts 6–9 months. Inadequate adherence to treatment is common, causing treatment failure, relapse, the development of drug resistance and transmission of infection. It has been hoped that treatment adherence could be improved if health workers or other individuals are present as observers when patients are taking their anti-tuberculosis medications. Although DOT was initially designed to be carried out by health workers in health facilities, community-based DOT has also been developed,

particularly in low- and middle-income countries (LMICs).2 A Cochrane systematic review of randomised controlled trials (RCTs), which concluded in 2007 that DOT was not more effective than self-administration of treatment (SAT) for TB patients,3 triggered considerable debate among researchers and professionals in terms of whether DOT is necessary, by whom, and in what settings.4,5 The controversy regarding this issue is partly due to the scarce evidence from RCTs. We searched the WHO International Clinical Trials Registry (March 2013) and found no relevant ongoing studies. Given the current policies and ethical considerations, it is unlikely that new evidence from RCTs comparing DOT and SAT for anti-tuberculosis treatment will be available in the near future. On the other hand, there is abundant evidence from non-randomised observational studies. Although there are challenges in using non-randomised studies for evaluating health interventions, such evidence is relevant and should be appropriately assessed and considered.6 We conducted a systematic review of both rando-

Correspondence to: Fujian Song, Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK. Tel: (þ44) 16 0359 1253. e-mail: [email protected] Article submitted 2 December 2013. Final version accepted 16 May 2014.

DOT vs. SAT for anti-tuberculosis treatment

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Figure Process of study identification and selection. RCT ¼ randomised controlled trial; NRS ¼ non-randomised study

mised and non-randomised controlled studies to evaluate the effects of DOT interventions on outcomes of anti-tuberculosis treatment.

METHODS Inclusion and exclusion criteria We included all RCTs and non-randomised studies that concurrently compared DOT and SAT or different types of DOT for treating adult TB patients. We excluded historically controlled studies, studies that included children (aged ,18 years) or those that exclusively included drug users. Given resource restrictions, we excluded studies published in languages other than English. Conference abstracts were excluded due to insufficient data for quality assessment. Literature search and study selection The literature search strategy used can be found in Appendix 1*. We searched the following databases: MEDLINE and EMBASE via OVIDSP and Web of Science (from inception to 6 March 2013). Further searches were performed by manually checking review articles and included studies. Two reviewers (JHT and FS) independently scanned the titles and abstracts and assessed the eligibility of the full text of * The Appendices are available in the online version of this article, at http://www.ingentaconnect.com/content/iuatld/ijtld/ 2014/00000018/00000009/art00014

the articles obtained. Any disagreements about study inclusion were resolved by discussion (JHT, FS and MOB). Data extraction and quality assessment Data extraction was conducted by one reviewer (JHT) and checked by a second reviewer (FS). Any disagreements between the two reviewers were resolved by discussion. The standard WHO definition of anti-tuberculosis treatment outcomes was adopted.1 The primary outcomes in this review are treatment success (defined as the proportion of patients who were cured or completed treatment) and cure (defined as the proportion of patients who were initially smear-positive and who were smearnegative in the last month of treatment and on at least one previous occasion). Other outcomes included death from any cause during treatment, treatment failure (initially smear-positive and remaining smearpositive at month 5 or later during treatment), treatment default (interrupted treatment for 72 consecutive months) and transfer out (transferred to another reporting unit with unknown treatment outcome). The risk of bias in RCTs was assessed using the methods recommended by the Cochrane Collaboration.7 The risk of bias in the non-randomised studies included was assessed using a checklist (see Appendix 1), by focusing on patient allocation methods and baseline comparability.8 The assessment of the risk of bias was independently performed by two reviewers.

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The International Journal of Tuberculosis and Lung Disease

Table 1 The main characteristics of the included studies

Study, year, reference

Design 10

Country

Kamolratanakul, 1999

RCT

Thailand

Lwilla, 200312 Newell, 200613 Walley, 200111

RCT RCT RCT

Tanzania Nepal Pakistan

Wandwalo, 200414 Wright, 200415 Zwarenstein, 199816

RCT RCT RCT

Zwarenstein, 200017

Interventions compared

Year of enrolment

Tanzania Swaziland South Africa

Clinic DOT vs. community DOT vs. family DOT vs. SAT Clinic DOT vs. community DOT Family DOT vs. community non-family DOT Health workers (clinic or community) DOT vs. family DOT vs. SAT Clinic DOT vs. family DOT Family DOT vs. community non-family DOT Clinic DOT vs. SAT

2001–2002 2000–2002 1994–1995

Follow-up months

Sample size n

1996–1997

6

836

1999–2000 2002–2003 1996–1999

7 8 8

522 907 497

8 Not recorded 6–8

587 1326 216

RCT

South Africa

Clinic DOT vs. community DOT vs. SAT

1994–1995

6

156

18

Akhtar, 2011 Akkslip, 199919

NRS NRS

Pakistan Thailand

Clinic DOT vs. family DOT Clinic DOT vs. family DOT vs. SAT

2003–2005 1996–1997

5 6

582 326

Anuwatnonthakate, 200820 Cavalcante, 200721

NRS NRS

Thailand Brazil

Clinic DOT vs. family DOT vs. SAT Clinic DOT vs. community DOT vs. SAT

2004–2006 2003–2004

6 6

8031 1811

Davidson, 199822

NRS

USA

Clinic DOT vs. SAT

1994–1995

8–12

319

Islam, 2002

NRS

Bangladesh

Community DOT vs. SAT

1996–1997

8

371

Mafigiri, 201224 Olle-Goig, 200125 Pungrassami, 200226

NRS NRS NRS

Uganda Haiti Thailand

2005–2006 1993–1994 1999

8 6–9 9

107 281 411

Radilla-Chavez, 200727 Singh, 200428 Soomro, 201229

NRS NRS NRS

Mexico India Pakistan

Clinic DOT vs. family DOT Community DOT vs. SAT Clinic DOT vs. community DOT vs. family DOT vs. SAT Clinic DOT vs. SAT Clinic DOT vs. community DOT Clinic DOT vs. family DOT vs. SAT

2000–2003 2000–2001 2008

6 6 Not clear

629 617 451

Thiam, 200730 van den Boogaard, 200931

NRS NRS

Senegal Tanzania

Clinic DOT vs. family DOT Clinic DOT vs. community DOT

2003–2005 2007

Zvavamwe, 200932

NRS

Namibia

Community DOT vs. SAT

23

2002

8 6 6–8

1552 2769 332

RCT ¼randomised controlled trial; DOT ¼ directly observed treatment; SAT ¼self-administered treatment; TB ¼ tuberculosis; NRS ¼ non-randomised study; HIV ¼ human immunodeficiency virus.

Any discrepancies between the two reviewers were resolved by discussion or the involvement of a third reviewer. The results of the assessment of risk of bias were incorporated into the analyses by excluding studies with a high risk of bias. Data synthesis When available, the estimates adjusted for possible confounding factors were used in our analysis. We used odds ratio (OR) in the meta-analyses, as OR estimates (with standard errors) were usually reported in studies that used logistic regression analysis to adjust for possible confounding factors. To help interpret results, we converted the estimated OR to relative risk (RR) for the main results of the metaanalysis, using RR ¼

OR 1 CP þ CP*OR

where CP is the event rate in the control group. Heterogeneity in results across studies was examined using I2 and v2 statistics, and random effects models were used for quantitative pooling of the results of individual studies.9 Subgroup analyses and

meta-regression analyses were conducted by study design, types of DOT and other study level variables (including year of patient recruitment, sample size and the overall event rate). We used funnel plots to detect publication bias.

RESULTS The study selection process is shown in the Figure. We excluded 43 records after examining 85 full-text articles for eligibility (Appendix 2). We identified a total of 11 RCTs and 34 non-randomised studies. These clinically relevant studies were assessed for the risk of bias. Risk of bias in the identified studies The risk of overall bias was considered to be high in three RCTs (see Appendix 3 for details). To compare different types of DOT, data from two included RCTs10,11 were used as non-randomised evidence when allocation of patients to different DOT observers was not randomised. Based on approaches to allocating patients to different groups and imbalanced baseline characteristics, the risk of bias was


Table 1

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(continued)

Participants

Outcomes reported

New smear-positive TB patients

Treatment success; cured; completed treatment; died; failed; defaulted; transferred out

New smear-positive TB patients New smear-positive TB patients New smear-positive TB patients

Cured; died; failed; defaulted; transferred out Treatment success; completed treatment; died Treatment success; cured; completed treatment; died; failed; defaulted; transferred out

New TB patients New TB patients New TB patients

Treatment success; cured; died; failed; defaulted; transferred out Treatment success; cured; completed treatment; died; failed; defaulted; transferred out Treatment success; cured; completed treatment; died; failed; transferred out; treatment interrupted Treatment success; cured; completed treatment; died; failed; transferred out; treatment interrupted Treatment success; cured; completed treatment; died; failed; defaulted; transferred out Treatment success; cured; completed treatment; died; failed; defaulted; transferred out; treatment interrupted Treatment success; cured; completed treatment; died; failed; defaulted; transferred out Cured; died; failed; defaulted; transferred out

New or retreatment TB patients New or retreatment TB patients New smear-positive TB patients New TB patients, some with HIV infection New or retreatment TB patients, some with HIV infection New or retreatment positive TB, some with HIV infection New or retreatments smear-positive TB patients New smear-positive TB patients New TB patients, some with HIV infection New smear-positive TB patients TB patients, some with HIV infection New smear-positive TB patients New smear-positive TB patients New smear-positive TB patients New or retreatment TB patients, some with HIV infection TB patients

Treatment success (based on defined treatment completion); died Treatment success; cured; completed treatment; died; failed; defaulted Treatment success; cured; completed treatment; died; failed; defaulted; transferred out Treatment success; cured; completed treatment; died; defaulted Treatment success; cured; completed treatment; died; failed; defaulted Cured; failed Treatment success; cured; died; failed; defaulted; transferred out Treatment success; unfavourable outcomes (including failure, defaulted and expired cases); transferred out Treatment success; cured; defaulted Treatment success; cured; completed treatment; died; failed; defaulted; transferred out Cured; defaulted

high in 16 non-randomised studies (Appendix 4). In addition, the risk of outcome reporting bias was deemed to be high in seven non-randomised studies that reported only a single outcome. A total of three RCTs and 19 non-randomised studies were therefore considered at high risk of bias and excluded from the primary analyses. The basic characteristics of the studies excluded due to a high risk of bias are shown in Appendix 5. The main characteristics of the included studies The basic characteristics of the 23 included studies (8 RCTs10–17 and 15 non-randomised studies18–32) are shown in Table 1. Most of the included studies (22/ 23) were conducted in LMICs. DOT interventions were compared with SAT in 14 studies, and different types of DOT observers were compared in 17 studies. Sixteen studies recruited only newly diagnosed TB patients, and six studies explicitly reported that some patients had human immunodeficiency virus infection. Among the 23 studies included, treatment success outcome was reported in 19 studies and cure outcome was available from 20 studies. Table 2 shows the results of meta-analysis for the two primary outcomes (treatment success and cure rate). Results of meta-analyses for all outcomes and

results that included studies with a high risk of bias are presented in Appendix 6. Treatment success and cure rate There was no significant difference in treatment success or cure rate between DOT (including any DOT interventions) and SAT according to data from RCTs, while results of non-randomised studies indicated that DOT was more effective than SAT (Table 2, and see Appendix 7 for the forest plots). For treatment success, the results of both RCTs and nonrandomised studies consistently suggested that community DOT was more effective than SAT (Table 2). For the outcome cure, community DOT tended to be more effective than SAT, although the result using data from two RCTs was statistically non-significant (P ¼ 0.088) (Table 2). When clinical DOT was compared with SAT for treatment success or cure rate outcome, evidence from both RCTs and nonrandomised studies indicated no significant differences in results (Table 2). For treatment success, community DOT was as effective as clinic DOT, according to data from both direct comparison RCTs and non-randomised studies (Table 2). For the outcome cure, results of nonrandomised studies indicated no difference between

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comparison RCTs and non-randomised studies (Table 2).

Table 2 Comparisons of different types of DOT and SAT: treatment success and cure rate outcomes Heterogeneity Comparisons

Design

Studies n

Treatment success Any DOT vs. SAT RCT 4 NRS 8 Community DOT vs. SAT RCT 3 NRS 7 Clinic DOT vs. SAT RCT 3 NRS 7 Community vs. clinic DOT RCT 2 NRS 10 Family vs. non-family DOT RCT 2 NRS 3 Cure rate Any DOT vs. SAT RCT 4 NRS 8 Community DOT vs. SAT RCT 2 NRS 8 Clinic DOT vs. SAT RCT 2 NRS 7 Community vs. clinic DOT RCT 3 NRS 9 Family vs. non-family DOT RCT 1 NRS 3

RR (95%CI)*

I2 %

P value

1.08 (0.96–1.19) 1.20 (1.11–1.28)

43 74

0.156 ,0.001

1.13 (1.02–1.24) 1.21 (1.07–1.33)

27 84

0.254 ,0.001

0.98 (0.75–1.19) 1.15 (1.06–1.23)

25 38

0.264 0.141

1.10 (0.94–1.21) 1.02 (0.95–1.08)

42 51

0.189 0.033

1.04 (0.98–1.08) 0.96 (0.86–1.04)

39 0

0.202 0.400

1.13 (0.88–1.39) 1.54 (1.24–1.83)

60 88

0.056 ,0.001

1.23 (0.97–1.49) 1.55 (1.27–1.82)

0 87

0.363 ,0.001

0.79 (0.46–1.24) 1.39 (0.95–1.83)

39 91

0.201 ,0.001

1.09 (1.00–1.17) 1.01 (0.92–1.10)

28 82

0.248 ,0.001

0.94 (0.85–1.01) 0.92 (0.80–1.02)

18

— 0.297

* OR estimates were converted to RR using: RR ¼ OR/(1-CPþCP*OR), where CP is the pooled event rate in the control group: CP ¼ 0.622 for treatment success, 0.357 for cure rate, 0.715 for clinic DOT and 0.802 for non-family community DOT. DOT ¼ observed treatment; SAT ¼ self-administered treatment; RR ¼ relative risk; CI ¼ confidence interval; RCT ¼ randomised controlled trial; NRS ¼ nonrandomised study; OR ¼ odds ratio.

community DOT and clinic DOT; however, data from three direct comparison RCTs suggested that community DOT was more effective than clinic DOT (P ¼ 0.048) (Table 2). For the treatment success or cure rate outcome, the difference between family DOT and non-family community DOT was statistically nonsignificant, according to data from both direct Table 3

Secondary outcomes Evidence from RCTs suggested that there was no significant difference in any secondary outcomes between DOT and SAT (Appendix 6). According to the results of non-randomised studies, there was no significant difference in death and treatment failure between DOT and SAT, although DOT was associated with a lower default rate and fewer patients transferred out than with SAT. There were no statistically significant differences in secondary outcomes between community DOT and clinic DOT, and between family DOT and non-family community DOT (Appendix 6). Results of subgroup analyses Table 3 shows the results of meta-regression analyses by study-level variables. The differences in results between RCTs and non-randomised studies were not statistically significant for treatment success (P ¼ 0.190) but were borderline significant for cure (P ¼ 0.064). The result for treatment success or cure was not statistically significantly associated with sample size, year of patient recruitment or the combined success rate. Testing for publication bias Funnel plots were not statistically significantly skewed for any of the evaluated outcomes when DOT was compared with SAT (Appendix 8). As the number of included studies was very small, the funnel plots and related statistical test results need to be interpreted with caution. The risk of publication bias cannot be ruled out in the included studies.

DISCUSSION The current systematic review found evidence from both RCTs and non-randomised studies indicating that community DOT was more effective than SAT for the outcome treatment success. This is also likely true for the cure outcome, although the result of

Results of meta-regression analyses using study-level variables: DOT vs. SAT for treatment success and cure rate outcomes* Treatment success rate

Independent variables RCT vs. NRS Sample size ,500 vs. 7500 Year of recruitment: since 2001 vs. before 2001 Combined response rate ,0.8 vs. 70.8

†

ROR (95%CI) 0.67 1.10 0.83 0.67

(0.36–1.26) (0.57–2.10) (0.38–1.79) (0.33–1.38)

P value 0.190 0.757 0.590 0.242

Treatment cure rate ROR (95%CI)† 0.53 1.41 1.67 0.94

(0.27–1.05) (0.73–2.70) (0.80–3.49) (0.38–2.30)

P value 0.064 0.265 0.151 0.882

* Random-effects meta-regression analysis was conducted using STATA ‘metareg’ command (Stata Corp, College Station, TX, USA). Study design variable (RCT or NRS) was included in meta-regression analyses of sample size, year of recruitment, and response rate. † Dependent variable was log OR, and independent variables were study-level factors; ROR ¼ 1, indicating that there is no difference between the subgroups in estimated ORs. DOT ¼ observed treatment; SAT ¼ self-administered treatment; ROR ¼ ratio of OR; CI ¼ confidence interval; RCT ¼ randomised controlled trial; NRS ¼ nonrandomised study; OR ¼ odds ratio.


RCTs was statistically non-significant (P ¼ 0.088). Clinic DOT was no more effective than SAT, according to data from the RCTs, which is different from the positive result of non-randomised studies. There were differences between the current systematic review and previous systematic reviews3,33 in terms of included studies (see Appendix 9) and the review methods used. The Cochrane systematic review included only RCTs.3 A recently published review focused on microbiological failure, and included only five RCTs and five non-randomised studies.33 In another systematic review of 75 observational studies, it was found that in patients with drug-resistant TB, fully implemented DOT reduced treatment default compared with partially implemented DOT or SAT, and community-based DOT was associated with a lower rate of treatment default than clinic-based DOT.34 The implementation of clinic DOT has been difficult in LMICs due to the heavy TB disease burden, limited resources and inconvenience to patients.35 Community DOT for anti-tuberculosis treatment was developed as a result.2 According to evidence from direct comparison RCTs, communitybased DOT is at least as effective as, or more effective than, clinic DOT for the outcome treatment success or cure. This may be because compulsory allocation of patients to clinic DOT might not be acceptable to them. Limitations In some non-randomised studies, the allocation of patients to different groups was clearly biased, and patients were not comparable at baseline between groups. Non-randomised studies that were clearly biased were not included in the main data analyses. It may be controversial whether relevant studies should be excluded based on the perceived risk of bias. We therefore conducted sensitivity analyses by including studies at high risk of bias (Appendix 6). In most cases, the estimated treatment effects became greater and more heterogeneous after including studies with high risk of bias. In addition, we used results adjusted for confounding factors when available, although only 6 of the 15 included non-randomised studies reported results adjusted for confounding factors (Appendix 4). Results from RCTs tended to be less favourable to DOT as compared to those from non-randomised studies, although the differences were not statistically significant for treatment success (P ¼ 0.190) and only borderline significant for cure (P ¼ 0.064). Due to resource restrictions, we excluded studies published in languages other than English. There may be some relevant studies published in other languages. In addition, conference abstracts were not included, as they contain insufficient information to assess risk of bias.

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There was significant heterogeneity across studies, which may be expected, given the differences in patients, care providers, health care systems and diverse socio-economic and cultural settings. Subgroup analyses found no clear explanations for the observed heterogeneity across studies (Table 3).

CONCLUSIONS There was considerable heterogeneity in the results of the studies included, which were mainly conducted in LMICs. Overall evidence from both RCTs and nonrandomised studies indicates that community-based DOT is more effective than SAT, and at least as effective as clinic DOT, for treating TB patients. Community DOT by non-family members might be the best option if it is more convenient for patients and less costly to health services than clinic DOT. Acknowledgements JHT received support from the Chinese Medical Board, Beijing, China. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Conflict of interest: none declared.

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APPENDIX 1 PROTOCOL OF A SYSTEMATIC REVIEW OF CONTROLLED STUDIES ON DOT VS. SAT FOR TUBERCULOSIS Objectives

To evaluate the effects of directly observed treatment (DOT) for anti-tuberculosis treatment To investigate sources of heterogeneity and factors related to the effectiveness of DOT

Inclusion and exclusion criteria Inclusion criteria:

Interventions: any DOT, including clinic-based, community-based DOT Comparators: self-administrated treatment (SAT) or different types of DOT Relevant outcomes: primary outcomes, cure rate and treatment success according to the standard World Health Organization (WHO) definition of treatment outcomes. Other outcomes include death, treatment failure, treatment default and transferred out Patients: patients who received treatment for tuberculosis (TB) Randomised controlled trials (RCTs), quasi-RCTs, experimental or observational studies that concurrently compare DOT and SAT, or different types of DOT for anti-tuberculosis treatment. Language restrictions: only studies published in the English language included.

Exclusion criteria:

Historically controlled studies Studies including only substance abusers Studies comparing different anti-tuberculosis drugs Studies published in languages other than English Studies available in abstract form only.

Literature search strategy Databases searched We will search the following databases: MEDLINE and EMBASE via OVIDSP, and Web of Science, using the following strategies: OvidSP search strategy (MEDLINE and EMBASE) #1 (directly observed or direct observation or DOT or DOTS).af. #2 tuberculosis.af. #3 #1 and #2 Web of Science@ search strategy (SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH) #1 Topic¼(directly observed) OR Topic¼(direct observation) OR Topic¼(DOT) OR Topic¼(DOTS) #2 Topic¼(tuberculosis) #3 #1 AND #2 To identify additional relevant studies, we will also

i

manually check references of review articles and included studies. Two reviewers will independently scan titles and abstracts, and assess the eligibility of the full text of obtained articles. Any disagreements for study inclusion will be resolved by discussion. Data extraction and quality assessment One reviewer will extract data from included studies, and a second reviewer will check the extracted data. The following main characteristics and results of included studies will be extracted:

Study design Country Year of patient enrolment Duration of follow-up Sample size Study participants Susceptibility to anti-tuberculosis drugs Treatment regimen Types of DOT and/or SAT Definition of treatment success and other relevant outcomes Results (to be specified as n/N by study arm)

Risk of bias assessment The risk of bias in RCTs will be assessed according to the methods recommended by the Cochrane Collaboration:

Appropriate sequence generation? Appropriate allocation concealment? Blinding of outcome assessors? Free of incomplete outcome data? Are there any other sources on bias? Risk of outcome reporting bias?

The risk of bias in the non-randomised studies included was assessed using the following checklist, by focusing on patient allocation methods and baseline comparability. 1) Risk of bias due to patient inclusion and data source: Low risk: cohort studies (prospectively) following up of well-defined patients and likely to be representative and unbiased. Unclear: identified from routine clinical records and patients were not well defined, included patients with different types or severities. 2) How patients were allocated to the various DOT interventions: Low risk: patients were assigned to different DOTs without clear risk of bias. For example, patients might be from different areas or different clinics but they were likely to be similar in baseline characteristics. Unclear risk: patient allocation may be biased but the extent and direction of bias was unclear. High risk: there were clear reasons to believe that

ii


allocation methods were biased. 3) Were patients comparable at baseline between different DOT groups? Low risk: no significant differences in baseline characteristics between groups, and there were sufficient data indicating similarity between groups. Unclear risk: insufficient data or unclear impact of imbalances in some baseline characteristics High risk: there was evidence on important imbalances in baseline characteristics between groups. 4) Were confounding factors adjusted in analysis? Low risk: balanced characteristics at baseline, or appropriately adjusting for confounding variables Unclear: lack of comparability at baseline and without adjusting for confounders 5) Risk of outcome reporting bias Low (unlikely): five or more WHO outcomes (including at least one of the two primary outcomes) Unclear: between low and high High: only one outcome reported The assessment of the risk of bias will be independently performed by two reviewers. Any discrepancies between the two reviewers will be resolved by discussion or the involvement of a third reviewer. The results of assessment of risk of bias will be incorporated into analyses by excluding studies with high risk of bias. Data analysis methods We will use odds ratio (OR) with 95% confidence intervals as the outcome statistic. When available, the estimates adjusted for possible confounding factors will be used in analysis. Heterogeneity in results across studies will be examined using I2 and v2 statistics, and random effects models will be used for quantitatively pooling results of individual studies. We will conduct subgroup analyses according to study design and types of DOT, and conduct exploratory meta-regression analyses to investigate possible causes of heterogeneity in meta-analysis. Funnel plots will be used to detect publication bias or small study effects.

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APPENDIX 2 RECORDS EXCLUDED AFTER EXAMINATION OF FULL-TEXT ARTICLES 1 Adatu F, Odeke R, Mugenyi M, et al. Implementation of the DOTS strategy for tuberculosis control in rural Kiboga District, Uganda, offering patients the option of treatment supervision in the community, 1998–1999. Int J Tuberc Lung Dis 2003; 7 (Suppl 1): S63–S71. Full-exclude: Before-after 2 Barrett J C, Dart S, Solamalai A, Snook C, Lipman M. Tuberculosis outcome following pre-treatment assessment for directly observed or self-administered therapy: still room for

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improvement? Thorax 2011; 66: A89. Full-exclude: meeting abstract only Bayer R, Stayton C, Desvarieux M, Healton C, Landesman S, Tsai W Y. Directly observed therapy and treatment completion for tuberculosis in the United States: is universal supervised therapy necessary? Am J Public Health 1998; 88: 1052–1058. Full-exclude: before-after Becx-Bleumink M, Djamaluddin S, Loprang F, De Soldenhoff R, Wibowo H, Aryono M. High cure rates in smear-positive tuberculosis patients using ambulatory treatment with onceweekly supervision during the intensive phase in Sulawesi, Republic of Indonesia. Int J Tuberc Lung Dis 1999; 3: 1066– 1072. Full-exclude: before-after Burman W J, Dalton C B, Cohn D L, Butler J R, Reves R R. A cost-effectiveness analysis of directly observed therapy vs selfadministered therapy for treatment of tuberculosis. Chest 1997; 112: 63–70. Full-exclude: review Carroll K, Malefoasi G. Comparison of outcomes from a district tuberculosis control programme in the Pacific: before and after the implementation of DOTS. Trop Doctor 2004; 34: 11–14. Full-exclude: before-after Cavalcante S C, Durovni B, Barnes G L, et al. Communityrandomized trial of enhanced DOTS for tuberculosis control in Rio de Janeiro, Brazil. Int J Tuberc Lung Dis 2010; 14: 203– 209. Full-exclude: TB screening Chengsorn N, Bloss E, Anekvorapong R, et al. Tuberculosis services and treatment outcomes in private and public health care facilities in Thailand, 2004–2006. Int J Tuberc Lung Dis 2009; 13: 888–894. Full-exclude: unclear control Clarke M, Dick J, Zwarenstein M, Lombard C J, Diwan V K. Lay health worker intervention with choice of DOT superior to standard TB care for farm dwellers in South Africa: a cluster randomised control trial.[Erratum appears in Int J Tuberc Lung Dis 2009; 13: 921]. Int J Tuberc Lung Dis 2005; 9: 673–679. Full-exclude: unclear DOT/control Coelho A G V, Zamarioli L A, Perandones C A, Cuntiere I, Waldman E A. (). Characteristics of pulmonary tuberculosis in a hyperendemic area-the city of Santos, Brazil. J Bras Pneumol 2009; 35: 998–1007. Full-exclude: unclear DOT Daniel O J. Pre- and post-directly observed treatment era in the management of TB: a teaching hospital experience. Trop Doctor 2006; 36: 163–165. Full-exclude: before-after de Figueiredo T M R M, Villa T C S, Scatena L M, et al. Performance of primary healthcare services in tuberculosis control. Revista de Saude Publica 2009; 43: 825–831. Fullexclude: lack relevant outcomes Deruaz J, Zellweger J P. Directly observed therapy for tuberculosis in a low prevalence region: first experience at the Tuberculosis Dispensary in Lausanne. Swiss Medical Weekly 2004; 134: 552–558. Full-exclude: unclear control do Prado T N, Wada N, Guidoni L M, Golub J E, Dietze R, Noia Maciel E L. Cost-effectiveness of community health worker versus home-based guardians for directly observed treatment of tuberculosis in Vitoria, Espirito Santo State, Brazil. Caud Saude Publica 2011; 27: 944–952. Full-exclude: unclear outcomes Egwaga S, Mkopi A, Range N, Haag-Arbenz V, Baraka A, Grewal P, Cobelens F, Mshinda H, Lwilla F, Van Leth F. Patientcentred tuberculosis treatment delivery under programmatic conditions in Tanzania: a cohort study. BMC Med 2009; 7: 80. Full-exclude: before-after Ferreira V, Brito C, Portela M, Escosteguy C, Lima S. DOTS in primary care units in the city of Rio de Janeiro, Southeastern Brazil. Revista de Saude Publica 2011; 45: 40–48. Full-exclude: duplication Heal G, Elwood R K, FitzGerald J M. Acceptance and safety of directly observed versus self-administered isoniazid preventive therapy in aboriginal peoples in British Columbia. Int J Tuberc Lung Dis 1998; 2: 979–983. Full-exclude: prevention


18 Horne D J, Hubbard R, Narita M, Exarchos A, Park D R, Goss C H. Factors associated with mortality in patients with tuberculosis. BMC Infect Dis 2010; 10: 258. Full-exclude: HR outcome 19 Hsieh C J, Lin L C, Kuo B I, Chiang C H, Su W J, Shih J F. Exploring the efficacy of a case management model using DOTS in the adherence of patients with pulmonary tuberculosis. J Clin Nursing 2008; 17: 869–875. Full-exclude: unclear dot/control 20 Hu D, Liu X, Chen J, et al. Direct observation and adherence to tuberculosis treatment in Chongqing, China: a descriptive study. Health Policy Plan 2008; 23: 43–55. Full-exclude: adherence outcome 21 Hunchangsith P, Barendregt J J, Vos T, Bertram M. Costeffectiveness of different strategies for tuberculosis control programs in Thailand. Value in Health 2010; 13: A504–A505. Full-exclude: review article 22 Ignotti E, Oliveira B F, Hartwig S, Oliveira H C, Scatena J H. Analysis of the Tuberculosis Control Program in the city of Caceres, Brazil, prior to and after the implementation of a Family Health Program. J Bras Pneumol 2007; 33: 287–294. Full-exclude: before-after 23 Jacobs B, Clowes C, Wares F, et al. Cost-effectiveness analysis of the russian treatment scheme for tuberculosis versus shortcourse chemotherapy: results from Tomsk, Siberia. Int J Tuberc Lung Dis 2002; 6: 396–405. Full-exclude: unclear control 24 Juan G, Lloret T, Perez C, et al. Directly observed treatment for tuberculosis in pharmacies compared with self-administered therapy in Spain. Int J Tuberc Lung Dis 2006; 10: 215–221. Full-exclude: before-after 25 Kapella B K, Anuwatnonthakate A, Komsakorn S, et al. Directly observed treatment is associated with reduced default among foreign tuberculosis patients in Thailand. Int J Tuberc Lung Dis 2009; 13: 232–237. Full-exclude: duplication 26 Khan M A, Walley J D, Witter S N, Imran A, Safdar N. Costs and cost-effectiveness of different DOT strategies for the treatment of tuberculosis in Pakistan. Directly Observed Treatment. Health Policy Plan 2002; 17: 178–186. Fullexclude: duplication 27 Mirzoev T N, Baral S C, Karki D K, Green A T, Newell J N. Community-based DOTS and family member DOTS for TB control in Nepal: costs and cost-effectiveness. Cost Eff Resour Alloc 2008; 6: 20. Full-exclude: economic study 28 Mkopi A, Range N, Lwilla F, et al. Adherence to tuberculosis therapy among patients receiving home-based directly observed treatment: evidence from the United Republic of Tanzania. PLOS ONE 2012; 7: e51828. Full-exclude: adherence outcome 29 Moalosi G, Floyd K, Phatshwane J, Moeti T, Binkin N, Kenyon T. Cost-effectiveness of home-based care versus hospital care for chronically ill tuberculosis patients, Francistown, Botswana. Int J Tuberc Lung Dis 2003; 7 (Suppl 1): S80–S85. Full-exclude: home vs inpatient 30 Mohan C I, Bishai D, Cavalcante S, Chaisson R E. The cost-

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42

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effectiveness of DOTS in urban Brazil. Int J Tuberc Lung Dis 2007; 11: 27–32. Full-exclude: review Moonan P K, Quitugua T N, Pogoda J M, et al. Does directly observed therapy (DOT) reduce drug-resistant tuberculosis? BMC Public Health 2011; 11: 19. Full-exclude: irrelevant outcomes Murray C J L. Results of directly observed short-course chemotherapy in 112 842 Chinese patients with smear-positive tuberculosis. Lancet 1996; 347: 358–362. Full-exclude: beforeafter Ntshanga S P, Rustomjee R, Mabaso M L. Evaluation of directly observed therapy for tuberculosis in KwaZulu-Natal, South Africa. Trans R Soc Trop Med Hyg 2009; 103: 571–574. Full-exclude: unclear control Ormerod L P, Horsfield N, Green R M. Tuberculosis treatment outcome monitoring: Blackburn 1988–2000. Int J Tuberc Lung Dis 2002; 6: 662–665. Full-exclude: before-after Pungrassami P, Johnsen S P, Chongsuvivatwong V, Olsen J. Has directly observed treatment improved outcomes for patients with tuberculosis in southern Thailand? Trop Med Int Health 2002; 7: 271–279. Full-exclude: unclear control Sass P, Cooper K, Robertson V. School-based tuberculosis testing and treatment program: comparing directly observed preventive therapy with traditional preventive therapy. J Public Health Manag Pract 1996; 2: 32–40. Full-exclude: TB screening/prevention Steffen R, Menzies D, Oxlade O, et al. Patients’ costs and costeffectiveness of tuberculosis treatment in dots and non-dots facilities in Rio de Janeiro, Brazil. PLOS ONE 2010; 5: e14014. Full-exclude: economic study Sun Q, Meng Q, Yip W, Yin X, Li H. DOT in rural China: experience from a case study in Shandong Province, China. Int J Tuberc Lung Dis 2008; 12: 625–630. Full-exclude: unclear DOT/control Tsuchida K, Koyanagi H. Outcome of directly observed therapy for tuberculosis in Yokohama City, Japan. Int J Tuberc Lung Dis 2003; 7: 730–734. Full-exclude: before-after Uzundag Iseri A, Dulkar G, Selcuk Sonmez O, Yilmaz Aydin L, Yilmaz B. Factors that effect sputum culture conversion rate in hospitalized patients with pulmonary tuberculosis who were applied directly observation therapy and non-directly observation therapy. Tuberk Toraks 2010; 58: 44–52. Full-exclude: before-after Weis S E, Slocum P C, Blais F X, et al. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994; 330: 1179–1184. Fullexclude: before-after Wong M Y, Leung C C, Tam C M, Lee S N. Directly observed treatment of tuberculosis in Hong Kong. Int J Tuberc Lung Dis 2005; 9: 443–449. Full-exclude: unclear DOT/control Xu W, Lu W, Zhou Y, Zhu L, Shen H, Wang J. Adherence to antituberculosis treatment among pulmonary tuberculosis patients: a qualitative and quantitative study. BMC Health Services Res 2009; 9: 169. Full-exclude: adherence outcome only

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APPENDIX 3

RISK OF BIAS IN THE INCLUDED RCTS COMPARING DIFFERENT DOT INTERVENTIONS

Author, year, reference

Appropriate sequence generation?

Design

Appropriate allocation concealment?

Blinding of outcome assessors?

Kamolratanakul, 19991

RCT: DOT vs. SAT

Yes

Unclear

No

Lwilla, 20032

RCT: community DOT vs. clinic DOT (cluster effects considered in analyses)

Unclear

Unclear

No

MacIntyre, 20033

RCT: family DOT vs. SAT (quasi design)

No: alternative sequence

No

No for treatment completion outcome

Madhav, 20044 Newell, 20065

RCT: clinic DOT vs. SAT RCT: family DOT vs. community DOT (cluster effects considered in analyses) RCT: community DOT vs. SAT

Unlikely Yes

Unlikely No

No No

Unlikely

Unlikely

No

Tandon, 20026

Walley, 20017

RCT: family DOT vs. health workers DOT vs. SAT

Yes

Yes

Yes

Wandwalo, 20048

Yes (coin tossing)

No

No

Unclear

Unclear

Yes

Zwarenstein, 199810

RCT: family DOT vs. community nonfamily DOT RCT: family DOT vs. community nonfamily DOT RCT: clinic DOT vs. SAT

Yes

Yes

No

Zwarenstein, 200011

RCT: clinic DOT vs. SAT

Yes

Yes

No

9

Wright, 2004

RCT ¼ randomised controlled trial; DOT ¼ directly observed treatment; SAT ¼self-administered treatment; ITT ¼ intention-to-treat.

References of RCTS identified 1 Kamolratanakul P, Sawert H, Lertmaharit S, et al. Randomized controlled trial of directly observed treatment (DOT) for patients with pulmonary tuberculosis in Thailand. Trans R Soc Trop Med Hyg 1999; 93: 552–557. 2 Lwilla F, Schellenberg D, Masanja H, et al. Evaluation of efficacy of community-based vs. institutional-based direct observed short-course treatment for the control of tuberculosis in Kilombero district, Tanzania. Trop Med Int Health 2003; 8: 204–210. 3 MacIntyre C R, Goebel K, Brown G V, et al. A randomised controlled clinical trial of the efficacy of family-based direct observation of anti-tuberculosis treatment in an urban, developed-country setting. Int J Tuberc Lung Dis 2003; 7: 848–854. 4 Madhav S M, Kiran N U. A comparative study of dots and nonDOTS interventions in tuberculosis cure. Indian J Community Med 2004; 29: 18–19. 5 Newell J N, Baral S C, Pande S B, Bam D S, Malla P. Familymember DOTS and community DOTS for tuberculosis control in Nepal: cluster-randomised controlled trial. Lancet 2006; 367: 903–909. 6 Tandon M, Gupta M, Tandon S, Gupta K B. DOTS versus self

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administered therapy (SAT) for patients of pulmonary tuberculosis: a randomised trial at a tertiary care hospital. Indian J Med Sci 2002; 56: 19–21. Walley J D, Khan M A, Newell J N, Khan M H. Effectiveness of the direct observation component of DOTS for tuberculosis: a randomised controlled trial in Pakistan. Lancet 2001; 357: 664–669. Wandwalo E, Kapalata N, Egwaga S, Morkve O. Effectiveness of community-based directly observed treatment for tuberculosis in an urban setting in Tanzania: a randomised controlled trial. Int J Tuberc Lung Dis 2004; 8: 1248–1254. Wright J, Walley J, Philip A, et al. Direct observation of treatment for tuberculosis: a randomized controlled trial of community health workers versus family members. Trop Med Int Health 2004; 9: 559–565. Zwarenstein M, Schoeman J H, Vundule C, Lombard C J, Tatley M. Randomised controlled trial of self-supervised and directly observed treatment of tuberculosis. Lancet 1998; 352: 1340–1343. Zwarenstein M, Schoeman J H, Vundule C, Lombard C J, Tatley M. A randomised controlled trial of lay health workers as direct observers for treatment of tuberculosis. Int J Tuberc Lung Dis 2000; 4: 550–554.


APPENDIX 3

(continued)

Free of incomplete outcome data? Yes (100% follow-up) Unclear (ITT analysis; drop-out rate 41% in community vs. 29% in clinic DOT at 7 months) Unclear (ITT analysis) Unclear Yes (ITT analysis) Unclear (not ITT analysis)

Likely (ITT analysis)

Yes (ITT analysis) Yes Likely (ITT analysis)

Yes (ITT analysis)

v

Other sources of bias

Outcomes reported

Overall risk of bias

Note: the comparison of different types of supervisors was non-randomised Possibly more patients with severe disease in a centre allocated to clinic DOT

Cured; completed treatment; died; failed; defaulted; transferred out Cured; died; failed; defaulted; transferred out

Low

Only 58% (50/87) of patients in the family DOT group received the assigned family-based DOT (living alone, refusal or other reasons) Brief report only, lack of details No other concerns

Successfully treated (based on defined treatment completion)

High

Cured Completed treatment; died; successfully treated Successfully treated

High Low

Brief report only, lack of details 53/206 patients changed from SAT to DOT; data analysis performed according to actual interventions received. Data from this study therefore analysed as non-randomised studies 1) 16% (27/170) of patients in the health worker DOT group and 2% in the family DOT group unable to receive the assigned interventions 2) Non-randomised comparison of clinic-based DOT vs. community health worker-based DOT 8/260 patients changed from community DOT to clinic DOT No other concerns 1) Of the 114 patients (Khayelitsha), 2 changed from SAT to DOT and 5 changed from DOT to SAT 2) Data from Elsies River not used due to duplication with Zwarenstein et al.11 13 community DOT patients and 8 SAT patients changed to clinic DOT; 2 clinic and 1 community DOT patient changed to SAT; 2 clinic DOT changed to community DOT

Unclear

High

Cured; completed treatment; died; failed; defaulted; transferred out

Unclear

Cured; died; failed; defaulted; transferred out; successfully treated Cured; completed treatment; died; failed; defaulted; transferred out Cured; completed treatment; died; failed; transferred out; treatment interrupted

Unclear

Cured; completed treatment; died; failed; transferred out; successfully treated; treatment interrupted

Low

Unclear Low

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APPENDIX 4

RISK OF BIAS IN THE NON-RANDOMISED STUDIES INCLUDED

Author, year, reference Abassi, 20071 Akhtar, 20112

Akkslip, 19993

Al-Honahi, 20104

Anuwatnonthakate, 20085

Balasubramanian, 20006

Barker, 20027

Becx-Bleumink, 20018

Bloss, 20129

Patient inclusion and data source

Patient allocation between DOT strategies

Comparability between DOT groups

Follow-up cohort study of new Patients in rural areas received DOT; Stated that DOT and non-DOT groups smear-positive TB cases patients in adjacent urban areas treated were comparable with non-DOT strategy (SAT) Cohort study with ‘quasiBoth clinic-based and family-based DOT Significant differences between groups experimental’ design were offered; patients decided which in terms of ethnicity, education, strategy to choose household size, income, financial constraints and distance from the clinics Review of patient records and DOT offered to all patients for the initial 2- Stated that demographic variables district registers month phase of treatment; patients and were similar between DOT and nonstaff together decided clinic-based or DOT patients, but was unclear community-based DOT; patients who between groups by different declined DOT received SAT (for observers unknown reasons) Study based on routinely DOT provided to all TB patients; patients Unclear collected records received clinic-based, volunteer-based or family-based DOT depending on distance from health facility and patient preference Cohort study based on Reasons for different DOT strategies Provided details on patient prospectively collected unclear, and varied across health characteristics, indicating some routine medical records providers baseline differences between groups

Review of patient records and patient and staff interviews

All patients reported to have received DOT. Staff and patients interviewed to identify non-adherence to DOT. Authors suspect that staff and patients possibly more likely to admit non-adherence to DOT for cases with failure outcomes Review of patient records All patients received supervised ambulatory care after intensive treatment phase. Nurses and patients discussed and decided on DOT observers according to distance from health facility and patient preference Review of patient records Patients in CBTP (DOT) and non-CBTP villages. CBTP (DOT) was implemented in selected villages with higher-thanaverage treatment results during the previous 2 years Review of patient records from All TB patients offered community-based CDC registration DOT; reasons for non-DOT unknown (See Yen33)

Very limited data provided; reported no significant differences between groups

Unclear

Before implementation of CBTP, treatment results were not statistically significant between CBTP and non-CBTP villages Non-DOT patients tended to be older, male or initially treated with a nonWHO-recommended regimen. DOT patients had higher rate of cavity (see also Yen33) Patients from slums had similar baseline characteristics. For nonslum residents: SAT patients were significantly older, more likely to have HIV infection, be female and have extra-pulmonary TB

Cavalcante, 200710

Retrospective cohort of TB patients based on registry databases

Cayla, 200911

Prospective cohort of TB In Spain, DOTS is a priority only for No details provided, but not likely to be patients receiving standard patients with high risk of bad adherence comparable anti-tuberculosis treatment; (homeless, prisoners, drug users, etc.). data collected via an electronic diary Review of TB case patients TB control programme actively The two groups were comparable in reported to the Philadelphia encouraged and recruited all patients terms of sex, age, HIV infection, Department of Public Health for DOT; however, treatment selection whether or not pulmonary TB and between July 1994 and June ultimately made by treating physician drug resistance. Significantly more 1995 and patient (reasons not provided) Black patients in the DOT group (84% vs. 69%); higher rate of foreign-born (11% vs. 20%) and Asian/Pacific race (8% v 15%) in the SAT group. Authors considered that ‘results are likely robust and minimally influenced by bias’.

Davidson, 199812

Community-based DOT provided in the Rocinha favela; clinic-based DOT provided in the remaining areas of the district. Patients who refused DOT (reasons unknown) were under SAT


APPENDIX 4 Risk of bias due to baseline comparability

vii

(continued)

Adjustment for confounders

Outcomes reported

Risk of bias

Low

Analyses not adjusted

Failed

High (reporting)

Unclear

Cure outcome adjusted using multivariable regression for age, ethnicity, education, household size, income and financial constraints; univariable and multivariable results were similar

Cured; completed treatment; died; failed; defaulted; transferred out; successfully treated

Low

Unclear


Cured; completed treatment; died; failed; defaulted; transferred out; treatment interrupted

Low

High



High (baseline)

Unclear


Low

High

Treatment success outcome adjusted for age, sex, marital status, nationality, mobility, whether or not urban resident, cough, history of drug use, history of incarceration, previous isoniazid therapy, diabetes, HIV infection, chest cavity, sputum positivity and enrolment quarter using multivariate regression analysis Analyses not adjusted

Cured; failed; defaulted

High (baseline)

Unclear


Successfully treated

High (reporting)

High


Cured; completed treatment; died; failed; defaulted; transferred out; successfully treated

High (baseline)

High

Multivariate analyses by factors based on biological plausibility, previous literature and statistical significance in bivariate analysis


High (baseline and reporting)

Slum patients: unclear Non-slum patients: high

Logistic regression for adjusted OR of treatment success; variables included age, sex, site of TB, new case or not, HIV status

Cured; died; failed; defaulted; transferred out

High (non-slum: baseline)

High

Multivariate analysis conducted (for died outcome)

Successfully treated, died.

High (baseline)

Unclear


Successfully treated (based on defined treatment completion); died

Unclear

viii


APPENDIX 4

(continued)

Author, year, reference Dudley, 200313

Islam, 200214 Jasmer, 200415

Jianzhao, 201116

Kironde, 200217

Maciel, 201018

Mafigiri, 201219

Mathema, 200120

Mathew, 200521

Okanurak, 200722

Olle-Goig, 200123

Patient inclusion and data source Records of adult TB patients registered at the clinics in Guguletu area from January 1998 to December 1999


Patients with the nurse in the Guguletu area could choose clinic-based or community-based DOT; nurses tended to keep patients with serious medical or social problems under clinic supervision Data on TB control collected Community DOT provided during the from NTP office in two areas intensive phase to patients in the BRAC area and SAT in other areas Patient charts of incident TB DOT recommended for patients with cases reported in San positive sputum smears, history of Francisco, CA, USA, from homelessness, drug use, HIV infection, 1998 to 2000 alcohol abuse, incarceration, ,21 years or too infirm. Other patients may be assigned SAT Prospective cohort of new Reasons for patients receiving different sputum smear-positive TB DOT or SAT unknown patients registered between January 2007 and June 2007. Patients and staff interviewed to obtain information on treatment received and outcomes Prospective study: patients and Patients asked to choose either clinicobserver interviews and data based or community-based DOT; SAT collection from formal health available when patients were unable to records be treated with DOT (reasons unknown) Prospective cohort of new TB Patients could chose family-based or patients treated from community worker-based DOT November 2004 to March 2007. Data from treatment records and TB laboratory

Comparability between DOT groups No differences observed between sites in terms of the variables shown in age, sex, patient origin, patient category, type of TB, and bacteriological results Socio-economic characteristics were similar between the two areas DOT patients more likely to be male, younger, born in the United States, had HIV infection, were sputum smear-positive, homeless, or drug user, and less likely to have a private medical provider Unclear (baseline characteristics not by DOT)

Unclear (baseline characteristics presented not by DOT) Similar age and sex in both groups, but family group had more illiterate patients (41% vs. 18.7%). Family DOT patients had more culturepositive TB (90.6% vs. 79.5%); community worker DOT group had more patients with sputum smear grades of 2 or 3þ (67% vs. 52%) No significant differences between groups in terms of age, sex, marriage, education and income

Prospective study of new TB Family-based or clinic-based DOT was patients. Data collected by assigned according to patient patient interviews at the clinic preference or at home, and from clinical records Cohort study of newly Patients from different centres that DOT group had more smear-positive registered TB patients; data adopted different DOT approaches: TB, younger patients. More from questionnaire interview clinic-based DOT in National importantly, centres with different and clinical records Demonstration and Training Centres, DOT methods differed with regard mixed DOT in phase-one DOT to funding sources, staff training and implementation centres and non-DOT in motivation, anti-tuberculosis drug other centres supply, laboratory access and other factors Retrospective review of a Patients residing within the area covered Patients were similar in terms of sex, hospital’s patient records by the RNTCP provided communityage and sputum-positive TB. Patients from January 2001 to June based DOT; patients outside this area under family-DOT had to travel 2003 provided home-based DOT. Quality of greater distances for follow-up, and care and payment systems were pay for anti-tuberculosis drugs. different in the two areas Family DOT group had fewer extrapulmonary TB cases (6% vs. 11.2%), more conversions after the intensive phase (88% vs. 76%), fewer new TB cases (56% vs. 72%) and more retreatment cases (44% vs. 28%) than community DOT group Prospective cohort study of Clinic-based DOT initially offered. Family Details on socio-demographic variables newly diagnosed TB patients. or community-based DOT suggested if provided showed some differences Data collected from patient clinic-based DOT not accepted. Patients in sex, age and education between interviews and clinical records treated under SAT if DOT was not DOT groups possible (e.g., worked long hours or lived alone) Retrospective analysis of clinical DOT areas selected according to the Patients’ demographic and clinical records of adult TB patients availability of previously cured TB characteristics similarly distributed in patients able to act as TB supervisors. both groups, with the exception of SAT for the rest of the district age



ix

(continued)


Outcomes reported

Risk of bias

High


Cured; completed treatment; died; failed; transferred out

High (baseline)

Unclear


Cured; completed treatment; died; failed; defaulted

Low

High


Cured; died; failed; transferred out

High (baseline)

Unclear

Logistic regression: DOT no longer associated with cure after adjusting for other factors

Cured

High (reporting)

Unclear



High (reporting)

Unclear


Cured

High (reporting)

Unclear



Low

High



High (baseline)

High


Cured; completed treatment; failed; defaulted; transferred out

High (baseline)

High

Logistic regression analyses used to adjust treatment success ORs for age, sex, educational level, occupation and income


High (baseline)

Low


Cured; completed treatment; died; defaulted; successfully treated

Low

x


APPENDIX 4

(continued)

Author, year, reference Ormerod, 200224

Pungrassami, 200225

Radilla-Chavez, 200726

Singh, 200427

Soares, 200628

Soomro, 201229

Thiam, 200730 van den Boogaard, 200931

Wang, 200932

Yen, 201233,34

Zvavamwe, 2009,35

Patient inclusion and data source Retrospective (1988–1998) and prospective (1999–2000) cases of pulmonary TB in Blackburn, UK From TB registers at 22 TB clinics, prospectively identified cohort of new, smear-positive, pulmonary TB patients who started treatment between February and September 1999. Data from patient records, patient interviews and observers Retrospective analysis of all cases diagnosed with TB and notified to the health jurisdiction of Ensenada, Mexico. Data obtained from patient records. Extrapulmonary TB cases and patients with missing data excluded Patients with new smearpositive TB treated in a TB unit in India between April 2000 and December 2001. Data obtained from patient records Retrospective cohort of patients with new pulmonary TB who started treatment between January 2000 and December 2001. Data obtained from routine clinical records


Comparability between DOT groups

SAT officially recommended, with regular All culture-confirmed TB cases treated checks on compliance. DOT used only with DOT for those who were thought likely to be non-compliant All patients recommended DOT: preferred Unclear (baseline characteristics not by choice in descending order was clinic-, DOT observers) community- and family-based. Lack of suitable observers claimed to be the reason for many patients with non-DOT. However, assigned DOT may differ from practical DOT Patients assigned to DOT or SAT according Mean age: DOT 36.4 vs. SAT 40 years. DOT group had more males (75% to their ability to travel to the health centre (distance) vs. 66%) and fewer rural dwellers (29% vs. 46%) than SAT patients. No significant difference in HIV infection (2.3% vs. 1.2%), substance abuse (16% vs. 11%) and diabetes (8% vs. 10%) Clinic DOT provided when possible. No details provided Community, volunteer-based DOT provided to patients in urban areas that were far from health facilities

DOT offered to all TB patients in the area. DOT patients were younger (37 vs. 38 SAT given to those who refused DOT years) and more likely to be smear-/ and those who were transferred from culture-positive (82 vs. 64), but likely other non-DOT clinics. Main reasons for to be HIV-positive (12 vs. 22) refusing DOT were work-related (incompatible clinic opening times) and difficulties attending the clinic every day due to age-related disability Retrospective cohort of smear- No details provided Baseline characteristics (sex, age and positive TB patients registered urban/rural) were presented; some in 2008 with available differences between DOT observers treatment outcomes; data collected from patient cards and TB register Patients included in the Nurses asked each patient to identify a Unclear (randomisation not by DOT intervention group of a DOT supporter observers) cluster RCT Retrospective cohort of TB TB patients allowed to choose between Community DOT patients more likely patients based on registry clinic-based and community DOT; clinic to be female (64% vs. 36%), aged databases DOT was less popular and mainly used ,15 years. (66% vs. 34%), HIVby in-patients positive (63% vs. 37%), smearpositive pulmonary TB (52 vs. 48%) and new cases (62 vs. 38%) than clinical-based DOT patients Random sample of TB patients Only 8.3% of patients received DOT; no Unclear (baseline characteristics not by who registered in two information about how patients were DOT) Chinese counties and who assigned to DOT or SAT could be contacted by telephone. Data obtained using face-to-face interviews or postal questionnaires Retrospective study of all TB DOT (community-trained observers) DOT patients more likely to have patients in Taipei, Taiwan, provided to all patients who were at positive smears (68% vs. 13%) or diagnosed between 2006 greatest risk for transmitting TB and cultures (90% vs. 45%) and have and 2008. Data obtained those with the severest disease (e.g., cavitary lesions (22% vs. 13%), or using patient interviews smear- or culture-positive) or at highest be unemployed (73% vs. 65%), but risk for treatment failure; SAT assigned less likely to have extra-pulmonary to those who were not provided DOT or TB (1.9% vs. 24.6%) who refused DOT Prospective cohort of TB TB patients allowed to select community No details provided patients discharged from a DOT (92.8%) or clinic DOT/SAT (7.2%) hospital



xi

(continued)

Outcomes reported

Risk of bias

High



Cured, completed, treatment failure, death, treatment interrupted, transfer out, relapse

High (baseline)

Unclear

Logistic regression (including demographic, health services and disease condition covariates) adjusted OR for lack of treatment success

Cured; completed treatment; died; failed; defaulted; successfully treated

Low

Unclear

Logistic regression adjusted OR for treatment failure

Cured; failed

Unclear

Unclear


Cured; died; failed; defaulted; transferred out; successfully treated

Low

High

Logistic regression adjusted OR for treatment success

Cured; died; failed; defaulted; transferred out; successfully treated

High (baseline)

Unclear


Treatment success; unfavourable outcomes (including failure, defaulted and expired cases); transferred out

Unclear

Unclear


Cured; defaulted; successfully treated

Unclear

Unclear

Logistic regression adjusted OR for successful treatment (not different from unadjusted OR)


Low

Unclear

Logistic regression analysis used to adjust for age and sex (treatment completion)

Successfully treated (based on defined treatment completion)

High (reporting)

High

Multivariate analyses were conducted to adjust for potential confounders

Death;33 successfully treated34

High (baseline)

Unclear


Cured; defaulted

Unclear

xii


References of non-randomised studies identified 1 Abassi A, Mansourian A R. Efficacy of DOTS strategy in treatment of respiratory tuberculosis in Gorgan, Islamic Republic of Iran. East Mediterr Health J 2007; 13: 664–669. 2 Akhtar S, Rozi S, White F, Hasan R. Cohort analysis of directly observed treatment outcomes for tuberculosis patients in urban Pakistan. Int J Tuberc Lung Dis 2011; 15: 90–96. 3 Akkslip S, Rasmithat S, Maher D, Sawert H. Direct observation of tuberculosis treatment by supervised family members in Yasothorn Province, Thailand. Int J Tuberc Lung Dis 1999; 3: 1061–1065. 4 Al-Honahi M H Y, Ohkado A, Masui T, Ali-Hussein I A, Saeed Al-Absi A N. A trial to mobilize NGO health volunteers to improve tuberculosis patient care in Sana’a City, Yemen. Kekkaku 2010; 85: 159–162. 5 Anuwatnonthakate A, Limsomboon P, Nateniyom S, et al. Directly observed therapy and improved tuberculosis treatment outcomes in Thailand. PLOS ONE 2008; 3: e3089. 6 Balasubramanian V N, Oommen K, Samuel R. DOT or not? Direct observation of anti-tuberculosis treatment and patient outcomes, Kerala State, India. Int J Tuberc Lung Dis 2000; 4: 409–413. 7 Barker R D, Millard F J, Nthangeni M E. Unpaid community volunteers–effective providers of directly observed therapy (DOT) in rural South Africa. S Afr Med J 2002; 92: 291–294. 8 Becx-Bleumink M, Wibowo H, Apriani W, Vrakking H. High tuberculosis notification and treatment success rates through community participation in central Sulawesi, Republic of Indonesia. Int J Tuberc Lung Dis 2001; 5: 920–925. 9 Bloss E, Chan P C, Cheng N W, et al. Increasing directly observed therapy related to improved tuberculosis treatment outcomes in Taiwan. Int J Tuberc Lung Dis 2012; 16: 462–467. 10 Cavalcante S C, Soares E C, Pacheco A G, Chaisson R E, Durovni B. Community DOT for tuberculosis in a Brazilian favela: comparison with a clinic model. Int J Tuberc Lung Dis 2007; 11: 544–549. 11 Cayla J A, Rodrigo T, Ruiz-Manzano J, et al. Tuberculosis treatment adherence and fatality in Spain. Respir Res 2009; 10: 121. 12 Davidson B L. A controlled comparison of directly observed therapy vs self-administered therapy for active tuberculosis in the urban United States. Chest 1998; 114: 1239–1243. 13 Dudley L, Azevedo V, Grant R, et al. Evaluation of community contribution to tuberculosis control in Cape Town, South Africa. Int J Tuberc Lung Dis 2003; 7 (Suppl 1): S48–S55. 14 Islam M A, Wakai S, Ishikawa N, Chowdhury A M, Vaughan J P. Cost-effectiveness of community health workers in tuberculosis control in Bangladesh. Bull World Health Organ 2002; 80: 445–450. 15 Jasmer R M, Seaman C B, Gonzalez L C, et al. Tuberculosis treatment outcomes: directly observed therapy compared with self-administered therapy. Am J Respir Crit Care Med 2004; 170: 561–566. 16 Jianzhao H, van den Hof S, Xu L, Yubang Q, van der Werf M J. Risk factors for non-cure among new sputum smear positive tuberculosis patients treated in tuberculosis dispensaries in Yunnan, China. BMC Health Serv Res 2011; 11: 97. 17 Kironde S, Meintjies M. Tuberculosis treatment delivery in high-burden settings: does patient choice of supervision matter? Int J Tuberc Lung Dis 2002; 6: 599–608. 18 Maciel E L, Guidoni L M, Brioshi A P, et al. Household members and health care workers as supervisors of tuberculosis treatment. Rev Saude Publica 2010; 44: 339–343. 19 Mafigiri D K, McGrath J W, Whalen C C. Task shifting for

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

tuberculosis control: a qualitative study of community-based directly observed therapy in urban Uganda. Glob Public Health 2012; 7: 270–284. Mathema B, Pande S B, Jochem K, et al. Tuberculosis treatment in nepal: a rapid assessment of government centers using different types of patient supervision. Int J Tuberc Lung Dis 2001; 5: 912–919. Mathew A, Binks C, Kuruvilla J, Davies P D. A comparison of two methods of undertaking directly observed therapy in a rural indian setting. Int J Tuberc Lung Dis 2005; 9: 69–74. Okanurak K, Kitayaporn D, Wanarangsikul W, Koompong C. Effectiveness of DOT for tuberculosis treatment outcomes: a prospective cohort study in Bangkok, Thailand. Int J Tuberc Lung Dis 2007; 11: 762–768. 23 Olle-Goig J E, Alvarez J. Treatment of tuberculosis in a rural area of Haiti: directly observed and non-observed regimens. The experience of Hospital Albert Schweitzer. Int J Tuberc Lung Dis 2001; 5: 137–141. Ormerod L P, Horsfield N, Green R M. Tuberculosis treatment outcome monitoring: Blackburn 1988–2000. Int J Tuberc Lung Dis 2002; 6: 662–665. Pungrassami P, Johnsen S P, Chongsuvivatwong V, Olsen J, Sorensen H T. Practice of directly observed treatment (DOT) for tuberculosis in southern Thailand: comparison between different types of DOT observers. Int J Tuberc Lung Dis 2002; 6: 389–395. Radilla-Chavez P, Laniado-Laborin R. Results of directly observed treatment for tuberculosis in Ensenada, Mexico: not all DOTS programs are created equally. Int J Tuberc Lung Dis 2007; 11: 289–292. Singh A A, Parasher D, Shekhavat G S, et al. Effectiveness of urban community volunteers in directly observed treatment of tuberculosis patients: a field report from Haryana, North India. Int J Tuberc Lung Dis 2004; 8: 800–802. Soares E C, Pacheco A G, Mello F C, et al. Improvements in treatment success rates with directly observed therapy in Rio de Janeiro City. Int J Tuberc Lung Dis 2006; 10: 690–695. Soomro M H, Qadeer E, Khan M A, Morkve O. Treatment supporters and their impact on treatment outcomes in routine tuberculosis program conditions in Rawalpindi District, Pakistan. Tanaffos 2012; 11: 15–22. Thiam S, LeFevre A M, Hane F, et al. Effectiveness of a strategy to improve adherence to tuberculosis treatment in a resourcepoor setting: a cluster randomized controlled trial. JAMA 2007; 297: 380–386. van den Boogaard J, Lyimo R, Irongo C F, et al. Community vs. facility-based directly observed treatment for tuberculosis in Tanzania’s Kilimanjaro Region. Int J Tuberc Lung Dis 2009; 13: 1524–1529. Wang J M, Shen H B. Direct observation and completion of treatment of tuberculosis in rural areas of China. Scand J Public Health 2009; 37: 304–309. Yen Y F, Rodwell T C, Yen M Y, et al. DOT associated with reduced all-cause mortality among tuberculosis patients in Taipei, Taiwan, 2006–2008. Int J Tuberc Lung Dis 2012; 16: 178–184. Yen Y F, Yen M Y, Shih H C, Deng C Y. Risk factors for unfavorable outcome of pulmonary tuberculosis in adults in Taipei, Taiwan. Trans R Soc Trop Med Hyg 2012; 106: 303– 308. Zvavamwe Z, Ehlers V J. Experiences of a community-based tuberculosis treatment programme in Namibia: a comparative cohort study. Int J Nurs Stud 2009; 46: 302–309.

NRS NRS

NRS NRS NRS

NRS NRS NRS NRS NRS

NRS NRS

NRS NRS NRS NRS NRS

Balasubramanian, 20006 Barker, 20027

Becx-Bleumink, 20018 Bloss, 20129 Cayla, 200910

Dudley, 200311 Jasmer, 200412 Jianzhao, 201113 Kironde, 200214 Maciel, 201015

Mathema, 200116 Mathew, 200517

Okanurak, 200718 Ormerod, 200219 Soares, 200620 Wang, 200921 Yen, 201222,23

Thailand UK Brazil China Taiwan

Nepal India

South Africa USA China South Africa Brazil

Indonesia Taiwan Spain

India South Africa

Australia India India Iran Yemen

Country

Clinic DOT vs. community DOT Clinic DOT vs. SAT Clinic DOT vs. family DOT vs. SAT Clinic DOT vs. community DOT vs. SAT Family DOT vs. community non-family DOT Clinic DOT vs. SAT Family DOT vs. community non-family DOT Clinic DOT vs. family DOT vs. SAT Clinic DOT vs. SAT Clinic DOT vs. SAT Clinic DOT vs. family DOT vs. SAT Community DOT vs. SAT

Family DOT vs. SAT Clinic DOT vs. SAT Community DOT vs. SAT Clinic DOT vs. SAT Clinic DOT vs. community DOT vs. family DOT Community DOT vs. SAT Clinic DOT vs. community DOT vs. family DOT Family DOT vs. SAT Community DOT vs. SAT Clinic DOT vs. SAT

Interventions compared

2004–2005 1988–2000 2000–2001 2004–2007 2006–2008

1996–1997 2001–2003

1998–1999 1998–2000 2007 1999–2000 2004–2007

1998 2007–2008 2006–2007

1995–1996 1997–1999

1998–2000 2003 1999–2000 1998–2000 2005–2006

Year of enrolment

6 6 6 8 12

6 6

6 6–7 6 6 6

6 12 6

6 6

6 6 6 6 Not recorded

Follow-up Months

931 205 9 929 531 1 616

759 517

729 372 756 598 171

1 122 11 528 1490

200 888

173 306 379 260 136

Total n

Participants

New TB patients Definitive pulmonary TB New smear-positive TB patients, some with HIV infection Smear-positive/negative TB patients TB patients

New TB patients TB patients

TB patients TB patients Newly diagnosed TB patients, excluded patients with known resistances New smear-positive TB patients TB patients, some with HIV infection, alcoholism New smear-positive TB patients, some with HIV infection New TB patients New TB patients, some with HIV infection

New smear-positive TB patients New smear-positive TB patients

New TB patients New smear-positive TB patients Smear-positive TB patients New smear-positive TB patients New smear-positive TB patients

RCT ¼ randomised controlled trial; DOT ¼ directly observed treatment; SAT ¼self-administered treatment; TB ¼ tuberculosis; NRS ¼ non-randomised studies; HIV ¼ human immunodeficiency virus.

RCT RCT RCT NRS NRS

MacIntyre, 20031 Madhav, 20042 Tandon, 20023 Abassi, 20074 Al-Honahi, 20105

Design

MAIN CHARACTERISTICS OF THE EXCLUDED STUDIES WITH HIGH RISK OF BIAS

Author, year, reference

APPENDIX 5


xiii

xiv


References of excluded studies 1 MacIntyre C R, Goebel K, Brown G V, et al. A randomised controlled clinical trial of the efficacy of family-based direct observation of anti-tuberculosis treatment in an urban, developed-country setting. Int J Tuberc Lung Dis 2003; 7: 848–854. 2 Madhav S M, Kiran N U. A comparative study of DOTS and non-DOTS interventions in tuberculosis cure. Indian J Community Med 2004; 29: 18–19. 3 Tandon M, Gupta M, Tandon S, Gupta K B. DOTS versus self administered therapy (SAT) for patients of pulmonary tuberculosis: a randomised trial at a tertiary care hospital. Indian J Med Sci 2002; 56: 19–21. 4 Abassi A, Mansourian A R. Efficacy of DOTS strategy in treatment of respiratory tuberculosis in Gorgan, Islamic Republic of Iran. East Mediterr Health J 2007; 13: 664–669. 5 Al-Honahi M H Y, Ohkado A, Masui T, Ali-Hussein I A, Saeed Al-Absi A N. A trial to mobilize NGO health volunteers to improve tuberculosis patient care in Sana’a City, Yemen. Kekkaku 2010; 85: 159–162. 6 Balasubramanian V N, Oommen K, Samuel R. DOT or not? Direct observation of anti-tuberculosis treatment and patient outcomes, Kerala State, India. Int J Tuberc Lung Dis 2000; 4: 409–413. 7 Barker R D, Millard F J, Nthangeni M E. Unpaid community volunteers—effective providers of directly observed therapy (DOT) in rural South Africa. S Afr Med J 2002; 92: 291–294. 8 Becx-Bleumink M, Wibowo H, Apriani W, Vrakking H. High tuberculosis notification and treatment success rates through community participation in central Sulawesi, Republic of Indonesia. Int J Tuberc Lung Dis 2001; 5: 920–925. 9 Bloss E, Chan P C, Cheng N W, et al. Increasing directly observed therapy related to improved tuberculosis treatment outcomes in Taiwan. Int J Tuberc Lung Dis 2012; 16: 462–467. 10 Cayla J A, Rodrigo T, Ruiz-Manzano J, et al. Tuberculosis treatment adherence and fatality in Spain. Respir Res 2009; 10: 121. 11 Dudley L, Azevedo V, Grant R, et al. Evaluation of community contribution to tuberculosis control in Cape Town, South Africa. Int J Tuberc Lung Dis 2003; 7 (Suppl 1): S48-S55. 12 Jasmer R M, Seaman C B, Gonzalez L C, et al. Tuberculosis

13

14

15

16

17

18

19

20

21

22

23

treatment outcomes: directly observed therapy compared with self-administered therapy. Am J Respir Crit Care Med 2004; 170: 561–566. Jianzhao H, van den Hof S, Xu L, Yubang Q, van der Werf M J. Risk factors for non-cure among new sputum smear positive tuberculosis patients treated in tuberculosis dispensaries in Yunnan, China. BMC Health Serv Res 2011; 11: 97. Kironde S, Meintjies M. Tuberculosis treatment delivery in high burden settings: does patient choice of supervision matter? Int J Tuberc Lung Dis 2002; 6: 599–608. Maciel E L, Guidoni L M, Brioshi A P, et al. Household members and health care workers as supervisors of tuberculosis treatment. Rev Saude Publica 2010; 44: 339–343. Mathema B, Pande S B, Jochem K, et al. Tuberculosis treatment in nepal: a rapid assessment of government centers using different types of patient supervision. Int J Tuberc Lung Dis 2001; 5: 912–919. Mathew A, Binks C, Kuruvilla J, Davies P D. A comparison of two methods of undertaking directly observed therapy in a rural indian setting. Int J Tuberc Lung Dis 2005; 9: 69–74. Okanurak K, Kitayaporn D, Wanarangsikul W, Koompong C. Effectiveness of DOT for tuberculosis treatment outcomes: a prospective cohort study in Bangkok, Thailand. Int J Tuberc Lung Dis 2007; 11: 762–768. Ormerod L P, Horsfield N, Green R M. Tuberculosis treatment outcome monitoring: Blackburn 1988–2000. Int J Tuberc Lung Dis 2002; 6: 662–665. Soares E C, Pacheco A G, Mello F C, et al. Improvements in treatment success rates with directly observed therapy in Rio de Janeiro City. Int J Tuberc Lung Dis 2006; 10: 690–695. Wang J M, Shen H B. Direct observation and completion of treatment of tuberculosis in rural areas of China. Scand J Public Health 2009; 37: 304–309. Yen Y F, Rodwell T C, Yen M Y, et al. DOT associated with reduced all-cause mortality among tuberculosis patients in Taipei, Taiwan, 2006–2008. Int J Tuberc Lung Dis 2012; 16: 178–184. Yen Y F, Yen M Y, Shih H C, Deng C Y. Risk factors for unfavorable outcome of pulmonary tuberculosis in adults in Taipei, Taiwan. Trans R Soc Trop Med Hyg 2012; 106: 303– 308.

xv


APPENDIX 6 RESULTS OF ALL META-ANALYSES CONDUCTED: DOT FOR TREATING PATIENTS WITH TUBERCULOSIS Table 6.1 Treatment success outcome: results of meta-analysis All identified studies Comparisons

Design

Excluding studies with high risk of bias 2

Studies n

OR (95%CI)

I %

P value

Studies n

OR (95%CI)

I2 %

P value

6 20

1.64 (0.96–2.80) 2.07 (1.28–3.37)

82 98

,0.001 ,0.001

4 8

1.24 (0.89–1.72) 1.78 (1.34–2.37)

43 74

0.156 ,0.001

5 13

2.08 (1.17–3.69) 2.41 (1.23–4.72)

80 98

0.001 ,0.001

3 7

1.45 (1.05–2.02) 1.87 (1.22–2.85)

27 84

0.254 ,0.001

3 16

0.96 (0.53–1.72) 1.37 (1.02–1.83)

25 85

0.264 ,0.001

3 7

0.96 (0.53–1.72) 1.52 (1.18–1.96)

25 38

0.264 0.141

2 17

1.45 (0.82–2.57) 1.44 (1.05–1.98)

42 89

0.189 ,0.001

2 10

1.45 (0.82–2.57) 1.06 (0.83–1.35)

42 51

0.189 0.033

2 6

1.22 (0.92–1.62) 0.66 (0.35–1.24)

39 74

0.202 0.002

2 3

1.22 (0.92–1.62) 0.82 (0.54–1.26)

39 0

0.202 0.400

DOT vs. SAT RCT NRS Community DOT vs. SAT RCT NRS Clinical DOT vs. SAT RCT NRS Community vs. clinical DOT RCT NRS Family vs. non-family DOT RCT NRS

DOT ¼ directly observed treatment; OR ¼ odds ratio; CI ¼ confidence interval; SAT ¼self-administered treatment; RCT ¼randomised controlled trial; NRS ¼ nonrandomised studies.

Table 6.2 Cure outcome: results of meta-analysis All identified studies Comparisons

Design


Studies n

OR (95%CI)

I %

P value

Studies n

OR (95%CI)

I2 %

P value

5 17

1.68 (0.84–3.36) 2.95 (1.91–4.54)

90 96

,0.001 ,0.001

4 8

1.21 (0.82–1.78) 2.20 (1.43–3.39)

60 88

0.056 ,0.001

2 12

1.40 (0.95–2.06) 2.27 (1.56–3.31)

0 89

0.363 ,0.001

2 8

1.40 (0.95–2.06) 2.23 (1.49–3.35)

0 87

0.363 ,0.001

3 14

1.67 (0.28–10.06) 2.46 (1.46–4.14)

95 96

,0.001 ,0.001

2 7

0.71 (0.35–1.42) 1.77 (0.92–3.41)

39 91

0.201 ,0.001

3 14

1.41 (1.00–2.00) 1.26 (0.90–1.77)

28 91

0.248 ,0.001

3 9

1.41 (1.00–2.00) 1.05 (0.76–1.45)

28 82

0.248 ,0.001

1 6

0.74 (0.53–1.04) 0.63 (0.38–1.04)

52

1 3

0.74 (0.53, 1.04) 0.70 (0.44–1.12)

18


— 0.065

— 0.297

OR ¼ odds ratio; CI ¼ confidence interval; DOT ¼ directly observed treatment; SAT ¼self-administered treatment; RCT ¼randomised controlled trial; NRS ¼ nonrandomised studies.

Table 6.3 Death outcome: results of meta-analysis All identified studies Comparisons

Design


Studies n

OR (95%CI)

I %

P value

Studies n

OR (95%CI)

I2 %

P value

4 16

1.40 (0.83–2.35) 0.81 (0.53–1.24)

0 88

0.789 ,0.001

4 7

1.40 (0.83–2.35) 1.00 (0.54–1.85)

0 83

0.789 ,0.001

2 10

2.16 (0.65–7.12) 0.88 (0.50–1.55)

0 91

0.806 ,0.001

2 7

2.16 (0.65–7.12) 1.00 (0.53–1.89)

0 84

0.806 ,0.001

2 14

0.93 (0.07–12.56) 0.80 (0.44–1.46)

23 83

0.254 ,0.001

2 7

0.93 (0.07–12.56) 1.02 (0.45–2.29)

23 60

0.254 0.020

3 13

0.57 (0.11–3.06) 0.93 (0.66–1.30)

81 48

0.006 0.028

3 9

0.57 (0.11–3.06) 1.10 (0.94–1.29)

81 0

0.006 0.806

2 4

0.89 (0.43–1.87) 0.69 (0.17–2.81)

82 72

0.020 0.013

2 3

0.89 (0.43–1.87) 1.33 (0.56–3.17)

82 0

0.020 0.873



xvi


Table 6.4 Treatment failure: results of meta-analysis All identified studies Comparisons

Design


Studies n

OR (95%CI)

I %

P value

Studies n

OR (95%CI)

I2 %

P value

4 14

1.07 (0.45–2.58) 0.89 (0.50–1.56)

0 62

0.874 0.001

4 6

1.07 (0.45–2.58) 1.45 (0.93–2.24)

0 0

0.874 0.870

1 10

1.24 (0.20–7.74) 0.72 (0.30–1.73)

65

— 0.002

1 7

1.24 (0.20–7.74) 1.50 (0.95–2.38)

— 0

0.900

3 12

1.16 (0.22–6.13) 1.25 (0.88–1.78)

0 7

0.445 0.382

3 6

1.16 (0.22–6.13) 1.27 (0.77–2.09)

0 0

0.445 0.824

3 11

0.89 (0.24–3.23) 0.84 (0.48–1.44)

5 26

0.348 0.196

3 8

0.89 (0.24–3.23) 0.88 (0.47–1.67)

5 34

0.348 0.156

1 4

1.00 (0.06–16.07) 0.97 (0.30–3.16)

— 0

0.785

1 3

1.00 (0.06–16.07) 0.67 (0.12–3.82)

— 0

0.689



Table 6.5 Treatment default: results of meta-analysis All identified studies Comparisons

Design


Studies n

OR (95%CI)

I %

P value

Studies n

OR (95%CI)

I2 %

P value

2 11

0.64 (0.35–1.18) 0.45 (0.26–0.76)

73 93

0.054 ,0.001

2 6

0.64 (0.35–1.18) 0.34 (0.20–0.56)

73 72

0.054 0.003

1 9

0.97 (0.61–1.55) 0.31 (0.21–0.44)

— 63

0.006

1 7

0.97 (0.61–1.55) 0.34 (0.22–0.51)

— 68

0.005

0 9

— 0.66 (0.33–1.33)

— 95

,0.001

0 4

— 0.48 (0.20–1.15)

— 89

,0.001

1 12

0.50 (0.15–1.60) 0.79 (0.53–1.18)

— 73

,0.001

1 9

0.50 (0.15–1.60) 0.85 (0.57–1.27)

— 74

,0.001

1 5

0.98 (0.72–1.33) 1.90 (0.42–8.55)

— 87

,0.001

1 3

0.98 (0.72–1.33) 0.87 (0.32–2.32)

— 60

0.081



Table 6.6 Patients who transferred out: results of meta-analysis All identified studies Comparisons

Design


Studies n

OR (95%CI)

I2 %

P value

0.123 0.012

4 5

0.94 (0.40–2.22) 0.46 (0.26–0.84)

48 63

0.123 0.028

49 39

0.161 0.119

2 6

0.58 (0.06–5.80) 0.45 (0.26–0.75)

49 53

0.161 0.058

1.77 (0.74–4.22) 1.03 (0.69–1.55)

0 67

0.933 0.001

2 6

1.77 (0.74–4.22) 0.84 (0.45–1.58)

0 36

0.933 0.169

3 13

0.47 (0.09–2.45) 0.49 (0.33–0.74)

83 71

0.003 ,0.001

3 9

0.47 (0.09–2.45) 0.76 (0.55–1.05)

83 13

0.003 0.329

1 3

0.76 (0.41–1.39) 1.27 (0.27–5.91)

0

1 2

0.76 (0.41–1.39) 1.12 (0.20–6.39)

0

Studies n

OR (95%CI)

I %

P value

4 11

0.94 (0.40–2.22) 0.72 (0.53–0.97)

48 56

2 8

0.58 (0.06–5.80) 0.47 (0.31–0.71)

2 11

DOT vs. SAT RCT NRS Community DOT vs. SAT RCT NRS Clinical DOT vs. SAT RCT NRS Community vs. Clinical DOT RCT NRS Family vs. non-family DOT RCT NRS

— 0.681

— 0.410



APPENDIX 7

FOREST PLOTS FOR TREATMENT SUCCESS AND CURE

Figure 7.1 DOT vs. SAT: forest plot for treatment success. OR ¼ odds ratio; CI ¼ confidence interval; DOT ¼ directly observed treatment; SAT ¼self-administered treatment; RCT ¼randomised controlled trial; NRS ¼ non-randomised studies

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Figure 7.2 DOT vs. SAT: forest plot for cure. OR ¼ odds ratio; CI ¼ confidence interval; DOT ¼ directly observed treatment; SAT ¼self-administered treatment; RCT ¼randomised controlled trial; NRS ¼ non-randomised studies


APPENDIX 8 FUNNEL PLOTS FOR DIFFERENT OUTCOMES: DOT VS. SAT FOR ANTI-TUBERCULOSIS TREATMENT

Figure 8.1

Treatment success. Arcsine-Thompson test P ¼ 0.217; OR ¼ odds ratio

Figure 8.2

Cure rate. Arcsine-Thompson test P ¼ 0.324

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Figure 8.3

Death outcome. Arcsine-Thompson test P ¼ 0.293

Figure 8.4

Treatment failure. Arcsine-Thompson test P ¼ 0.527


Figure 8.5

Treatment default outcome. Arcsine-Thompson test P ¼ 0.476

Figure 8.6

Transferred out. Arcsine-Thompson test P ¼ 0.975

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APPENDIX 9

COMPARISON OF INCLUDED STUDIES WITH PREVIOUS SYSTEMATIC REVIEWS

Author, year, reference Randomised controlled studies Kamolratanakul, 19991 Lwilla, 20032 Newell, 20065 Walley, 20017 Wandwalo, 20048 Wright, 20049 Zwarenstein, 199810 Zwarenstein, 200011 Chaisson, 2001 Malotte, 2001 Tuberculosis Research Centre, Chennai, 1997 MacIntyre, 20033 Madhav, 20044 Tandon, 20026 Non-randomised studies Anuwatnonthakate, 20085 Jasmer, 200415 Okanurak, 200722 Ormerod, 200224 Pungrassami, 200225 Akhtar, 20112 Akkslip, 19993 Cavalcante, 200710 Davidson, 199812 Islam, 200214 Mafigiri, 201219 Olle-Goig, 200123 Radilla-Chavez, 200726 Singh, 200427 Soomro, 201229 Thiam, 200730 van den Boogaard, 200931 Abassi, 20071 Al-Honahi, 20104 Balasubramanian, 20006 Barker, 20027 Becx-Bleumink, 20018 Bloss, 20129 Cayla, 200911 Dudley, 200313 Jianzhao, 201116 Kironde, 200217 Maciel, 201018 Mathema, 200120 Mathew, 200521 Soares, 200628 Wang, 200932 Yen, 2012333,34 Abbate, 2012 Anger, 2010 Banerjee, 2008 Bang, 2010 Bartu, 2007 Bashar, 2001 Bendayan, 2011 Bonilla, 2008 Bonnet, 2011 Brust, 2011 Brust, 2010 Burgos, 2005 Chiang, 2006 Cox, 2007 Datta, 2010 Dhingra, 2008 Escudero, 2006 Farley, 2011

Volmink & Garner, 2007

Pasipanodya & Gumbo, 2013

Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yes

Toczek et al., 2012

Present systematic review Yes Yes Yes Yes Yes Yes Yes Yes No

Yes Yes Yes

Yes

No Yes

No High risk of bias High risk of bias High risk of bias

Yes Yes Yes Yes Yes

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yes High High High Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes High High High High High High High High High High High High High High High High No No No No No No No No No No No No No No No No No No

Reasons for non-inclusion in the present systematic review

TST-positive drug users, patients with active TB excluded TST-positive drug users, patients with active TB excluded Trial comparing different anti-tuberculosis regimens Not included in analysis Not included in analysis Not included in analysis

risk of bias risk of bias risk of bias

Not included in analysis Not included in analysis Not included in analysis

risk risk risk risk risk risk risk risk risk risk risk risk risk risk risk risk

Not included in analysis Not included in analysis Not included in analysis Not included in analysis Not included in analysis Not included in analysis Not included in analysis Not included in analysis Not included in analysis Not included in analysis Not included in analysis Not included in analysis Not included in analysis Not included in analysis Not included in analysis Not included in analysis No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control No DOT/SAT control

of of of of of of of of of of of of of of of of

bias bias bias bias bias bias bias bias bias bias bias bias bias bias bias bias


APPENDIX 9

(continued)

Author, year, reference Ferrara, 2005 Ferrer, 2010 Gammino, 2011 Geerligs, 2000 Gegia, 2012 Gelmanova, 2011 He, 2010 Heller, 2010 Hersi, 1999 Isaakidis, 2011 Jeon, 2009 Jeon, 2011 Joseph, 2011 Karagoz, 2009 Keshavjee, 2008 Khurram, 2012 Kim, 2008 Kim, 2007 Kim, 2001 Kliiman, 2009 Kunawararak, 2011 Kvasnovsky, 2011 Kwon, 2008 Laniado-Laborin, 2012 Leimane, 2010 Liu, 2011 Lockman, 2001 Loveday, 2012 Malla, 2009 Masjedi, 2010 Migliori, 2007 Mitnick, 2003 Mitnick, 2008 Mohammadi, 2008 Munsiff, 2006 Olle-Goig, 2005 Palacios, 2012 Palmero, 2004 Park, 2004 Pawar, 2009 Rao, 2009 Riekstina, 2007 Schecter, 2010 Sharma, 2011 Shean, 2008 Shin, 2010 Singla, 2012 Singla, 2009 Suarez, 2002 Tabarsi, 2011 Tang, 2011 Thomas, 2011 Torun, 2007 Tupasi, 2006 Van Deun, 2004 Vasankari, 2012 Xu, 2012

Volmink & Garner, 2007

Pasipanodya & Gumbo, 2013

Toczek et al., 2012 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Present systematic review No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No

Reasons for non-inclusion in the present systematic review No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No

DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control DOT/SAT control

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RESUME C O N T E X T E : L’efficacité du traitement sous surveillance directe (DOT) en matière de traitement de la tuberculose (TB) fait l’objet de controverses. Cette revue systématique vise a` synthétiser les résultats des e´ tudes qui ont comparé le DOT et le traitement auto-administré (SAT) ou différents types de DOT pour le traitement de la TB. M E´ T H O D E S : De nombreuses bases de données ont e´ té examin e´ es par deux r e´ viseurs inde´ pendants afin d’identifier les e´ tudes randomise´ es (RCT) et nonrandomise´ es pertinentes. Le risque de biais a e´ te´ inde´ pendamment e´ value´ par deux re´ viseurs et les e´ tudes a` haut risque de biais ont e´ t e´ exclues. L’extraction des données a e´ té réalisée par un réviseur et vérifiée par un deuxième réviseur. Les mesures de résultats principaux consistaient en guérison et succès du traitement.

Nous avons inclus 8 RCT et 15 e´ tudes non-randomisées réalisées en majorité dans des pays a` revenu faible et moyen. Il n’a pas e´ té démontré que le DOT en milieu médical e´ tait plus efficace que le SAT. Les conclusions a` la fois des RCT et des e´ tudes nonrandomisées ont suggéré que le DOT en communauté e´ tait plus efficace que le SAT. Ce DOT communautaire e´ tait aussi efficace ou davantage que le DOT en milieu médical. Il n’y avait pas de différence statistiquement significative de résultats entre le DOT communautaire dans la famille ou hors de la famille. C O N C L U S I O N S : Le DOT communautaire par des personnes hors de la famille est peut-être la meilleure option si elle est plus pratique pour les patients et moins onéreuse pour les services de santé que le DOT en milieu médical. R E´ S U LT A T S :

RESUMEN M A R C O D E R E F E R E N C I A: Existe controversia sobre la eficacia del tratamiento antituberculoso directamente observado (DOT). En el presente examen sistema´tico de las publicaciones cient´ıficas se busco´ resumir los datos fidedignos provenientes de estudios que comparan el DOT con el tratamiento autoadministrado (SAT) o diversos tipos de DOT. M E´ T O D O S: Dos investigadores realizaron una busqueda ´ en multiples ´ bases de datos de manera independiente con el objeto de seleccionar los estudios aleatorizados (RCT) o no aleatorizados que fuesen pertinentes. Cada investigador evaluo´ independientemente el riesgo de sesgos en los estudios y se excluyeron los art´ıculos con un alto riesgo. Uno de los investigadores extrajo los datos y el segundo los verifico. ´ Los criterios primarios de evaluacion ´ fueron la curacion ´ y el e´ xito terapéutico. R E S U LT A D O S: Se incluyeron en el ana´lisis ocho estudios

RCT y 15 estudios no aleatorizados, realizados en su mayor´ıa en pa´ıses con ingresos bajos y medianos. No se encontraron datos fehacientes sobre la superioridad del DOT en comparacion ´ con el SAT. Los datos de ambos tipos de estudios indican que el DOT facilitada en la comunidad es ma´s eficaz que el SAT. El DOT comunitario es tan eficaz o ma´s eficaz que el DOT administrado en los consultorios. No se observo´ una diferencia estad´ısticamente significativa en los resultados obtenidos con el DOT facilitada en la comunidad por un familiar o por alguien ajeno a la familia. ´ N: El DOT facilitada en la comunidad por CONCLUSIO personas ajenas a la familia podr´ıa representar la mejor opcion ´ para los pacientes y una mayor disminucion ´ de los costos de los servicios de salud que el DOT administrada en los consultorios.

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