Directly Observed Therapy For Treating Tuberculosis (Review)

Directly observed therapy for treating tuberculosis (Review)
Volmink J, Garner P
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2012, Issue 5 http://www.thecochranelibrary.com
Directly observed therapy for treating tuberculosis (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Direct observation versus self administration, Outcome 1 Cure. . . . . . . . . . Analysis 1.2. Comparison 1 Direct observation versus self administration, Outcome 2 Cure or completion of treatment. Analysis 1.3. Comparison 1 Direct observation versus self administration, Outcome 3 Completion of treatment. . . Analysis 2.1. Comparison 2 Direct observation versus self administration: stratied by location of direct observation, Outcome 1 Cure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.2. Comparison 2 Direct observation versus self administration: stratied by location of direct observation, Outcome 2 Cure or completion of treatment. . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.1. Comparison 3 Direct observation: home versus clinic, Outcome 1 Cure or completion of treatment. . Analysis 4.1. Comparison 4 Home-based direct observation: family member versus community health worker, Outcome 1 Cure or completion of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 5.1. Comparison 5 Intravenous drug users: direct observation versus self administration, Outcome 1 Completion of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 6.1. Comparison 6 Intravenous drug users: choose own location versus treatment centre, Outcome 1 Completion of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 4 4 5 7 7 8 8 11 20 22 23 23 24 25 26 26 27 27 27 28 29 30 30 31 31 31 31
[Intervention Review]
Directly observed therapy for treating tuberculosis

Jimmy Volmink1 , Paul Garner2 for Evidence-based Health Care, Stellenbosch University, Tygerberg, South Africa. 2 International Health Group, Liverpool School of Tropical Medicine, Liverpool, UK Contact address: Jimmy Volmink, Centre for Evidence-based Health Care, Stellenbosch University, PO Box 19063, Tygerberg, 7505, South Africa. jvolmink@sun.ac.za. Editorial group: Cochrane Infectious Diseases Group. Publication status and date: Stable (no update expected for reasons given in Whats new), published in Issue 5, 2012. Review content assessed as up-to-date: 13 August 2007. Citation: Volmink J, Garner P. Directly observed therapy for treating tuberculosis. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003343. DOI: 10.1002/14651858.CD003343.pub3. Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1 Centre
ABSTRACT Background Using a pilot system we have categorised this review as: Current question - no update intended (Results conclusive) Please see Published notes section of the review for more details. For tuberculosis treatment, policies have been introduced to encourage adherence to treatment regimens. One such policy is directly observed therapy (DOT), which involves people directly observing patients taking their antituberculous drugs. Objectives To compare DOT with self administration of treatment or different DOT options for people requiring treatment for clinically active tuberculosis or prevention of active disease. Search methods In May 2007, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2007, Issue 2), MEDLINE, EMBASE, LILACS, and mRCT. We also checked article reference lists and contacted relevant researchers and organizations. Selection criteria Randomized and quasi-randomized controlled trials comparing a health worker, family member, or community volunteer routinely observing people taking antituberculous drugs compared with routine self administration of treatment at home. We include people requiring treatment for clinically active tuberculosis or medication for preventing active disease. Data collection and analysis Both authors independently assessed trial methodological quality and extracted data. Data were analysed using relative risks (RR) with 95% condence intervals (CI) and the xed-effect model when there was no statistically signicant heterogeneity (chi square P > 0.1). Trials of drug users were analysed separately.
Directly observed therapy for treating tuberculosis (Review) Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1
Main results Eleven trials with 5609 participants met the inclusion criteria. No statistically signicant difference was detected between DOT and self administration in terms of cure (RR 1.02, 95% CI 0.86 to 1.21, random-effects model; 1603 participants, 4 trials), with similar results for cure plus completion of treatment. When stratied by location, DOT provided at home compared with DOT provided at clinic suggests a possible small advantage with home-based DOT for cure (RR 1.10, 95% CI 1.02 to 1.18; 1365 participants, 3 trials). There was no signicant difference detected in clinical outcomes between DOT at a clinic versus by a family member or community health worker (2 trials), or for DOT provided by a family member versus a community health worker (1326 participants, 1 trial). Two small trials of tuberculosis prophylaxis in intravenous drugs users found no statistically signicant difference between DOT and self administration (199 participants, 1 trial) or a choice of location for DOT for completion of treatment (108 participants, 1 trial). Authors conclusions The results of randomized controlled trials conducted in low-, middle-, and high-income countries provide no assurance that DOT compared with self administration of treatment has any quantitatively important effect on cure or treatment completion in people receiving treatment for tuberculosis.
PLAIN LANGUAGE SUMMARY Directly observing people taking their tuberculosis drugs did not improve the cure rate compared with people without direct monitoring of treatment Using a pilot system we have categorised this review as: Current question - no update intended (Results conclusive). Please see Published notes section of the review for more details. Tuberculosis is a very serious health problem with two million people dying each year, mostly in low-income countries. Effective drugs for tuberculosis have been available since the 1940s, but the problem still abounds. People with tuberculosis need to take the drugs for at least six months, but many do not complete their course of treatment. For this reason, services for people with tuberculosis often use different approaches to encourage people to complete their course of treatment. This review found no evidence that direct observation by health workers, family members, or community members of people taking their medication showed better cure rates that people having self administered treatment. The intervention is expensive to implement, and there appears to be no sound reason to advocate its routine use until we better understand the situations in which it may be benecial.
BACKGROUND
Adherence in tuberculosis management

Effective drugs for tuberculosis have been available since the 1940s, but two million people continue to die each year, mostly in lowincome countries (Dye 1999; Netto 1999). People with tuberculosis require treatment for at least six to eight months. Many nd it difcult to complete their course of treatment and this serves as a major constraint to eradicating the disease (Fox 1958; Addington 1979; Cuneo 1989). Poor adherence to treatment can lead to prolonged infectiousness, drug resistance, relapse of tuberculosis, or even death. Incomplete treatment thus poses a serious risk for the individual as well as the community.
There are three groups of people for whom adherence is important: people under evaluation for suspected tuberculosis (to ensure they complete the diagnostic regimen or start treatment); people receiving prophylaxis (preventive therapy), where antituberculous drugs are given to people exposed to tuberculosis or thought to be at particular risk; and people with diagnosed tuberculosis in whom completion of treatment helps ensure cure. Adherence to a tuberculosis treatment programme requires accessible and appropriate health care. People need to be diagnosed correctly, provided with information about their disease and the need for completion of treatment, and supplied with appropriate outpatient drugs. But even where these services are available, people may not adhere to the intended regimen. Healthcare providers have responded by developing a variety of specic measures to improve
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adherence (Cuneo 1989; CDC 1993; Sbarbaro 1994). These interventions are aimed at inuencing the behaviour of healthcare personnel, the organization of the service, or the behaviour of the person with suspected or conrmed tuberculosis. Originally we included all these interventions in one Cochrane Review, but this approach did not allow us to consider the particulars of each of the following interventions, and why in one set of circumstances it may be effective and another it may not. This Cochrane Review is one of several planned or in progress to evaluate each type of intervention: Directly observed therapy (DOT): an appointed agent (health worker, community volunteer, family member) directly monitors people swallowing their antituberculous drugs (this review). Staff motivation and supervision: training and management processes that aim to improve how providers care for people with tuberculosis. Reminder systems and late patient tracers in the diagnosis and management of tuberculosis: routinely reminding patients to keep an appointment and actions taken when patients fail to keep an appointment (Liu 2007). Education and counselling for promoting adherence to the treatment of active tuberculosis: provision of information or oneto-one or group counseling about tuberculosis and the need to attend for treatment (MImunya 2007). Incentives and reimbursements: money or cash in kind to reimburse expenses of attending services, or to improve the attractiveness of visiting the service. Contracts: written or verbal agreements to return for an appointment or course of treatment (Bosch-Capblanch 2007). Peer assistance: people from the same social group helping someone with tuberculosis return to the health service by prompting or accompanying them.
sive recipient of advice and treatment (Donovan 1992; Sumartojo 1993); resource implications for such a policy are substantial, particularly in low-income and middle-income countries where the case load is high; and it may make adherence worse if it is rigidly applied in an authoritarian setting or where people are expected to travel considerable distances to have their treatment supervised
Programmes that include DOT

Over the years DOT has come to mean much more than the supervised swallowing of drugs, causing considerable confusion. In the USA, DOT programmes are complex and consist of several components including social support, housing, food tokens, and jail for recalcitrant people (ATS 1992; Volmink 2000b). The World Health Organization (WHO) promotes another version of DOT called directly observed therapy, short course (DOTS). This is a comprehensive tuberculosis management programme that focuses on low-income countries. DOTS is a ve-element strategy for the control of tuberculosis that consists of political commitment, improved laboratory analysis, direct patient observation while swallowing each dose of medication, a drug supply that provides for the correct complete short course antituberculous drug combination for free, and a reporting system that documents the progress in curing the patient (WHO 1997). The WHO believes that direct observation is a key element for the success of DOTS and has retained it in more recent denitions of the DOTS strategy, although their documentation has clearly taken into account criticisms of their blanket policy. For example, the WHO states that the third component of their expanded strategic framework is standardized short-course chemotherapy to all cases of TB [tuberculosis] under proper case-management conditions including direct observation of treatment (WHO 2002). The 2004 progress report mentions direct observation for at least the rst two months of treatment (WHO 2004). Even so, how this is interpreted in countries varies, and direct observation by a health worker remains national policy in China, for example. In contrast, we have previously suggested that the benets associated with DOT programmes found in observational studies may be attributable to simultaneous inputs rather than direct observation specically (Volmink 1997a). An informed debate is important because direct observation has considerable resource implications; it therefore important to determine how important this intervention is for improving adherence to tuberculosis treatment and ensuring cure. Since our initial Cochrane Review (Volmink 1997b), which documented the absence of randomized controlled trials of DOT, several trials have been conducted aimed at disaggregating the effects of this specic intervention from those of accompanying inputs, and they are included in this review update. Not only is there a debate about whether DOT is effective, there is also a debate about who should provide this. This may be contingent practically on an individuals circumstances, but the specialists are divided in their recommendations: some consider family
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DOT
DOT seeks to improve the adherence of people to tuberculosis treatment through health workers, family members, or community members directly observing them taking their antituberculous drugs. This approach was rst adopted in studies in Madras, India, and Hong Kong as early as the 1960s (Bayer 1995), and a number of specialists now widely recommend DOT for the control of tuberculosis (Bass 1994; Maher 1997; Chaulk 1998; Enarson 2000). Indeed, Frieden and Sbarbaro state that it is essential and that it prevents relapse occurring and drug resistance developing (Frieden 2007). The advantages of DOT are that people can be closely monitored and that there is a social process with peer pressure that may improve adherence. On the other hand, the disadvantages associated with DOT are that it moves away from adherence models of communication with cooperation between patient and provider back to a traditional medical approach with the patient as the pas-
members can help, whereas others regard family observation as a seductive but risky concept (Frieden 2007). We therefore also summarize trials comparing DOT through different providers and settings.
Types of outcome measures
Primary
Cure. Completion of treatment. Development of clinical tuberculosis (in trials of drug prophylaxis).
OBJECTIVES
To compare DOT with self administration of treatment or different DOT options for people requiring treatment for clinically active tuberculosis or prevention of active disease.
Secondary
Keeping outpatient appointments.
Search methods for identication of studies METHODS

We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).
Criteria for considering studies for this review

Databases We searched the following databases using the search terms and strategy described in Appendix 1: Cochrane Infectious Diseases Group Specialized Register (May 2007); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2007, Issue 2); MEDLINE (1966 to May 2007); EMBASE (1974 to May 2007); and LILACS (1982 to May 2007). We also searched the metaRegister of Controlled Trials (mRCT) using tuberculosis AND DOT* (May 2007).
Types of studies Randomized and quasi-randomized controlled trials.
Types of participants People requiring treatment for clinically active tuberculosis or medication for preventing active disease (prophylaxis or preventive therapy).
Researchers and organizations For unpublished and ongoing trials, we contacted individual researchers working in the eld and the following organizations: World Health Organization (1997 and 2004), the International Union Against Tuberculosis and Lung Disease (IUATLD) (1997), and the Centers for Disease Control and Prevention (1997).
Types of interventions
Intervention
Reference lists We also checked the reference lists of all studies identied by the above methods.
Health worker, family member, or community volunteer routinely observes participants taking their antituberculous drugs.
Control
Data collection and analysis
Routine self administration of treatment at home, with intermittent clinic visits for drugs with or without treatment adherence checks. Where researchers explored different methods of implementing direct observation, the experimental method was allocated to the intervention group and the standard method to the control.
Selection of studies Both authors independently applied the inclusion criteria to all identied trials. We used the titles and abstracts of the identied citations to exclude trials that clearly did not meet the inclusion
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criteria. If either author judged that the trial might be eligible for inclusion, we obtained the full paper. We independently screened the full articles of selected trials to conrm eligibility and resolved any disagreements by discussion.
2003); and two in the USA that examined prophylaxis in intravenous drug users (Chaisson 2001; Malotte 2001). Two trials were cluster randomized (Lwilla 2003; Newell 2006). One trial used a quasi-random method of allocation (MacIntyre 2003).
Data extraction and management We independently extracted the data and checked whether authors had conducted an intention-to-treat analysis. Trialists were contacted to supply missing information and to clarify issues. We resolved discrepancies through discussion.
Services for general populations
DOT versus self administration of treatment
Assessment of risk of bias in included studies We independently evaluated the methodological quality of each trial, classifying the generation of allocation sequence and concealment of allocation as adequate, inadequate, or unclear according to Jni 2001. We classied blinding as adequate if steps were taken to ensure the people recording the main outcome of the study were blind to the assigned interventions and inadequate if this was not the case or if there was no mention of attempts to blind the observers. We assessed completeness of follow up as adequate if 90% or more, inadequate if less than 90%, or unclear if not mentioned.
Five trials compared DOT with self administration of treatment. There is some overlap of data in two of these trial reports, but we have taken this into account in the analyses: Zwarenstein 1998 combined data from two communities in which trials compared direct observation by nurses at clinics with self administration of treatment, while Zwarenstein 2000 described data from one of these trials that had three arms of direct observation by nurses, lay health workers, and self administration. Kamolratanakul 1999 allowed participants to choose between DOT by a health worker, community leader, or family member; most chose the latter. Walley 2001 compared DOT by a health worker or community health worker with DOT by a family member and with self administration of treatment. MacIntyre 2003 evaluated DOT by a family member.
Data synthesis We used Review Manager 5 to analyse the data, using relative risk (RR) with 95% condence intervals (CI) to assess estimates of effect. We used the xed-effect model when there was no statistically signicant heterogeneity (chi square P > 0.1).
Alternative DOT delivery options
A cluster-randomized trial from Tanzania (Lwilla 2003) compared a community health worker observing people at home with DOT at a health facility. Three trials compared DOT by a family member with either DOT by a health worker at a health facility (Wandwalo 2004) or DOT by a community health worker (Wright 2004; Newell 2006).
RESULTS
Services for intravenous drug users
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies. Eleven trials with 5609 participants met the inclusion criteria (see Characteristics of included studies). Twelve studies that initially seemed to t the inclusion criteria were eventually excluded from our review; reasons for these decisions are provided in the Characteristics of excluded studies. Eight of the 11 trials were conducted in low-income and middle-income countries and evaluated DOT for treating people with active tuberculosis: Pakistan (Walley 2001); South Africa (Zwarenstein 1998; Zwarenstein 2000); Tanzania (Lwilla 2003; Wandwalo 2004); Nepal (Newell 2006); Thailand ( Kamolratanakul 1999); and Swaziland (Wright 2004). Three trials were in high-income countries: one in Australia (MacIntyre
Two trials from the USA evaluated DOT in drug users on prophylaxis for latent tuberculosis (Chaisson 2001; Malotte 2001). Malotte 2001 studied intravenous and crack cocaine users, and compared DOT by an outreach worker at a site chosen by the participant (with or without a US$5 at each visit) with DOT at a community clinic with a US$5 at each visit. Chaisson 2001 involved intravenous drug users, and studied DOT by an outreach nurse with self administration either with monthly peer support or monthly clinic visits.
Outcomes
The numbers of people cured, cured and completed treatment, or completed treatment were the main outcomes assessed in the included trials.
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Adjustment for clustering
Both cluster trials adjusted for clustering appropriately: standard error of the coefcients for clustering on units corrected using the Huber-White-Sandwich method (Lwilla 2003); and, in Newell 2006, using the coefcient of variation between clusters.
Risk of bias in included studies

See Table 1 for a summary of the assessment.
Generation of allocation sequence Seven trials used adequate methods computer-generated random sequences (Zwarenstein 1998; Zwarenstein 2000; Walley 2001; Chaisson 2001), a random-number table (Kamolratanakul 1999), coin tossing (Wandwalo 2004), and random draws of paper from a basket (Newell 2006). One trial used alternate allocation, an inadequate method (MacIntyre 2003). The remaining trial reports did not provide information (Malotte 2001; Lwilla 2003; Wright 2004).
Treatment outcomes were similar among participants in the DOT and self administration of treatment arms. There was no statistically signicant difference between the interventions for the number of people cured (1603 participants, 4 trials, Analysis 1.1), cured or completed treatment (1603 participants, 4 trials, Analysis 1.2), or completed treatment (173 participants, 1 trial, Analysis 1.3). There was signicant heterogeneity between the trials for cure (chi squared 8.41; df = 3), but the point estimate of the RR was close to one, and no difference was demonstrated with either xed-effect or random-effects models (Analysis 1.1). We explored whether different effect sizes were associated with home-based and clinic-based DOT. Effect size was similar in the two groups (Analysis 2.1 and Analysis 2.2 ). Home-based DOT was strongly inuenced by the trial from Thailand ( Kamolratanakul 1999), and there was a statistically signicant improvement in cure, but the difference was small (RR 1.10, 95% CI 1.02 to 1.18; 1365 participants, 3 trials, Analysis 2.1).
DOT: family member or community health worker versus at clinic
Allocation concealment Four trials employed adequate methods for concealing allocation (Zwarenstein 1998; Zwarenstein 2000; Walley 2001; Malotte 2001). Allocation concealment was unclear in three trials (Chaisson 2001; Lwilla 2003; Wright 2004) and not used in the remaining trials (MacIntyre 2003; Kamolratanakul 1999; Wandwalo 2004; Newell 2006).
Wandwalo 2004 found cure or treatment completion to be similar for those observed by a family member compared with a health worker (587 participants, 1 trial, Analysis 3.1). A cluster-randomized trial, Lwilla 2003, which evaluated DOT by a community health worker, found no difference for sputum conversion at two months (OR 0.62, 95% CI 0.23 to 1.71) or cure at the end of treatment (OR 1.58, 95% CI 0.32 to 7.88; trial authors adjusted for design effects).
Blinding Outcome assessment was blind in only four trials (Walley 2001; MacIntyre 2003; Wright 2004; Newell 2006).
DOT: family member versus by a community health worker
Completeness of follow up In two trials, more than 10% of participants were excluded from the analysis (Chaisson 2001; Lwilla 2003). A further four trials did not provide sufcient information to assess this aspect of study quality (Zwarenstein 2000; Malotte 2001; Walley 2001; MacIntyre 2003). In the rest of the trials follow up was adequate.
Wright 2004 found no statistically signicant difference in the number of people cured or who completed treatment (1326 participants, Analysis 4.1. A cluster-randomized trial, Newell 2006, which compared community-based DOT by a community health worker or village health worker with family-based DOT, found no statistically signicant difference in success rates (cure and treatment completion) (85% vs 89%; OR 0.67, 95% CI 0.41 to 1.10; trial authors adjusted for design effects).
2. Services for intravenous drug users Chaisson 2001 found no statistically difference in the number of people who completed twice-weekly clinic-based DOT and those on daily self administration of treatment (199 participants, Analysis 5.1). For participants receiving prophylaxis, Malotte 2001 studied people receiving prophylaxis and found no statistically signicant difference in the number who completed treatment between those allowed to choose their DOT location and those receiving DOT at a community clinic (108 participants, Analysis 6.1).
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Effects of interventions
1. Services for general public
DOT versus self administration of treatment
DISCUSSION
Direct observation of people taking their antituberculous drugs is widely advocated and forms part of the World Health Organizations directly observed therapy, short course (DOTS) strategy. While this strategy includes a number of useful components, the available evidence does not provide strong support for the routine adoption of direct observation in favour of self administration of treatment either for people with active tuberculosis or those with latent tuberculosis requiring prophylaxis. There is also no evidence that one form of direct observation is better than another: direct, randomized comparisons between clinic-based DOT and community-based DOT did not demonstrate a difference; and, within community-based DOT, comparisons between DOT provided by a family member versus a community health worker had similar outcomes. Given the prevailing support for DOT-based programmes, these ndings are important. We have previously suggested that the benets associated with DOT programmes in observational studies may be attributable to simultaneous interventions rather than direct observation being the key adherence-promoting strategy (Volmink 2000b). A qualitative study notes that the implementation of DOT is in the process of shifting from being a rigid model involving observation of drug swallowing to one that includes an array of incentives and enablers for supporting the patient (Macq 2003). Within such a package of patient-centred interventions it remains to be established whether direct observation is necessary at all. Of interest in this regard are the ndings of a cluster-randomized trial in a rural South Africa in which motivation and support from a lay health worker (with or without DOT) was shown to be more effective in ensuring treatment than a conventional DOTbased service (Clarke 2005). People with tuberculosis are often poor and encounter numerous barriers to treatment adherence. Strategies aimed at reducing social and health system barriers may therefore be preferable to coercive approaches that impact negatively on patient autonomy. The encouraging results of a recent trial in Senegal using a multifaceted approach to address these challenges, which also included a exible approach to DOT, lend support to this notion (Thiam 2007). Further rigorous trials, in particular those testing interventions social and family barriers to adherence, are needed (Garner 2007). One of the trials included in our review found a modest improvement with DOT for cure and treatment completion (Kamolratanakul 1999), and one may speculate about the reasons for these ndings. The Thai health system is relatively well resourced and has a tuberculosis control programme that is well organized. This is in contrast to the trials in South Africa (Zwarenstein 1998; Zwarenstein 2000) and Pakistan (Walley 2001) where the trials were conducted in areas with high disease burden, overcrowded tuberculosis clinics, and poorly motivated staff. On the other hand, DOT did not improve treatment completion rates in either Australia (MacIntyre 2003) or the USA (Chaisson 2001;
Malotte 2001), both of which are low burden, highly resourced settings. A second reason one might posit is that cultural responses to supervision may vary with Thai people being more responsive to this approach. Finally, Kamolratanakul 1999 is so far the only trial to have allowed participants to choose their supervisor, and this patient-centred approach may also have inuenced the effects. Can adopting a DOT policy make adherence worse? The authors of the South African trial suggest an increasingly negative and demoralizing effect of direct observation on participants with tuberculosis (Zwarenstein 1998). This trial found that in participants with a rst episode of tuberculosis, the outcomes were equivalent in DOT and self administration of treatment arms, while retreatment participants who were assigned to DOT fared worse than those who self administered treatment. Given the small numbers of participants in the retreatment group, further research is warranted to conrm the ndings. Bias could have inuenced the results in some of the trials. As outlined in the methodological quality assessment, the number of trials with adequate quality criteria was limited: four with adequate method for concealing treatment allocation; four with blinding of the outcome assessors; and two trials that excluded more than 10% of participants from the analysis. Nevertheless, these trials are not easy to implement and are a credit to the researchers who have worked hard to develop the evidence base for rational decision making.
AUTHORS CONCLUSIONS Implications for practice

Randomized controlled trials provide no assurance that the routine use of DOT in low- and middle-income countries improves cure or treatment completion in people with tuberculosis. There is also no rigorous evidence to support the use of DOT for prophylaxis in people with latent tuberculosis. There appears to be no sound reason to advocate the allocation of resources to the routine use of DOT until we better understand the situations in which it may be benecial. In the meantime, it could reasonably be argued that resources should be invested in interventions that have been shown to be effective for improving adherence, such as providing patient motivation and support, incentives, and defaulter action.
Implications for research

The relation between DOT and treatment outcome is complex. Factors that determine its usefulness in various settings require further study. The extent to which the quality of interaction between patients and their observers inuences outcome would be a particularly fruitful topic for future research. It will also be worth
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testing whether DOT efcacy differs in people receiving tuberculosis treatment for the rst time compared with those requiring retreatment, and in men compared with women. Comparisons of DOT in relation to other strategies aimed at improving adherence should be determined.
ACKNOWLEDGEMENTS
To the Global Health Council and the Department of Arts, Culture, Science and Technology of South Africa for supporting Jimmy Volmink in the preparation of the review in the period before the 2006 update. This document is an output from a project funded by the UK Department for International Development (DFID) for the benet of developing countries. The views expressed are not necessarily those of DFID.
REFERENCES
References to studies included in this review

Chaisson 2001 {published data only} Chaisson RE, Barnes GL, Hackman J, Watkinson L, Kimbrough L, Metha S, et al.A randomized, controlled trial of interventions to improve adherence to isoniazid therapy to prevent tuberculosis in injection drug users. American Journal of Medicine 2001;110(8):6105. Kamolratanakul 1999 {published data only} Kamolratanakul P, Sawert H, Lertmaharit S, Kasetjaroen Y, Akksilp S, Tulaporn C, et al.Randomized controlled trial of directly observed treatment (DOT) for patients with pulmonary tuberculosis in Thailand. Transactions of the Royal Society of Tropical Medicine and Hygiene 1999;93(5): 5527. Lwilla 2003 {published data only} Lwilla F, Schellenberg D, Masanja H, Acosta C, Galindo C, Aponte J, et al.Evaluation of efcacy of communitybased vs. institutional-based direct observed short-course treatment for the control of tuberculosis in Kilombero district, Tanzania. Tropical Medicine and International Health 2003;8(3):20410. MacIntyre 2003 {published data only} MacIntyre CR, Goebel K, Brown GV, Skull S, Starr M, Fullinfaw RO. A randomised controlled trial of the efcacy of family-based direct observation of anti-tuberculosis treatment in an urban, developed-country setting. International Journal of Tuberculosis and Lung Disease 2003; 7(9):84854. Malotte 2001 {published data only} Malotte CK, Hollingshead JR, Larro M. Incentives vs outreach workers for latent tuberculosis treatment in drug users. American Journal of Preventive Medicine 2001;20(2): 1037. Newell 2006 {published data only} Newell JN, Baral SC, Pande SB, Bam DS, Malla P. Familymember DOTS and community DOTS for tuberculosis control in Nepal: cluster-randomised controlled trial. Lancet 2006;367(9514):9039. Walley 2001 {published data only} Khan MA, Walley JD, Witter SN, Imran A, Safdar N. Costs and cost-effectiveness of different DOT strategies for
the treatment of tuberculosis in Pakistan. Health Policy and Planning 2002;17(2):17886. Walley JD, Khan MA, Newell JN, Khan MH. Effectiveness of direct observation component of DOTS for tuberculosis: a randomised controlled trial in Pakistan. Lancet 2001;357 (9275):6649. Wandwalo 2004 {published data only} 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. International Journal of Tuberculosis and Lung Disease 2004;8(10):124854. Wright 2004 {published data only} Wright J, Walley J, Phillip A, Pushpananthan S, Dlamini E, Newell J, et al.Direct observation of treatment for tuberculosis: a randomized controlled trial of community health workers versus family members. Tropical Medicine and International Health 2004;9(5):55965. Zwarenstein 1998 {published data only} Zwarenstein M, Schoeman JH, Vundule C, Lombard CJ, Tatley M. Randomised controlled trial of self-supervised and directly observed treatment of tuberculosis. Lancet 1998;352(9137):13403. Zwarenstein 2000 {published data only} Zwarenstein M, Schoeman JH, Vundule C, Lombard CJ, Tatley M. A randomised trial of lay health workers as direct observers for treatment of tuberculosis. International Journal of Tuberculosis and Lung Disease 2000;4(6):5504.
References to studies excluded from this review

Batki 2001 {published data only} Batki SL, Gruber VA, Bradley JM, Bradley M, Delucchi K. A controlled trial of methadone treatment combined with directly observed isoniazid for tuberculosis prevention in injection drug users. Drug and Alcohol Dependence 2002;66 (3):28393. Carroll 2004 {published data only} Carroll K, Malefoasi G. Comparison of outcomes from a district tuberculosis control programme in the Pacic: before and after the implementation of DOTS. Tropical Doctor 2004;34(1):114.
8
Hwang 2004 {published data only} Hwang TG, Kim SD, Yoo SH, Shin YC. Sputum smear conversion during mDOT. Tuberculosis and Respiratory Diseases 2004;56:48594. Jasmer 2004 {published data only} Jasmer RM, Seaman CB, Gonzalez LC, Kawamura LM, Osmond DH, Daley CL. Tuberculosis treatment outcomes: directly observed therapy compared with self-administered therapy. American Journal of Respiratory and Critical Care Medicine 2004;170(5):5616. Lewin 2004 {published data only} Lewin S, Dick J, Zwarenstein M, Lombard CJ. Staff training and ambulatory tuberculosis outcomes: a cluster randomized controlled trial in South Africa. Bulletin of the World Health Organization 2005;83(4):2509. Mathew 2002 {published data only} Matthew AJ, Eicher A, Davies PD. Comparison of hospital checked directly observed therapy with family supervised and unchecked tuberculosis treatment in a rural setting in North India. European Respiratory Journal 2002;20 Suppl 38:215. Moulding 2001 {published data only} Moulding TS, Caymittes M. Managing medication compliance of tuberculosis patients in Haiti with medication monitors. International Journal of Tuberculosis and Lung Disease 2002;6(4):3139. Pungrassami 2002 {published data only} Pungrassami P, Chongsuvivatwong V. Are health personnel the best choice for directly observed treatment in southern Thailand? A comparison of treatment outcomes among different types of observers. Transactions of the Royal Society of Tropical Medicine and Hygiene 2002;96(6):6959. Pungrassami P, Johnsen SP, Chongsuvivatwong V, Olsen J. Has directly observed treatment improved outcomes for patients with tuberculosis in southern Thailand?. Tropical Medicine and International Health 2002;7(3):2719. Sorete-Abore 2002 {published data only} Sorete-Arbore A, Mihaescu T. Three years of DOTS strategy in Iasi county, Romania. European Respiratory Journal 2002; 20 Suppl 38:217. Tandon 2002 {published data only} Tandon M, Gupta M, Tandon S, Gupta KB. DOTS versus self adminstered therapy (SAT) for patients with pulmonary tuberculosis: a randomised trial at a tertiary care hospital. Indian Journal of Medical Science 2002;56(1):1921. Thiam 2007 {published data only} Thiam S, LeFevre AM, Hane F, Ndiaye A, Ba F, Fielding KL, et al.Effectiveness of a strategy to improve adherence to tuberculosis treatment in a resource-poor setting: a cluster randomized controlled trial. JAMA 2007;297(4):3806. Toyota 2003 {published data only} Toyota E, Kobayashi N, Houjou M, Yoshizawa A, Kawana A, Kudo K. Usefulness of directly observed therapy (DOT) during hospitalization as DOTS in Japanese style. Kekkaku 2003;78(9):5815.
Additional references
Addington 1979 Addington WW. Patient compliance: The most serious remaining problem in the control of tuberculosis in the United States. Chest 1979;76 Suppl 6:7413. ATS 1992 American Thoracic Society/Centers for Disease Control and Prevention. Control of tuberculosis in the United States. American Review of Respiratory Disease 1992;146(6): 162333. Bass 1994 Bass JB Jr, Farer LS, Hopewell PC, OBrien R, Jacobs RF, Ruben F, et al.Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and The Centers for Disease Control and Prevention. American Journal of Respiratory and Critical Care Medicine 1994;149(5):135974. Bayer 1995 Bayer R, Wilkinson D. Directly observed therapy for tuberculosis: history of an idea. Lancet 1995;345(8964): 15458. Bosch-Capblanch 2007 Bosch-Capblanch X, Abba K, Prictor M, Garner P. Contracts between patients and healthcare practitioners for improving patients adherence to treatment, prevention and health promotion activities. Cochrane Database of Systematic Reviews 2007, Issue 2. [DOI: 10.1002/ 14651858.CD004808.pub3] CDC 1993 Centers for Disease Control and Prevention (CDC). Approaches to improving adherence to antituberculosis therapy--South Carolina and New York, 1986-1991. Morbidity and Mortality Weekly Report 1993;42(4):74-5, 81. Chaulk 1998 Chaulk CP, Kazandjian VA. Directly observed therapy for treatment completion of pulmonary tuberculosis: Consensus Statement of the Public Health Tuberculosis Guidelines Panel. JAMA 1998;279(12):9438. Clarke 2005 Clarke M, Dick J, Zwarenstein M, Lombard CJ, Diwan VK. Lay health worker intervention with choice of DOT superior to standard TB care for farm dwellers in South Africa: a cluster randomised control trial. International Journal of Tuberculosis and Lung Disease 2005;9(6):6739. Cuneo 1989 Cuneo WD, Snider DE Jr. Enhancing patient compliance with tuberculosis therapy. Clinics in Chest Medicine 1989; 10(3):37580. Donovan 1992 Donovan JL, Blake DR. Patient non-compliance: Deviance or reasoned decision-making?. Social Science and Medicine 1992;34(5):50713. Dye 1999 Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis:
9
estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 1999;282(7):67786. Enarson 2000 Enarson DA, Rieder HL, Arnadottir T, Trebucq A. Management of tuberculosis: a guide for low income countries. 5th Edition. Paris: International Union Against Tuberculosis and Lung Disease, 2000. Fox 1958 Fox W. The problem of self-administration of drugs: with particular reference to pulmonary tuberculosis. Tubercle 1958;39(5):26974. Frieden 2007 Frieden TR, Sbarbaro JA. Promoting adherence to treatment for tubercuoisis: the importance of direct observation. Bulletin of the World Health Organization 2007;85(5): 4079. Garner 2007 Garner P, Smith H, Munro S, Volmink J. Promoting adherence to tuberculosis treatment. Bulletin of the World Health Organization 2007;85(5):4049. Higgins 2006 Higgins J, Green S, editors. Highly sensitive search strategies for identifying reports of randomized controlled trials in MEDLINE. Cochrane Handbook for Systematic Reviews of Interventions 4.2.6 [updated September 2006]; Appendix 5b. www.cochrane.org/resources/handbook/ hbook.htm (accessed 1 May 2007). Jni 2001 Jni P, Altman DG, Egger M. Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ 2001;323(7303):426. Liu 2007 Liu Q, Abba K, Alejandria MM, Balanag VM, Berba RP, Lansang MA. Reminder systems and late patient tracers in the diagnosis and management of tuberculosis (Protocol). Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/14651858.CD006594] MImunya 2007 MImunya MJ, Volmink J. Education and counselling for promoting adherence to the treatment of active tuberculosis (Protocol). Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/14651858.CD006591; : ] Macq 2003 Macq JC, Theobald S, Dick J, Dembele M. An exploration of the concept of directly observed treatment (DOT) for tuberculosis patients: from a uniform to a customised approach. International Journal of Tuberculosis and Lung Disease 2003;7(2):1039. Maher 1997 Maher D, Chaulet P, Spinaci S, Harries A. Treatment of tuberculosis: guidelines for national programmes. 2nd Edition. Geneva: World Health Organization, 1997.
Netto 1999 Netto EM, Dye C, Raviglione MC. Progress in global tuberculosis control 1995-1996, with emphasis on 22 highincidence countries. Global Monitoring and Surveillance Project. International Journal of Tubercle and Lung Disease 1999;3(4):31020. Review Manager 5 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008. Sbarbaro 1994 Sbarbaro JA, Sbarbaro JB. Compliance and supervision of chemotherapy of tuberculosis. Seminars in Respiratory Infections 1994;9(2):1207. Sumartojo 1993 Sumartojo E. When tuberculosis treatment fails, a social behavioural account of patient adherence. American Review of Respiratory Disease 1993;147(5):131120. Volmink 1997a Volmink J, Garner P. Directly observed therapy [letter]. Lancet 1997;349(9062):1399400. Volmink 2000b Volmink J, Matchaba P, Garner P. Directly observed therapy and treatment adherence. Lancet 2000;355(9212): 134550. WHO 1997 WHO Global Tuberculosis Programme. TB : WHO report on the tuberculosis epidemic 1997. Geneva: World Health Organization, 1997. WHO 2002 WHO Global Tuberculosis Programme. An expanded DOTS framework for effective tuberculosis control: stop TB communicable diseases. World Health Organization: Geneva, 2002. WHO 2004 World Health Organization, Stop TB Dept. Progress report on the global plan to stop tuberculosis. Geneva: World Health Organization, 2004.
References to other published versions of this review

Volmink 1997b Volmink J, Garner P. Systematic review of randomised controlled trials of strategies to promote adherence to tuberculosis treatment. BMJ 1997;315(7120):14036. Volmink 2000a Volmink J, Garner P. Interventions for promoting adherence to tuberculosis management. Cochrane Database of Systematic Reviews 2000, Issue 4. [DOI: 10.1002/ 14651858.CD000010] Volmink 2001 Volmink J, Garner P. Directly observed therapy for treating tuberculosis. Cochrane Database of Systematic Review 2001, Issue 4.[Art. No.: CD003343. DOI: 10.1002/ 14651858.CD003343.pub3]
10
Volmink 2003 Volmink J, Garner P. Directly observed therapy for treating tuberculosis. Cochrane Database of Systematic Reviews 2003, Issue 1. [DOI: 10.1002/14651858.CD003343] Volmink 2006 Volmink J, Garner P. Directly observed therapy for treating tuberculosis. Cochrane Database of Systematic Reviews 2006, Issue 2. [DOI: 10.1002/14651858.CD003343] Indicates the major publication for the study
11
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Chaisson 2001 Methods Generation of allocation sequence: randomized, with factorial overlay; computer-generated random numbers Allocation concealment: not stated Blinding: none Completeness of follow up: 88% Number: 300 randomized; 73% men; 85% unemployed; 27% with documented human immunodeciency virus (HIV) infection Included: adult, intravenous drug users with positive tuberculin skin test (at least 10 mm induration or 5 mm if HIV positive); given isoniazid preventive therapy for 6 months Excluded: people with active tuberculosis 1. Directly observed therapy (DOT) twice weekly by outreach nurse at clinic or community location 2. Daily self administration of treatment, monthly peer counselling group meetings with lunch, and clinical assessments by a nurse; peer counsellor was a former injection user who had completed preventive therapy, and who was trained in counselling and supervised by a health educator 3. Daily self administration of treatment with monthly clinic assessment; factorial design with immediate or deferred US$10 stipend at the end of each month; deferred payments credited each month and given when treatment completed or participant withdrew 1. 6 months treatment completed, dened as 80% or more of treatments taken (observed for DOT group and 6 monthly visits plus reporting that at least 80% medication taken during a month for other groups) 2. Pill counts 3. Isoniazid metabolites in the urine 4. Electronically monitored bottle opening in a subset Location: Baltimore City Health Department TB Clinic, USA Date: 1995-7 Duration of DOT duration not stated
Participants
Interventions
Outcomes
Notes
Kamolratanakul 1999 Methods Generation of allocation sequence: central block random allocation scheme prepared for each of 15 study sites; random-number table used Allocation concealment: none Blinding: no blinding of assessors Completeness of follow up: 100% (no losses) Number: 837 randomized; 73% male Included: new smear positive adults (aged 15+) 1. Daily supervision: participants chose their supervisor from (a) health centre staff, (b) community members, or (c) family members; for (b) and (c) health workers visited homes twice monthly (rst 2 months) or monthly for checking of treatment cards, pill counts, and urine tests
12
Participants
Interventions
Kamolratanakul 1999
(Continued)
2. Self administration of treatment: 1 month drug supply given at diagnosis and after each follow-up visit; no treatment supervision between visits All participants received the same drug regimen: isoniazid-rifampicin-pyrazinamide-ethambutol for 2 months and isoniazid-rifampicin for 4 months Outcomes 1. Cure rate (primary outcome): completed 6 months antituberculous therapy, with 2 negative sputum exams, 1 at end of treatment 2. Treatment completion: completed 6 months antituberculous therapy but less than 2 sputum exams 3. Sputum conversion rate: negative sputum at end of third month 4. Percentage defaults 5. Percentage transfers 6. Caseholding rate Location: Thailand Date: 1996-7 Duration of Directly observed therapy (DOT) not stated Informed consent not obtained as participants were not told that they were participating in a study Choice of supervisor for DOT participants: 352 chose a family member; 34 chose a community member; and 24 chose health centre staff One participant in daily supervision arm excluded due to protocol violation so not strictly intention-to-treat
Notes
Lwilla 2003 Methods Cluster-randomized controlled trial: 9 pairs of centres matched by type and size Generation of allocation sequence: unclear Allocation concealment: unclear Blinding: none Completeness of follow up: 87% at 2 months and 69% at 7 months Number: 18 clusters randomized; 522 participants; mean age 35; 60% male Included: new smear positive adults 1. Community-based directly observed therapy (DOT): daily observation by community health volunteer (site not stated) for intensive 2-month treatment period; health worker visited volunteer every 2 weeks and district co-ordinator visited volunteer monthly; at each visit participants treatment card checked and drugs counted 2. Institution-based DOT: required to attend health facility daily for 2 months, and then monthly after this Continuation phase of 6 months: both groups managed the same and expected to self administer treatment daily 1. Sputum negative at 2 months (primary outcome) 2. Cure at 7 months (sputum negative at 2 months and at 5 to 7 months) Location: Tanzania Date: 1999-2000 Duration of DOT not stated
Participants
Interventions
Outcomes
Notes
13
MacIntyre 2003 Methods Quasi-randomized controlled trial Generation of allocation sequence: alternate allocation Concealment of allocation: none Blinding: assessment of urinary isoniazid blinded Completeness of follow up: not stated Number: 173 recruited, mostly foreign nationals; male 51%; mean age 41 (range 14 to 83) Included: new tuberculosis participants Excluded: multiple-drug resistant tuberculosis; relapsed tuberculosis; human immunodeciency virus (HIV)-positive cases; and nontuberculous mycobacterial infections 1. Family-based directly observed therapy (DOT): daily observation by a nominated family member who received education and was expected to record participant compliance with pill taking; weekly phone calls from a nurse; nurse on call; nurse home visit every 2 weeks 2. Self administration of treatment: daily Both groups had monthly visits to health facilities and standardized recording charts Treatment completion measured by: 1. Percentage clinic attendances to collect drugs 2. Urinary isoniazid (6 random checks over months; all had to be > 0) Location: Australia Date: 1998 to December 2000 Duration of DOT not stated
Participants
Interventions
Outcomes
Notes
Malotte 2001 Methods Generation of allocation sequence: randomized, blocks of 18 Allocation concealment: sequentially numbered, opaque, sealed envelopes Blinding: none Completeness of follow up: not stated Number: 163 randomized; 82% male Included: active or recent injection or crack cocaine users screened for tuberculosis with positive tuberculin skin test (at least 10 mm induration or 5 mm if human immunodeciency virus (HIV)-positive) Excluded: people with active tuberculosis 1. Directly observed therapy (DOT) by outreach worker (location decided by participant) plus US$5 at each visit 2. As (1) but no money 3. DOT at study community site plus US$5 All participants received isoniazid 2 times a week for 6 months or 1 year (depending on HIV status) 1. Percentage medication taken on time; excludes medication taken late (next day) 2. Completion of medication Location: Long Beach, California, USA Date: 1994-7 Lost to follow up included prison or moved and were included in outcome (1) but excluded completely from outcome
14
Participants
Interventions
Outcomes
Notes
Malotte 2001
(Continued)
(2)
Newell 2006 Methods Cluster-randomized controlled trial Generation of allocation sequence: 5 randomly selected districts allocated to each arm; the name of each district was written on an individual paper and randomly drawn from a basket Allocation concealment: method not stated Blinding: laboratory technicians assessing the primary outcomes were blinded Completeness of follow up: 100% (no clusters or individuals lost) Number: 10 districts with 907 people randomized; all smear positive; 67% male Included: people with tuberculosis (aged 15+); new smear-positive cases, diagnosed at health facilities in the study area; human immunodeciency virus (HIV) status not known 1. Community-based directly observed therapy (DOT): daily treatment supervised by a female community health worker (unpaid volunteer selected by the district health authority) or village health worker (community worker paid by government). Patients mainly visited at home, but occasionally patients met their supervisor at her home. Supervision was for the duration of treatment with drugs provided to the supervisor monthly. Tracing by the supervisor was undertaken for patients who discontinued treatment 2. Family-based DOT: daily supervision by a household member chosen by the participant with drugs provided to the supervisory weekly. Government workers traced those who discontinued treatment 1. Treatment success: cure plus treatment completion [primary] 2. Treatment success compared with the World Health Organization target of 85% 3. Estimated case detection rate with the World Health Organization target of 70% 4. Compare the above rates in men and women Location: hill and mountain districts of Nepal Date: 2002-3
Participants
Interventions
Outcomes
Notes
Walley 2001 Methods Generation of allocation sequence: computer-generated random numbers Allocation concealment: opaque, sealed envelopes Blinding: assessors blinded Completeness of follow up: not stated Number: 497 randomized; 51.3% male Included: adults (aged 15+); new smear-positive cases 1. Directly observed therapy (DOT) by a health worker at a health facility that met access criteria or a community health worker at or near the participants home: access criteria were return journey from the participants home to facility < 2 km, < 2 h duration, and < 10 rupees, and for unmarried women an accompanying relative was available; participants had to attend a health facility or meet a community health worker 6 times per week for 2 months to take their drugs; thereafter they self administered drugs that the participants collected twice a month 2. DOT by a family member chosen by the participant 3. Self administration of drugs collected by participant fortnightly
15
Participants
Interventions
Walley 2001
(Continued)
All participants received isoniazid-rifampicin-pyrazinamide-ethambutol for 2 months and isoniazid-ethambutol for 6 months Outcomes 1. Cure: sputum negative at 7 or 8 months and on at least 1 previous occasion 2. Treatment completion: treatment completed, but smear results not available on at least 2 occasions before completion of treatment 3. Treatment failure 4. Death 5. Default 6. Transferred out Location: Pakistan Date: 1996-8
Notes
Wandwalo 2004 Methods Generation of allocation sequence: coin tossing in each of 5 clinics Allocation concealment: none Blinding: none Completeness of follow up: 100% (no losses) Number: 587 randomized; 322 smear positive, 182 smear negative, and 83 extrapulmonary tuberculosis; 57% male Included: people with tuberculosis (aged 5+); new smear positive, smear negative, and extrapulmonary cases; human immunodeciency virus (HIV) status not known Excluded: previously treated for tuberculosis; severe illness; transferred from another clinic; previously enrolled in the study 1. Community-based directly observed therapy (DOT): daily treatment supervised at home by guardian (usually a family member) during 2-month intensive period; supervisors trained to observe drug taking, encourage participants to complete treatment, keep records, collect drugs, and assess drug side effects; during rst 2 months participants received spot visits by health workers who conducted treatment card checks and pill counts; during rst 2 months participants also requested to attend clinic every 2 weeks for clinical review and progress monitoring 2. Health facility-based DOT: daily supervision at clinic by health workers during the 2 month intensive period Apart from the observation option participants received the same standardized management including drug therapy 1. Treatment success: cure plus treatment completion 2. Cure: smear positive initially and negative at 7 or 8 months and on at least 1 previous occasion 3. Treatment completion: positive results initially, negative at 2 months and no results at end of treatment; or smear negative initially and received treatment on clinical grounds; or those who completed full course of treatment but had no initial or end-of-treatment results 4. Death: from all causes 5. Treatment failure: participants who remained or became smear positive or 5 months or later 6. Default: failed to collect medication for > 2 consecutive months 7. Transferred out: transferred to a clinic in another area Location: Dar es Salaam, Tanzania Date: 2001-3
Participants
Interventions
Outcomes
Notes
16
Wright 2004 Methods Generation of allocation sequence: unclear; stratied into adults and children; then, within each group, randomized by type of tuberculosis (sputum positive, sputum negative, extrapulmonary, relapse) Allocation concealment: unclear; sealed, sequentially numbered envelopes not stated if opaque Blinding: assessors of sputum results blinded Completeness of follow up: 98% Number: 1353 randomized; 55% male; most 15+ years Included: adults and children with smear positive or negative, extrapulmonary tuberculosis, or relapse of previously treated tuberculosis Excluded: died before discharge; or too ill to receive outpatient treatment; lived in area without treatment supporter; or referred in after treatment commenced 1. Directly observed therapy (DOT) by community health worker: participants visited for observation daily; community health worker trained to provide daily treatment supervision, record adherence on Treatment Support Card, remind participants who did not report for treatment, and notify diagnostic centre about those who defaulted treatment 2. DOT by family member: family member or carer chosen by participant trained to provide daily treatment supervision, record adherence on Treatment Support Card, and remind participants who did not report for treatment; participants also required to visit the community health worker weekly to check side effects and adherence and receive health education; defaulters reported to the diagnostic centre 1. Cure or treatment completion: cure dened as smear negative at 6 months and on at least 1 previous occasion; treatment completion dened as treatment completed but smear results not available on at least 2 occasions before treatment completion 2. Death 3. Treatment failure: remained or became smear positive at > = 5 months 4. Default: failed to collect medication for > 2 consecutive months 5. Transferred out: formally transferred to another centre Location: Swaziland Date: 2000-2
Participants
Interventions
Outcomes
Notes
Zwarenstein 1998 Methods Generation of allocation sequence: computer-generated random numbers Allocation concealment: consecutively numbered, opaque, sealed envelopes in each of 5 clinics Blinding: none Completeness of follow up: 114/120 (95%) in 1 trial and 102/120 (85%) in other trial excluded from analysis Number: 216 included in analysis; 62% male; 57% < 35 years Included: adults (aged 15+) with pulmonary tuberculosis; both new and retreatment cases Excluded: severe disease or multiple drug resistance; treatment at a non-study clinic for more than 2 weeks; need to be supervised at school or at the workplace; and leaving the area within a month 1. Directly observed therapy (DOT) by clinic nurses: participants asked to visit the clinic 5 days a week for 8 weeks (new participants) or for 12 weeks (retreatment participants); thereafter expected attendance was 3 days a week for the continuation phase; clinic visits restricted to normal working hours and adherence card signed and dated by a nurse at each visit and kept at the clinic 2. Self administration of treatment: participants had to visit clinic once a week or send a relative to collect drugs;
17
Participants
Interventions
Zwarenstein 1998
(Continued)
participants completed their own adherence card for every day of drug taking and a nurse recorded the weekly drug collection; adherence card handed to nurse at the weekly clinic visit New cases received Rifater (combined rifampicin-isoniazid-pyrazinamide) for 8 weeks followed by Rinah 4 (combined rifampicin-isoniazid) plus additional isoniazid for 18 weeks Retreatment participants received Rifater plus ethambutol for 12 weeks and Rinah plus rifampicin-ethambutol for 22 weeks Outcomes 1. Successful treatment included those who were cured and those who completed treatment; cured applied to those who converted from a positive smear and/or culture to a negative smear and/or culture at the end of treatment (6 months for new participants and 8 months for retreatment participants); treatment completed referred to participants who (a) completed the full course of treatment but had no pretreatment or post-treatment bacteriological results; (b) had negative pretreatment results and had been treated on clinical grounds; or (c) had positive pretreatment results, negative results after 2 months and no post-treatment results 2. Treatment failure applied to participants with a positive smear or culture at the end of treatment 3. Treatment interrupters applied to participants who stopped taking treatment for 8 or more weeks during the treatment period 4. Transfer to another treatment facility 5. Death from tuberculosis or other causes while on treatment Location: 1 trial in each of 2 low-income communities near Cape Town, South Africa Date: 1994-5 Results combined 54 participants in 1 trial allocated to community supervision not reported in this paper Exclusions from analysis: trial 1 (6 cases of multiple drug resistance) and trial 2 (12 cases of multiple drug resistance and 6 not tuberculosis) Number of exclusions per arm of the 2 trials not given
Notes
Zwarenstein 2000 Methods Generation of allocation sequence: computer-generated random numbers Allocation concealment: consecutively numbered, opaque, sealed envelopes Blinding: none Completeness of follow up: not stated Number: 174 randomized Included: new or retreatment participants aged 15+ who were sputum or culture positive 1. Directly observed therapy (DOT) by clinic nurses (see Zwarenstein 1998) 2. Self administration (see Zwarenstein 1998) 3. DOT by lay health workers: participants took drugs at home of a lay health worker under supervision; if participant missed treatment for 1 day, a lay health worker visited participants home and if necessary a member of the South African Tuberculosis Association (SANTA) also visited the participant As for Zwarenstein 1998 Location: 4 clinics in a township near Cape Town, South Africa Date: 1994-5 18 participants excluded from analysis: 12 with multiple-drug resistant tuberculosis and 6 not tuberculosis
Participants
Interventions
Outcomes Notes
18
Characteristics of excluded studies [ordered by study ID]
Study Batki 2001
Reason for exclusion Compared direct observation plus with methadone treatment for injecting drug users with routine tuberculosis treatment without methadone Before-and-after study; no control group Not randomized Different criteria for allocation to self administration or direct observation An educational intervention was evaluated Cohort study Trial evaluating devices that monitor treatment using uranium along a strip of photographic lm 2 publications reporting the same study; not randomly allocated Cohort study Described as a randomized trial, but the randomization led to very different numbers in the 2 groups; subsequently over 50 participants (out of a total of 379) crossed over from self treatment to direct observation and were excluded from the analysis; little detail for the rest of the study provided Multifaceted intervention including directly observed therapy Patients in hospital
Carroll 2004 Hwang 2004 Jasmer 2004 Lewin 2004 Mathew 2002 Moulding 2001 Pungrassami 2002 Sorete-Abore 2002 Tandon 2002
Thiam 2007 Toyota 2003
19
DATA AND ANALYSES
Comparison 1. Direct observation versus self administration
Outcome or subgroup title 1 Cure 2 Cure or completion of treatment 3 Completion of treatment
No. of studies 4 4 1
No. of participants 1603 1603
Statistical method Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Effect size 1.02 [0.86, 1.21] 1.06 [1.00, 1.13] Totals not selected
Comparison 2. Direct observation versus self administration: stratied by location of direct observation
Outcome or subgroup title 1 Cure 1.1 Direct observation at home 1.2 Direct observation at clinic 2 Cure or completion of treatment 2.1 Direct observation at home 2.2 Direct observation at clinic
No. of studies 4 3 2 3 3 2
No. of participants
Statistical method Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)
Effect size Subtotals only 1.10 [1.02, 1.18] 0.88 [0.72, 1.06] Subtotals only 1.09 [1.02, 1.16] 0.92 [0.78, 1.08]
1365 444
1365 444
Comparison 3. Direct observation: home versus clinic
Outcome or subgroup title 1 Cure or completion of treatment
No. of studies 1
No. of participants
Statistical method Risk Ratio (M-H, Fixed, 95% CI)
Effect size Totals not selected
20
Comparison 4. Home-based direct observation: family member versus community health worker
Outcome or subgroup title 1 Cure or completion of treatment
No. of studies 1
No. of participants
Comparison 5. Intravenous drug users: direct observation versus self administration
Outcome or subgroup title 1 Completion of treatment
No. of studies 1
No. of participants
Comparison 6. Intravenous drug users: choose own location versus treatment centre
Outcome or subgroup title 1 Completion of treatment
No. of studies 1
No. of participants
21
Analysis 1.1. Comparison 1 Direct observation versus self administration, Outcome 1 Cure.
Review: Directly observed therapy for treating tuberculosis
Comparison: 1 Direct observation versus self administration Outcome: 1 Cure Study or subgroup DOT n/N Kamolratanakul 1999 Walley 2001 Zwarenstein 1998 Zwarenstein 2000 315/414 199/335 18/53 55/112 Self n/N 283/422 100/162 31/61 18/44 Risk Ratio MH,Random,95% CI Weight Risk Ratio MH,Random,95% CI 1.13 [ 1.04, 1.24 ] 0.96 [ 0.83, 1.12 ] 0.67 [ 0.43, 1.05 ] 1.20 [ 0.80, 1.79 ]
41.5 % 34.2 % 11.2 % 13.1 %
Total (95% CI)

Total events: 587 (DOT), 432 (Self)
914
689
100.0 %
1.02 [ 0.86, 1.21 ]
Heterogeneity: Tau2 = 0.02; Chi2 = 8.41, df = 3 (P = 0.04); I2 =64% Test for overall effect: Z = 0.21 (P = 0.84) Test for subgroup differences: Not applicable
0.2
0.5 Favours self
Favours DOT
22
Analysis 1.2. Comparison 1 Direct observation versus self administration, Outcome 2 Cure or completion of treatment.
Comparison: 1 Direct observation versus self administration Outcome: 2 Cure or completion of treatment
Study or subgroup
DOT n/N
Self n/N 320/422 105/162 37/61 26/44
Risk Ratio M-H,Fixed,95% CI
Weight
Kamolratanakul 1999 Walley 2001 Zwarenstein 1998 Zwarenstein 2000
347/414 216/335 27/53 73/112
59.8 % 26.7 % 6.5 % 7.0 %
1.11 [ 1.03, 1.18 ] 0.99 [ 0.87, 1.14 ] 0.84 [ 0.60, 1.17 ] 1.10 [ 0.83, 1.46 ]
Total (95% CI)

914
689
100.0 %
1.06 [ 1.00, 1.13 ]
Heterogeneity: Chi2 = 4.25, df = 3 (P = 0.24); I2 =29% Test for overall effect: Z = 1.80 (P = 0.071) Test for subgroup differences: Not applicable
0.5
0.7
1.5
Favours self
Favours DOT
Analysis 1.3. Comparison 1 Direct observation versus self administration, Outcome 3 Completion of treatment.
Comparison: 1 Direct observation versus self administration Outcome: 3 Completion of treatment
Study or subgroup
DOT n/N
Self n/N 78/86
Risk Ratio M-H,Fixed,95% CI 1.06 [ 0.98, 1.15 ]
MacIntyre 2003
84/87
0.5
0.7
1.5
Favours self
Favours DOT
23
Analysis 2.1. Comparison 2 Direct observation versus self administration: stratied by location of direct observation, Outcome 1 Cure.
Comparison: 2 Direct observation versus self administration: stratied by location of direct observation Outcome: 1 Cure
Study or subgroup
DOT n/N
Self n/N
Weight
1 Direct observation at home Kamolratanakul 1999 Walley 2001 Zwarenstein 2000 315/414 161/269 31/54 283/422 100/162 18/44 66.0 % 29.4 % 4.7 % 1.13 [ 1.04, 1.24 ] 0.97 [ 0.83, 1.13 ] 1.40 [ 0.92, 2.14 ]
Subtotal (95% CI)

737
628
100.0 %
1.10 [ 1.02, 1.18 ]
Heterogeneity: Chi2 = 4.30, df = 2 (P = 0.12); I2 =53% Test for overall effect: Z = 2.45 (P = 0.014) 2 Direct observation at clinic Walley 2001 Zwarenstein 1998 38/66 42/111 100/162 49/105 53.5 % 46.5 % 0.93 [ 0.73, 1.19 ] 0.81 [ 0.59, 1.11 ]
Subtotal (95% CI)

177
267
100.0 %
0.88 [ 0.72, 1.06 ]
Heterogeneity: Chi2 = 0.50, df = 1 (P = 0.48); I2 =0.0% Test for overall effect: Z = 1.34 (P = 0.18)
0.2
0.5 Favours self
Favours DOT
24
Analysis 2.2. Comparison 2 Direct observation versus self administration: stratied by location of direct observation, Outcome 2 Cure or completion of treatment.
Comparison: 2 Direct observation versus self administration: stratied by location of direct observation Outcome: 2 Cure or completion of treatment
Study or subgroup
DOT n/N
self n/N
Weight
1 Direct observation at home Kamolratanakul 1999 Walley 2001 Zwarenstein 1998 347/414 176/269 40/54 320/422 105/162 26/44 66.5 % 27.5 % 6.0 % 1.11 [ 1.03, 1.18 ] 1.01 [ 0.88, 1.16 ] 1.25 [ 0.94, 1.68 ]
Subtotal (95% CI)

Total events: 563 (DOT), 451 (self)
737
628
100.0 %
1.09 [ 1.02, 1.16 ]
Heterogeneity: Chi2 = 2.17, df = 2 (P = 0.34); I2 =8% Test for overall effect: Z = 2.64 (P = 0.0082) 2 Direct observation at clinic Walley 2001 Zwarenstein 1998 40/66 60/111 105/162 63/105 48.4 % 51.6 % 0.94 [ 0.75, 1.17 ] 0.90 [ 0.71, 1.14 ]
Subtotal (95% CI)

Total events: 100 (DOT), 168 (self)
177
267
100.0 %
0.92 [ 0.78, 1.08 ]
Heterogeneity: Chi2 = 0.05, df = 1 (P = 0.82); I2 =0.0% Test for overall effect: Z = 1.04 (P = 0.30)
0.5
0.7
1.5
Favours self
Favours DOT
25
Analysis 3.1. Comparison 3 Direct observation: home versus clinic, Outcome 1 Cure or completion of treatment.
Comparison: 3 Direct observation: home versus clinic Outcome: 1 Cure or completion of treatment
Study or subgroup
Home n/N
Clinic n/N 271/327
Wandwalo 2004
221/260
0.5
0.7
1.5
Favours clinic
Favours home
Analysis 4.1. Comparison 4 Home-based direct observation: family member versus community health worker, Outcome 1 Cure or completion of treatment.
Comparison: 4 Home-based direct observation: family member versus community health worker Outcome: 1 Cure or completion of treatment
Study or subgroup
Family member n/N
Health worker n/N 453/664
Wright 2004
440/662
0.5
0.7
1.5
Favours worker
Favours family
26
Analysis 5.1. Comparison 5 Intravenous drug users: direct observation versus self administration, Outcome 1 Completion of treatment.
Comparison: 5 Intravenous drug users: direct observation versus self administration Outcome: 1 Completion of treatment
Study or subgroup
DOT n/N
Self n/N 79/100
Chaisson 2001
80/99
0.5
0.7
1.5
Favours self
Favours DOT
Analysis 6.1. Comparison 6 Intravenous drug users: choose own location versus treatment centre, Outcome 1 Completion of treatment.
Comparison: 6 Intravenous drug users: choose own location versus treatment centre Outcome: 1 Completion of treatment
Study or subgroup
Own location n/N
Treatment centre n/N 33/55
Malotte 2001
28/53
0.5
0.7
1.5
Favours centre
Favours own choice
27
ADDITIONAL TABLES
Table 1. Risk of bias assessmenta Trial Randomization type Individual Individual Allocation se- Allocation quence generation concealment Adequate Adequate Unclear Inadequate Blinding (assessors) Inadequate Inadequate Completeness follow up Inadequate Adequate of
Chaisson 2001 Kamolratanakul 1999 Lwilla 2003 MacIntyre 2003 Malotte 2001 Newell 2006 Walley 2001 Wandwalo 2004 Wright 2004 Zwarenstein 1998 Zwarenstein 2000
a Details
Cluster Individual Individual Cluster Individual Individual Individual Individual Individual
Unclear Inadequate Unclear Adequate Adequate Adequate Unclear Adequate Adequate
Unclear Inadequate Adequate Inadequate Adequate Inadequate Unclear Adequate Adequate
Inadequate Adequate Inadequate Adequate Adequate Inadequate Adequate Inadequate Inadequate
Inadequate Unclear Unclear Adequate Unclear Adequate Adequate Adequate Unclear
of methods in the Characteristics of included studies.
APPENDICES Appendix 1. Search methods: detailed search strategies
Search set 1 2
CIDG SRa tuberculosis DOT*
CENTRAL tuberculosis
MEDLINEb tuberculosis
EMBASEb tuberculosis
LILACSb tuberculosis
PATIENT COMPLI- PATIENT COMPLI- PATIENT COMPLI- DOT* ANCE ANCE ANCE
28
(Continued)
directly therapy 2 or 3 1 and 4
observed PATIENT PARTICI- PATIENT PARTICI- PATIENT PATION PATION MONITORING patient monitoring MOTIVATION MOTIVATION DOT$
supervision
4 5
2 or 3 observed 1 and 4
DEdirectly CISION SUPPORT therapy TECHNIQUES compliance
DEDOT* CISION SUPPORT TECHNIQUES DOT* directly therapy observed compliance
observed motivation
directly therapy compliance defaulter* adheren* supervision* 2-12/or 1 and 13 -
patient$
9 10 11 12 13 14 15
a Cochrane b Search
patient* defaulter* adheren* supervis* 2-12/or 1 and 13 Limit 14 to human
defaulter$ adheren$ supervis$ 2-11/or 1 and 12 Limit 13 to human -
Infectious Diseases Group Specialized Register. terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2006); upper case: MeSH or EMTREE heading; lower case: free text term.
WHATS NEW
Last assessed as up-to-date: 13 August 2007.
29
Date 11 August 2011
Event Review declared as stable
Description Categorised as Current question - no update intended (results conclusive). See Published notes section for details Pilot classication system added; explanation provided in published notes section
10 August 2011
Amended
HISTORY
Protocol rst published: Issue 4, 2001 Review rst published: Issue 4, 2001
Date 19 September 2008 13 August 2007
Event Amended New citation required and conclusions have changed
Description Converted to new review format with minor editing. 2007, Issue 4: One new trial included (Newell 2006) . Also added references to new tuberculosis adherence reviews in the Background section and reworded objectives to clarify that the review encompasses comparisons between different types of directly observed therapy 2006, Issue 2 (Volmink 2006): Four new trials included (Lwilla 2003; MacIntyre 2003; Wandwalo 2004; Wright 2004). 2003, Issue 1: Two trials added (Chaisson 2001; Malotte 2001). 2001, Issue 4 (Volmink 2001): rst version of this review on directly observed therapy 2000, Issue 4 (Volmink 2000a): original review split into a series of Cochrane Reviews, each focusing on particular intervention promotion strategies, such as directly observed therapy in this review 1997, Issue 2: review rst published as Interventions for promoting adherence to tuberculosis management
15 February 2006
Amended
19 November 2003
New citation required and conclusions have changed
8 August 2001
New citation required and major changes
30
CONTRIBUTIONS OF AUTHORS
Jimmy Volmink initiated the review, wrote the protocol, applied the inclusion criteria, conducted the data extraction, and drafted the review. Paul Garner helped write the protocol, applied the inclusion criteria, constructed comparisons, and helped draft the review. Both authors remain actively involved in updating.
DECLARATIONS OF INTEREST
None known.
SOURCES OF SUPPORT Internal sources

South African Medical Research Council, South Africa. Liverpool School of Tropical Medicine, UK.
External sources
Department for International Development, UK.
NOTES
2011, Issue 9: The Cochrane Infectious Diseases Group are piloting a system to indicate whether the question is currently relevant, and the status of the review with regards to being up to date. For relevance, we classify reviews into: historical question, where an intervention or policy has been superseded by new medical developments (such as a new drug), current question, which are still relevant to current policy or practice. For status, we have three categories, with an explanation after each: up to date; update pending; no update intended. For this review, we have categorised the review as: Current question - no update intended (Results conclusive).
INDEX TERMS
31
Medical Subject Headings (MeSH)

Directly
Observed Therapy; Antitubercular Agents [ therapeutic use]; Randomized Controlled Trials as Topic; Tuberculosis, Pulmonary therapy] [ drug
MeSH check words

Humans
32

Directly Observed Therapy For Treating Tuberculosis (Review)

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Directly observed therapy for treating tuberculosis (Review)

Directly observed therapy for treating tuberculosis

Adherence in tuberculosis management

Programmes that include DOT

Types of outcome measures

Keeping outpatient appointments.

Search methods for identication of studies METHODS

Criteria for considering studies for this review

Types of studies Randomized and quasi-randomized controlled trials.

Data collection and analysis

Services for general populations

DOT versus self administration of treatment

Adjustment for clustering

Risk of bias in included studies

DOT: family member or community health worker versus at clinic

DOT: family member versus by a community health worker

1. Services for general public

DOT versus self administration of treatment

AUTHORS CONCLUSIONS Implications for practice

Implications for research

References to studies included in this review

References to studies excluded from this review

References to other published versions of this review

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Study Batki 2001

Thiam 2007 Toyota 2003

DATA AND ANALYSES

Comparison 1. Direct observation versus self administration

Outcome or subgroup title 1 Cure 2 Cure or completion of treatment 3 Completion of treatment

No. of participants 1603 1603

Comparison 3. Direct observation: home versus clinic

Outcome or subgroup title 1 Cure or completion of treatment

Statistical method Risk Ratio (M-H, Fixed, 95% CI)

Effect size Totals not selected

Outcome or subgroup title 1 Cure or completion of treatment

Statistical method Risk Ratio (M-H, Fixed, 95% CI)

Effect size Totals not selected

Comparison 5. Intravenous drug users: direct observation versus self administration

Outcome or subgroup title 1 Completion of treatment

Statistical method Risk Ratio (M-H, Fixed, 95% CI)

Effect size Totals not selected

Outcome or subgroup title 1 Completion of treatment

Statistical method Risk Ratio (M-H, Fixed, 95% CI)

Effect size Totals not selected

41.5 % 34.2 % 11.2 % 13.1 %

Total (95% CI)

1.02 [ 0.86, 1.21 ]

0.5 Favours self

Self n/N 320/422 105/162 37/61 26/44

Risk Ratio M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

Kamolratanakul 1999 Walley 2001 Zwarenstein 1998 Zwarenstein 2000

347/414 216/335 27/53 73/112

59.8 % 26.7 % 6.5 % 7.0 %

Total (95% CI)

1.06 [ 1.00, 1.13 ]

Comparison: 1 Direct observation versus self administration Outcome: 3 Completion of treatment

Self n/N 78/86