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Referencias

References to studies included in this review

Chaisson 2001 USA {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):610‐5.

Hsieh 2008 TWN {published data only}

Hsieh CJ, Lin LC, Kuo BI, Chiang CH, Su WJ, Shih JF. Exploring the efficacy of a case management model using DOTS in the adherence of patients with pulmonary tuberculosis. Journal of Clinical Nursing 2008;17(7):869‐75.

Kamolratanakul 1999 THA {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):552‐7.

Lwilla 2003 TZA {published data only}

Lwilla F, Schellenberg D, Masanja H, Acosta C, Galindo C, Aponte J, 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. Tropical Medicine and International Health 2003;8(3):204‐10.

MacIntyre 2003 AUS {published data only}

MacIntyre CR, Goebel K, Brown GV, Skull S, Starr M, Fullinfaw RO. A randomised controlled trial of the efficacy 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):848‐54.

Newell 2006 NPL {published data only}

Newell JN, Baral SC, Pande SB, Bam DS, Malla P. Family‐member DOTS and community DOTS for tuberculosis control in Nepal: cluster‐randomised controlled trial. Lancet 2006;367(9514):903‐9.

Walley 2001 PAK {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. Directly Observed Treatment. Health Policy and Planning 2002;17(2):178‐86.
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):664‐9.

Wandwalo 2004 TZA {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):1248‐54.

Wright 2004 SWZ {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):559‐65.

Zwarenstein 1998 ZAF {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):1340‐3.

Zwarenstein 2000 ZAF {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):550‐4.

References to studies excluded from this review

Batki 2002 {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):283‐93.

Carroll 2004 {published data only}

Carroll K, Malefoasi G. Comparison of outcomes from a district tuberculosis control programme in the Pacific: before and after the implementation of DOTS. Tropical Doctor 2004;34(1):11‐4.

Hwang 2004 {published data only}

Hwang TG, Kim SD, Yoo SH, Shin YC. Sputum smear conversion during mDOT. Tuberculosis and Respiratory Diseases 2004;56(5):485‐94.

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):561‐6.

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):250‐9.

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):103‐7.

Matthew 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 2002 {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):313‐9.

Pungrassami 2002a {published data only}

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):271‐9.

Pungrassami 2002b {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):695‐9.

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 administered therapy (SAT) for patients with pulmonary tuberculosis: a randomised trial at a tertiary care hospital. Indian Journal of Medical Science 2002;56(1):19‐21.

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):380‐6.

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):581‐5.

Anuwatnonthakate 2008

Anuwatnonthakate A, Limsomboon P, Nateniyom S, Wattanaamornkiat W, Komsakorn S, Moolphate S, et al. Directly observed therapy and improved tuberculosis treatment outcomes in Thailand. PLoS One 2008;3(8):e3089.

Barbara 2013

Seaworth BJ, Armitige LY, Griffith DE. First do no harm—adverse events, drug intolerance, and hepatotoxicity: how can we not justify directly observed therapy for treating tuberculosis?. Clinical Infectious Diseases 2013;57(7):1063‐4.

Bayer 1995

Bayer R, Wilkinson D. Directly observed therapy for tuberculosis: history of an idea. Lancet 1995;345(8964):1545‐8.

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]

Chan 2002

Chan ED, Iseman MD. Current medical treatment for tuberculosis. BMJ 2002;325(7375):1282‐6.

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):943‐8.

Chien 2013

Chien JY, Lai CC, Tan CK, Chien ST, Yu CJ, Hsueh PR. Decline in rates of acquired multidrug‐resistant tuberculosis after implementation of the directly observed therapy, short course (DOTS) and DOTS‐Plus programmes in Taiwan. Journal of Antimicrobial Chemotherapy 2013;68(8):1910–6.

Dick 2005

Dick J, Murray E, Botha E. Operations Research Results. The effectiveness of TB DOTS supporters in South Africa. April 2005. https://www.usaidassist.org/sites/assist/files/pnadf972.pdf (accessed 23 January 2014).

Ford 2009

Ford N, Nachega JB, Engel ME, Mills EJ. Directly observed antiretroviral therapy: a systematic review and meta‐analysis of randomised clinical trials. Lancet 2009;374(9707):2064‐71.

Frieden 2003

Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C. Tuberculosis. Lancet 2003;362(9387):887‐99.

Frieden 2007

Frieden TR, Sbarbaro JA. Promoting adherence to treatment for tuberculosis: the importance of direct observation. Bulletin of the World Health Organization 2007;85(5):407‐9.

Gross 2009

Gross R, Tierney C, Andrade A, Lalama C, Rosenkranz S, Eshleman SH, et al. Modified directly observed antiretroviral therapy compared with self‐administered therapy in treatment‐naïve HIV‐1–infected patients: a randomized trial. Archives of Internal Medicine 2009;169(13):1224‐32.

Higgins 2011

Higgins J, Green S (editors). Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org (accessed 20 August 2013).

Hirpa 2013

Hirpa S, Medhin G, Girma B, Melese M, Mekonen A, Suarez P, et al. Determinants of multidrug‐resistant tuberculosis in patients who underwent first‐line treatment inAddis Ababa: a case control study. BMC Public Health 2013;13:782.

Hopewell 2006

Hopewell PC, Pai M, Maher D, Uplekar M, Raviglione MC. International Standards for Tuberculosis Care. Lancet Infectious Diseases 2006;6(11):710‐25.

Jüni 2001

Jüni P, Altman DG, Egger M. Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ 2001;323(7303):42‐6.

Khan 2003

Khan MA, Walley JD, Witter SN, Imran A, Safdar N. Cost and cost effectiveness of different DOT strategies for the treatment of tuberculosis in Pakistan. Directly observed treatment. Health Policy and Planning 2003;17(2):178‐86.

Liu 2008

Liu Q, Abba K, Alejandria MM, Balanag VM, Berba RP, Lansang MAD. Reminder systems and late patient tracers in the diagnosis and management of tuberculosis (Review). Cochrane Database of Systematic Reviews 2008, Issue 4. [DOI: 10.1002/14651858.CD006594.pub2]

Lutge 2012

Lutge EE, Wiysonge CS, Knight SE, Volmink J. Material incentives and enablers in the management of tuberculosis. Cochrane Database of Systematic Reviews 2012, Issue 1. [DOI: 10.1002/14651858.CD007952.pub2]

M'Imunya 2012

M'Imunya JM, Kredo T, Volmink J. Patient education and counselling for promoting adherence to treatment for tuberculosis. Cochrane Database of Systematic Reviews 2012, Issue 5. [DOI: 10.1002/14651858.CD006591.pub2]

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):103‐9.

Mohan 2007

Mohan CI, Bishai D, Cavalcante S, Chaisson RE. The cost‐effectiveness of DOTS in urban Brazil. International Journal of Tuberculosis and Lung Disease 2007;11(1):27‐32.

Moonan 2011

Moonan PK, Quitugua TN, Pogoda JM, Woo G, Drewyer G, Sahbazian B, et al. Does directly observed therapy (DOT) reduce drug resistant tuberculosis?. BMC Public Health 2011;11:19.

Munro 2007

Munro SA, Lewin SA, Smith HJ, Engel ME, Fretheim A, Volmink J. Patient adherence to tuberculosis treatment: a systematic review of qualitative research. PLoS Medicine 2007;4(7):e238.

Pasipanodya 2013

Pasipanodya JG, Gumbo T. A meta‐analysis of self‐administered vs directly observed therapy effect on microbiologic failure, relapse, and acquired drug resistance in tuberculosis patients. Clinical Infectious Diseases 2013;57(1):21‐31.

Review Manager 5 [Computer program]

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Sepkowitz 1995

Sepkowitz KA, Raffalli J, Riley L, Kiehn TE, Armstrong D. Tuberculosis in the AIDS era. Clinical Microbiology Reviews 1995;8(2):180‐99.

Smieja 2010

Smieja M, Marchetti C, Cook D, Smaill FM. Isoniazid for preventing tuberculosis in non‐HIV infected persons. Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/14651858.CD001363]

Steffen 2010

Steffen R, Menzies D, Oxlade O, Pinto M, de Castro AZ, Monteiro P, et al. Patients' costs and cost‐effectiveness of tuberculosis treatment in DOTS and non‐DOTS facilities in Rio de Janeiro, Brazil. PLoS One 2010;5(11):e14014.

Tian 2014

Tian JH,  Lu ZX,  Bachmann MO,  Song FJ. Effectiveness of directly observed treatment of tuberculosis: a systematic review of controlled studies. International Journal Tuberculosis and Lung Disease 2014 September;18(9):1092‐8. [DOI: 10.5588/ijtld.13.0867.]

van den Boogaard 2012

van den Boogaard J, Msoka E, Homfray M, Kibiki GS, Heldens JJ, Felling AJ, et al. An exploration of patients perceptions of adherence to tuberculosis treatment in Tanzania. Qualitative Health Research 2012;22(6):835‐45.

Volmink 2000b

Volmink J, Matchaba P, Garner P. Directly observed therapy and treatment adherence. Lancet 2000;355(9212):1345‐50.

WHO 2002

WHO Global Tuberculosis Programme. An Expanded DOTS Framework for Effective Tuberculosis Control. Stop TB Communicable Diseases. Geneva: World Health Organization, 2002.

WHO 2010

World Health Organization. Treatment of tuberculosis guidelines: Fourth edition. 2010. http://apps.who.int/iris/bitstream/10665/44165/1/9789241547833_eng.pdf?ua=1&ua=1 (accessed 01 August 2014).

WHO 2013

WHO Global TB Programme. Global Tuberculosis Report 2013. http://apps.who.int/iris/bitstream/10665/91355/1/9789241564656_eng.pdf (accessed 01 August 2014).

References to other published versions of this review

Volmink 1997

Volmink J, Garner P. Systematic review of randomised controlled trials of strategies to promote adherence to tuberculosis treatment. BMJ 1997;315(7120):1403‐6.

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 Reviews 2001, Issue 4. [DOI: 10.1002/14651858.CD003343]

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.pub2]

Volmink 2007

Volmink J, Garner P. Directly observed therapy for treating tuberculosis. Cochrane Database of Systematic Reviews 2007, Issue 4. [DOI: 10.1002/14651858.CD003343.pub3]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Chaisson 2001 USA

Methods

Generation of allocation sequence: randomized, with factorial overlay; computer‐generated random numbers.

Allocation concealment: not stated.

Blinding: none.

Completeness of follow‐up: 88%.

Participants

Number: 300 randomized; 73% men; 85% unemployed; 27% with documented human immunodeficiency 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 TB.

Interventions

  1. 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.

Outcomes

  1. 6 months treatment completed, defined 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.

Notes

Location: Baltimore City Health Department TB Clinic, USA.

Date: 1995 to 1997.

Duration of DOT duration not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"generated using computer algorithm".

Allocation concealment (selection bias)

Unclear risk

No details reported.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

None. "Blinding of the study was not possible."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

There were losses to follow‐up in each arm though not differential there are no reports on them.

Selective reporting (reporting bias)

Low risk

All outcomes stated in the methodology are reported.

Other bias

Unclear risk

Not applicable.

Hsieh 2008 TWN

Methods

Generation of allocation sequence: not stated.

Randomization: stratified.

Allocation concealment: not stated.

Blinding: not stated.

Completeness of follow‐up: no losses (18/114) dropped to enable matching.

Participants

Number; 96 randomized into three groups; Matched by age and gender; confirmed TB diagnosis and over 18 yrs.

Interventions

  1. Case manager directly supervised medicine intake for first two months, then self‐administration with weekly unscheduled visit.

  2. Self‐administration with monthly unscheduled visit by the case manager.

  3. Routine care in the ward with monthly visit by case manager.

Outcomes

  1. Monthly adherence levels (>80% or <80%) >80% defined as at most 5 drug interruptions per month.

  2. Completion rate ‐ Proportion of patients who completed the treatment course.

  3. Success rate ‐ Proportion of patients who completed treatment plus confirmed negative sputum result.

Notes

Location: Taiwan.

Trial period: May 2002 to July 2003.

Duration of observation was 6 months.

The patients were not given a choice of DOT observer.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"There were 114 subjects meeting the sampling criteria who were then matched by age and gender and randomized into one of three groups".

Allocation concealment (selection bias)

Unclear risk

No details reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No details reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

18/114 dropped to enable matching.

Selective reporting (reporting bias)

Unclear risk

All outcomes stated in the methodology are reported.

Other bias

Unclear risk

Not applicable.

Kamolratanakul 1999 THA

Methods

Generation of allocation sequence: central block random allocation scheme prepared for each of 15 trial sites; random‐number table used.

Allocation concealment: none.

Blinding: no blinding of assessors.

Completeness of follow‐up: 100% (no losses).

Participants

Number: 837 randomized; 73% male.

Included: new smear positive adults (aged 15+).

Interventions

  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 (first 2 months) or monthly for checking of treatment cards, pill counts, and urine tests.

  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.

Notes

Location: Thailand.

Date: 1996 to 1997.

Duration of

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.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Generated using random number tables.

Allocation concealment (selection bias)

Unclear risk

Inadequate information.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Investigators not blinded though the patients were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

There were no exclusions.

Selective reporting (reporting bias)

Unclear risk

All outcomes stated in the methodology are reported.

Other bias

Unclear risk

Not applicable.

Lwilla 2003 TZA

Methods

Cluster‐RCT: 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.

Participants

Number: 18 clusters randomized; 522 participants; mean age 35; 60% male.

Included: new smear positive adults.

Interventions

  1. Community‐based 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.

Outcomes

  1. Sputum negative at 2 months (primary outcome).

  2. Cure at 7 months (sputum negative at 2 months and at 5 to 7 months).

Notes

Location: Tanzania.

Date: 1999 to 2000.

Duration of DOT not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No details reported.

Allocation concealment (selection bias)

Unclear risk

No details reported.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

None. "This study was an unmasked cluster randomized trial".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Only 68% (311/437 participants) were evaluated at 7 months. (This could affect the cure outcome).

Selective reporting (reporting bias)

Low risk

All outcomes stated in the methodology are reported.

Recruitment bias

Unclear risk

No details of any shifting, though the cluster sizes varied from as low as 2 persons to 232 persons.

Baseline imbalance

Low risk

Clusters were similar though the size varied and one cluster had possibly a more sicker patient profile due to its highly specialized nature.

Loss of clusters

Unclear risk

One cluster in the community based intervention did not have patients hence was dropped in the analysis.

Incorrect analysis

Low risk

Cluster adjusted hence comparable to other RCTs randomizing individuals.

MacIntyre 2003 AUS

Methods

Quasi‐RCT

Generation of allocation sequence: alternate allocation

Concealment of allocation: none

Blinding: assessment of urinary isoniazid blinded

Completeness of follow‐up: not stated

Participants

Number: 173 recruited, mostly foreign nationals; male 51%; mean age 41 (range 14 to 83).

Included: new TB participants.

Excluded: multiple‐drug resistant TB; relapsed TB; human immunodeficiency virus (HIV)‐positive cases; and nontuberculous mycobacterial infections.

Interventions

  1. Family‐based 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.

Outcomes

Treatment completion measured by:

  1. Percentage clinic attendances to collect drugs.

  2. Urinary isoniazid (6 random checks over months; all had to be > 0).

Notes

Location: Australia.

Date: 1998 to December 2000.

Duration of DOT not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Not randomly. "Patients were systematically allocated to receive FDOT or ST".

Allocation concealment (selection bias)

High risk

Systematic allocation "The first patient was randomly allocated to the ST arm, every second patient was allocated to FDOT, and the remainder to ST".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information as to what happened to those who refused family DOT.

Selective reporting (reporting bias)

Unclear risk

All outcomes stated in the methodology are reported.

Other bias

Unclear risk

Not applicable.

Newell 2006 NPL

Methods

Cluster‐RCT.

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).

Participants

Number: 10 districts with 907 people randomized; all smear positive; 67% male.

Included: people with TB (aged 15+); new smear‐positive cases, diagnosed at health facilities in the trial area; human immunodeficiency virus (HIV) status not known.

Interventions

  1. Community‐based 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.

Outcomes

  1. Treatment success: cure plus treatment completion (primary).

  2. Treatment success compared with the WHO target of 85%.

  3. Estimated case detection rate with the WHO target of 70%.

  4. Compare the above rates in men and women.

Notes

Location: hill and mountain districts of Nepal.

Date: 2002 to 2003.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information on selection of 10 districts out of 17.

Allocation concealment (selection bias)

Low risk

Randomly picked papers from an opaque bag.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No cluster was lost to follow‐up or excluded.

Selective reporting (reporting bias)

Low risk

All outcomes stated in the methodology are reported.

Recruitment bias

Unclear risk

Not reported if there were patients who shifted to the different intervention arms, though they were separated by a mountainous region.

Baseline imbalance

Low risk

Characteristics similar.

Loss of clusters

Low risk

No loss reported.

Incorrect analysis

Low risk

Cluster adjustment done.

Walley 2001 PAK

Methods

Generation of allocation sequence: computer‐generated random numbers.

Allocation concealment: opaque, sealed envelopes.

Blinding: assessors blinded.

Completeness of follow‐up: not stated.

Participants

Number: 497 randomized; 51.3% male.

Included: adults (aged 15+); new smear‐positive cases.

Interventions

  1. DOT by a health worker at a health facility that met "access criteria" or a community health worker at or near the participant's home: access criteria were return journey from the participant's home to facility < 2 km, < 2 hr 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.

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.

Notes

Location: Pakistan

Date: 1996 to 1998

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer generated random sequence.

Allocation concealment (selection bias)

Low risk

Opaque envelopes were used and third party calls.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessors  were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

There were no exclusions after randomization.

Selective reporting (reporting bias)

Low risk

All outcomes stated in the methodology are reported.

Other bias

Unclear risk

Not applicable.

Wandwalo 2004 TZA

Methods

Generation of allocation sequence: coin tossing in each of 5 clinics.

Allocation concealment: none.

Blinding: none.

Completeness of follow‐up: 100% (no losses).

Participants

Number: 587 randomized; 322 smear positive, 182 smear negative, and 83 extrapulmonary TB; 57% male.

Included: people with TB (aged 5+); new smear positive, smear negative, and extrapulmonary cases; human immunodeficiency virus (HIV) status not known.

Excluded: previously treated for TB; severe illness; transferred from another clinic; previously enrolled in the study.

Interventions

  1. Community‐based 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 first 2 months participants received 'spot' visits by health workers who conducted treatment card checks and pill counts; during first 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.

Outcomes

  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.

Notes

Location: Dar es Salaam, Tanzania.

Date: 2001 to 2003.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomly by coin toss".

Allocation concealment (selection bias)

High risk

None.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No details reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No exclusions.

Selective reporting (reporting bias)

Low risk

All outcomes stated in the methodology are reported.

Other bias

Unclear risk

Not applicable.

Wright 2004 SWZ

Methods

Generation of allocation sequence: unclear; stratified into adults and children; then, within each group, randomized by type of TB (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%.

Participants

Number: 1353 randomized; 55% male; most 15+ years.

Included: adults and children with smear positive or negative, extrapulmonary TB, or relapse of previously treated TB.

Excluded: died before discharge; or too ill to receive outpatient treatment; lived in area without treatment supporter; or referred in after treatment commenced.

Interventions

  1. 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.

Outcomes

  1. Cure or treatment completion: cure defined as smear negative at 6 months and on at least 1 previous occasion; treatment completion defined 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.

Notes

Location: Swaziland.

Date: 2000 to 2002.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information.

Allocation concealment (selection bias)

Unclear risk

Use of sealed envelopes not clear whether opaque. "

sealed, sequentially numbered, stratum specific envelopes containing treatment assignments".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Laboratory assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Non differential loss to follow‐up (4/664 and 5/662).

Selective reporting (reporting bias)

Unclear risk

All outcomes stated in the methodology are reported.

Other bias

Unclear risk

Not applicable.

Zwarenstein 1998 ZAF

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.

Participants

Number: 216 included in analysis; 62% male; 57% < 35 years.

Included: adults (aged 15+) with pulmonary TB; both new and re‐treatment 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.

Interventions

  1. DOT by clinic nurses: participants asked to visit the clinic 5 days a week for 8 weeks (new participants) or for 12 weeks (re‐treatment 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; 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 Rifinah 4 (combined rifampicin‐isoniazid) plus additional isoniazid for 18 weeks.

Retreatment participants received Rifater plus ethambutol for 12 weeks and Rifinah 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 or culture, or both, to a negative smear or culture, or both, at the end of treatment (6 months for new participants and 8 months for re‐treatment 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 TB or other causes while on treatment.

Notes

Location: 1 trial in each of 2 low‐income communities near Cape Town, South Africa.

Date: 1994 to 1995.

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 TB).

Number of exclusions per arm of the 2 trials not given.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Random sequence generated by a computer algorithm".

Allocation concealment (selection bias)

Low risk

"Consecutively numbered opaque sealed envelops were used".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information on whether there was any blinding or not.

Incomplete outcome data (attrition bias)
All outcomes

High risk

There was differential exclusions between the intervention and control arms.

Selective reporting (reporting bias)

Low risk

All outcomes stated in the methodology are reported.

Other bias

Unclear risk

Not applicable.

Zwarenstein 2000 ZAF

Methods

Generation of allocation sequence: computer‐generated random numbers.

Allocation concealment: consecutively numbered, opaque, sealed envelopes.

Blinding: none.

Completeness of follow‐up: not stated.

Participants

Number: 174 randomized.

Included: new or re‐treatment participants aged 15+ who were sputum or culture positive.

Interventions

  1. DOT by clinic nurses (see Zwarenstein 1998 ZAF).

  2. Self‐administration (see Zwarenstein 1998 ZAF).

  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 participant's home and if necessary a member of the South African Tuberculosis Association (SANTA) also visited the participant.

Outcomes

As for Zwarenstein 1998 ZAF.

Notes

Location: 4 clinics in a township near Cape Town, South Africa.

Date: 1994 to 1995.

18 participants excluded from analysis: 12 with multiple‐drug resistant TB and 6 not TB.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random sequence generated by a computer algorithm.

Allocation concealment (selection bias)

Low risk

Consecutively numbered opaque sealed envelopes.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information on whether there was any blinding or not.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

There were exclusions though not differentiated between intervention arms.

"After exclusion of 12 MDR and six non‐TB patients".

Selective reporting (reporting bias)

Unclear risk

All outcomes stated in the methodology are reported.

Other bias

Unclear risk

Not applicable.

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Batki 2002

Compared direct observation plus with methadone treatment for injecting drug users with routine TB treatment without methadone.

Carroll 2004

Before‐and‐after study; no control group.

Hwang 2004

Not randomized.

Jasmer 2004

Different criteria for allocation to self‐administration or direct observation.

Lewin 2004

An educational intervention was evaluated.

Malotte 2001

Evaluates incentives for IV drug users within the context of a direct observation programme.

Matthew 2002

Cohort study.

Moulding 2002

Trial evaluating devices that monitor treatment using uranium along a strip of photographic film.

Pungrassami 2002a

Not randomly allocated; A publication reporting same data as Pungrassami 2002b.

Pungrassami 2002b

Not randomly allocated; A publication reporting same data as Pungrassami 2002a.

Sorete‐Abore 2002

Cohort study.

Tandon 2002

Described as a RCT, 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.

Thiam 2007

Multifaceted intervention including DOT.

Toyota 2003

Patients in hospital.

Data and analyses

Open in table viewer
Comparison 1. Directly observed versus self‐administered

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cure (negative sputum smear in last month of Rx in patients +ve initially) Show forest plot

5

1645

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.91, 1.27]

Analysis 1.1

Comparison 1 Directly observed versus self‐administered, Outcome 1 Cure (negative sputum smear in last month of Rx in patients +ve initially).

Comparison 1 Directly observed versus self‐administered, Outcome 1 Cure (negative sputum smear in last month of Rx in patients +ve initially).

2 Cure (by intensity of monitoring in control group) Show forest plot

5

1645

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [1.00, 1.15]

Analysis 1.2

Comparison 1 Directly observed versus self‐administered, Outcome 2 Cure (by intensity of monitoring in control group).

Comparison 1 Directly observed versus self‐administered, Outcome 2 Cure (by intensity of monitoring in control group).

2.1 Monthly monitoring of patients in self administered group

2

900

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.06, 1.25]

2.2 Once every two weeks monitoring of patients in self‐administered group

1

497

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.83, 1.12]

2.3 Weekly monitoring of patients in self‐administered group

2

248

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.68, 1.21]

3 Treatment completion (both with smear sputum test at end and those without) Show forest plot

6

1839

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.96, 1.19]

Analysis 1.3

Comparison 1 Directly observed versus self‐administered, Outcome 3 Treatment completion (both with smear sputum test at end and those without).

Comparison 1 Directly observed versus self‐administered, Outcome 3 Treatment completion (both with smear sputum test at end and those without).

4 Treatment completion (grouped by frequency of monitoring in the self‐administered therapy group) Show forest plot

6

1839

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.96, 1.19]

Analysis 1.4

Comparison 1 Directly observed versus self‐administered, Outcome 4 Treatment completion (grouped by frequency of monitoring in the self‐administered therapy group).

Comparison 1 Directly observed versus self‐administered, Outcome 4 Treatment completion (grouped by frequency of monitoring in the self‐administered therapy group).

4.1 Monthly monitoring of self‐administered treatment

3

1073

Risk Ratio (M‐H, Random, 95% CI)

1.12 [0.95, 1.31]

4.2 Once every two weeks monitoring of self‐administered treatment

1

497

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.87, 1.14]

4.3 Weekly monitoring of self‐administered treatment

2

269

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.74, 1.46]

Open in table viewer
Comparison 2. Home observed versus clinic observed

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially) Show forest plot

4

1556

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.88, 1.18]

Analysis 2.1

Comparison 2 Home observed versus clinic observed, Outcome 1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially).

Comparison 2 Home observed versus clinic observed, Outcome 1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially).

2 Treatment completion (both with smear sputum test at end and those without) Show forest plot

3

1034

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.91, 1.17]

Analysis 2.2

Comparison 2 Home observed versus clinic observed, Outcome 2 Treatment completion (both with smear sputum test at end and those without).

Comparison 2 Home observed versus clinic observed, Outcome 2 Treatment completion (both with smear sputum test at end and those without).

3 Cure (stratified by intensity of observation) Show forest plot

4

1556

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.91, 1.11]

Analysis 2.3

Comparison 2 Home observed versus clinic observed, Outcome 3 Cure (stratified by intensity of observation).

Comparison 2 Home observed versus clinic observed, Outcome 3 Cure (stratified by intensity of observation).

3.1 DOT (Intense supervision of observer)

1

522

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.91, 1.28]

3.2 Routine supervision of DOT

3

1034

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.86, 1.10]

Open in table viewer
Comparison 3. Community observed vs family observed

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially) Show forest plot

2

1493

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.86, 1.21]

Analysis 3.1

Comparison 3 Community observed vs family observed, Outcome 1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially).

Comparison 3 Community observed vs family observed, Outcome 1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially).

2 Treatment completion (both with smear sputum test at end and those without) Show forest plot

2

1493

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.90, 1.22]

Analysis 3.2

Comparison 3 Community observed vs family observed, Outcome 2 Treatment completion (both with smear sputum test at end and those without).

Comparison 3 Community observed vs family observed, Outcome 2 Treatment completion (both with smear sputum test at end and those without).

Open in table viewer
Comparison 4. Injecting drug users

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment completion Show forest plot

1

300

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.88, 1.13]

Analysis 4.1

Comparison 4 Injecting drug users, Outcome 1 Treatment completion.

Comparison 4 Injecting drug users, Outcome 1 Treatment completion.

Factors influencing adherence and possible intervention points.
Figuras y tablas -
Figure 1

Factors influencing adherence and possible intervention points.

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.
Figuras y tablas -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.
Figuras y tablas -
Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.

Comparison 1 Directly observed versus self‐administered, Outcome 1 Cure (negative sputum smear in last month of Rx in patients +ve initially).
Figuras y tablas -
Analysis 1.1

Comparison 1 Directly observed versus self‐administered, Outcome 1 Cure (negative sputum smear in last month of Rx in patients +ve initially).

Comparison 1 Directly observed versus self‐administered, Outcome 2 Cure (by intensity of monitoring in control group).
Figuras y tablas -
Analysis 1.2

Comparison 1 Directly observed versus self‐administered, Outcome 2 Cure (by intensity of monitoring in control group).

Comparison 1 Directly observed versus self‐administered, Outcome 3 Treatment completion (both with smear sputum test at end and those without).
Figuras y tablas -
Analysis 1.3

Comparison 1 Directly observed versus self‐administered, Outcome 3 Treatment completion (both with smear sputum test at end and those without).

Comparison 1 Directly observed versus self‐administered, Outcome 4 Treatment completion (grouped by frequency of monitoring in the self‐administered therapy group).
Figuras y tablas -
Analysis 1.4

Comparison 1 Directly observed versus self‐administered, Outcome 4 Treatment completion (grouped by frequency of monitoring in the self‐administered therapy group).

Comparison 2 Home observed versus clinic observed, Outcome 1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially).
Figuras y tablas -
Analysis 2.1

Comparison 2 Home observed versus clinic observed, Outcome 1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially).

Comparison 2 Home observed versus clinic observed, Outcome 2 Treatment completion (both with smear sputum test at end and those without).
Figuras y tablas -
Analysis 2.2

Comparison 2 Home observed versus clinic observed, Outcome 2 Treatment completion (both with smear sputum test at end and those without).

Comparison 2 Home observed versus clinic observed, Outcome 3 Cure (stratified by intensity of observation).
Figuras y tablas -
Analysis 2.3

Comparison 2 Home observed versus clinic observed, Outcome 3 Cure (stratified by intensity of observation).

Comparison 3 Community observed vs family observed, Outcome 1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially).
Figuras y tablas -
Analysis 3.1

Comparison 3 Community observed vs family observed, Outcome 1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially).

Comparison 3 Community observed vs family observed, Outcome 2 Treatment completion (both with smear sputum test at end and those without).
Figuras y tablas -
Analysis 3.2

Comparison 3 Community observed vs family observed, Outcome 2 Treatment completion (both with smear sputum test at end and those without).

Comparison 4 Injecting drug users, Outcome 1 Treatment completion.
Figuras y tablas -
Analysis 4.1

Comparison 4 Injecting drug users, Outcome 1 Treatment completion.

Summary of findings for the main comparison. Directly observed therapy (DOT) versus self‐administered TB treatment

Directly observed therapy (DOT) versus self‐administered TB treatment

Patient or population: Patients on TB treatment
Settings: Low‐, middle‐ or high‐income countries
Intervention: DOT
Comparison: Self‐administered therapy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Self‐administered therapy

DOT

Cure
Follow‐up: up to 6 months

617 per 1000

666 per 1000
(561 to 784)

RR 1.08
(0.91 to 1.27)

1645
(5 trials)

⊕⊕⊕⊝
moderate1,2,3,4

Treatment completion

Follow‐up: 2 to 8 months5

709 per 1000

751 per 1000
(680 to 829)

RR 1.07
(0.96 to 1.19)

1839
(6 trials)

⊕⊕⊕⊝
moderate1,2,3,4

The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; DOT: directly observed therapy; TB: tuberculosis.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1No serious risk of bias: three trials adequately described allocation concealment. Exclusion of trials at unclear or high risk of bias did not substantially change the result.
2Downgraded by 1 for inconsistency: trials include qualitative differences in effect size and direction. The benefit reached standard levels of statistical significance in the two trials where those receiving self‐administered therapy had less frequent contact with health services compared to the directly observed group, so any effect probably due to confounding.
3No serious indirectness: The trials were conducted in low‐, middle‐ and high‐income countries between 1995 and 2008.
4No serious imprecision: The analysis is adequately powered to detect clinically important differences between treatment arms.
5Some trials checked for completion of intensive phase treatment and others the completion of the whole therapy, hence the 2 to 8 months.

Figuras y tablas -
Summary of findings for the main comparison. Directly observed therapy (DOT) versus self‐administered TB treatment
Summary of findings 2. Home DOT versus clinic DOT

Home DOT versus clinic DOT

Patient or population: Patients with TB treatment
Settings: Low‐, middle‐ or high‐income countries
Intervention: Home observation
Comparison: Clinic observation

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Clinic observation

Home observation

Cure
Follow‐up: up to 6 months

492 per 1000

502 per 1000
(433 to 580)

RR 1.02
(0.88 to 1.18)

1556
(4 trials)

⊕⊕⊕⊝
moderate1,2,3

Treatment completion4
Follow‐up: 2 to 6 months

751 per 1000

781 per 1000
(684 to 879)

RR 1.04
(0.91 to 1.17)

1029
(3 trials)

⊕⊕⊕⊝
moderate1,2,3

The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; DOT: directly observed therapy; TB: tuberculosis.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Downgraded by 1 for risk of bias: selection bias is probable in one trial, Wandwalo 2004 TZA, as there was no blinding and no allocation concealment. In Lwilla 2003 TZA, sequence generation and allocation concealment were unclear and there was no blinding. This could bias the measurement of treatment completion.
2No serious indirectness: The trials were conducted in low‐, middle‐ and high‐income countries between 1995 and 2008.
3No serious imprecision: The analysis is adequately powered to detect clinically important differences between treatment arms.
4Some trials checked for completion of intensive phase treatment and others the completion of the whole therapy, hence the 2 to 6 months.

Figuras y tablas -
Summary of findings 2. Home DOT versus clinic DOT
Summary of findings 3. Summary of findings table 3

Community DOT versus family DOT

Patient or population: Patients on TB treatment
Settings: Low‐, middle‐ or high‐income countries
Intervention: Community DOT
Comparison: Family DOT

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Family DOT

Community DOT

Cure

Follow‐up: up to 6 months

766 per 1000

781 per 1000
(659 to 927)

RR 1.02 (0.86 to 1.21)

1493

(2 trials)

⊕⊕⊕⊝
moderate1

Treatment completion

Follow‐up: 2 to 6 months

827 per 1000

869 per 1000
(744 to 1000)

RR 1.05 (0.90 to 1.22)

1493

(2 trials)

⊕⊕⊝⊝
low1,2

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; DOT: directly observed therapy; TB: tuberculosis.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Downgraded by 1 for risk of bias. Both trials had unclear random sequence generation and recruitment bias could not be ruled out for Newell 2006 NPL.
2Downgraded by 1 for risk of bias for the outcome of treatment completion as there was no allocation concealment and selective reporting could not be ruled out in Wright 2004 SWZ.

Figuras y tablas -
Summary of findings 3. Summary of findings table 3
Summary of findings 4. DOT versus self‐administered therapy for intravenous drug users

DOT versus self‐administered therapy for intravenous drug users

Patient or population: Patients on TB treatment
Settings: Low‐, middle‐ or high‐income countries
Intervention: DOT
Comparison: Self‐administered treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Self‐administered therapy

DOT

Treatment completion

Follow‐up for 6 months

79 per 100

79 per 1000
(70 to 89)

RR 1.00 (0.88 to 1.13)

300
(1 trial)

⊕⊕⊝⊝
low1,2,3

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; DOT: directly observed therapy; TB: tuberculosis.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Downgraded by 1 for risk of bias. There was no blinding of outcome assessment and allocation concealment was unclear and treatment completion can be a bit subjective hence the results might be biased. The level of completeness to follow‐up was 88%.
2Downgraded by 1 for indirectness. The self‐administered group had a 10 dollar stipend which is may have enhanced adherence in this group.
3There may have been some imprecision. The study was had a small sample size and may have been underpowered to detect clinically important differences.

Figuras y tablas -
Summary of findings 4. DOT versus self‐administered therapy for intravenous drug users
Table 1. Summary of interventions in trials of DOT versus self‐administered

Trial ID

DOT

Self administered therapy

Who observed?

Where?

How often?

Adherence recorded at each contact

Cure

Frequency of contact with health service

Adherence recorded at each contact

Cure

Intensive phase

Consolidation phase

Zwarenstein 1998 ZAF

Nurses

Clinic

5 times per week

3 times per week

Yes

38%

(42/111)

Weekly

Yes

51%

(31/61

Zwarenstein 2000 ZAF

Nurse

Clinic

5 times per week

3 times per week

Yes

57%

(31/54)

Weekly

Yes

41%

(9/22)

Lay health worker

Lay health workers home

Kamolratanakul 1999 THA1

Healthcare worker

Clinic

Daily

Daily

Yes

76%
(315/414)

Monthly

Unclear

67%

(283/422)

Community health worker

Home

Daily

Daily

Family member

Home

Daily

Daily

Walley 2001 PAK

Healthcare worker

Clinic

6 times per week

2 times per month

Yes

59%

(199/335)

Every two weeks

Unclear

62%

(100/162)

Community health worker

Home

Family member

Home

Daily

Daily

MacIntyre 2003 AUS2

Family member

Home

Daily

Daily

Yes

Not reported

Monthly

Yes

Not reported

Hsieh 2008 TWN3

Case manager or

Hospital care

Hospital

Daily

Once per week

Yes

94%

(30/32)

Monthly unscheduled visit

Yes

69%

(22/32)

1In Kamolratanakul 1999 THA patients could choose which observer they preferred and there a more intense supervision of observers in the intensive phase.
2In MacIntyre 2003 AUS nurses made weekly calls to the patients who were observed by a family member.
3In Hsieh 2008 TWN the case manager directly supervised medicine intake for first two months (Intensive phase), then self‐administration with weekly unscheduled visit.

Figuras y tablas -
Table 1. Summary of interventions in trials of DOT versus self‐administered
Table 2. Interventions comparing home versus clinic direct observation

Trial ID

DOT at patient's home

DOT at clinic

Who observed?

How often?

Supervision of observer

Cure

Who observed?

How often?

Cure

Intensive phase

Consolidation phase

Intensive phase

Consolidation phase

Walley 2001 PAK1

Family member

Daily

Not described

Observers collected drugs from the clinic every 2 weeks

55%

(91/165)

Health worker

6 times per week

Self‐supervised

64%

(108/170)

Wandwalo 2004 TZA1

Family member or former TB patient

Daily

Self‐supervised

Observers collected drugs from clinic weekly and spot checks were conducted by health worker

43%

(111/260)

Health worker

Daily

Self‐supervised

43%

(141/327)

Zwarenstein 2000 ZAF

Lay health worker2

'Several times a week'

Not described

Observer collected drugs monthly

57%

(31/54)

Health worker

5 times a week

3 times a week

41%

(24/58)

Lwilla 2003 TZA1

Community volunteer

Daily

Self‐supervised

Observer was visited every two weeks by the health worker and every month by the district co‐ordinator3

53%

(117/221)

Health worker

Daily

Self‐supervised

49%

(148/301)

1In Lwilla 2003 TZA, Walley 2001 PAK and Wandwalo 2004 TZA observation was during the intensive phase, while in the clinic observation arm of Zwarenstein 2000 ZAF it continued in the consolidated phase.
2In Zwarenstein 2000 ZAF the observation took place in the lay health worker's home, not the patient's home.
3In Lwilla 2003 TZA there was additional supervision by the district coordinator.

Figuras y tablas -
Table 2. Interventions comparing home versus clinic direct observation
Table 3. Interventions comparing family‐administered DOT versus community health worker DOT

Trial ID

Who observed?

Where?

How often?

Additional intervention

Who observed?

Where?

How often?

Intensive phase

Consolidation phase

Intensive phase

Consolidation phase

Newell 2006 NPL

Family member

Patient's home

Daily

Daily

Drugs supplied to supervisor every week

Community health worker

Patient's home1

Daily

Daily

Wright 2004 SWZ

Family member

Patient's home

Daily

Daily

Patient reviewed at the diagnostic centre once per month

Recorded in a patient adherence card

Community health worker

Community health worker's home

Daily

Daily

1In Newell 2006 NPL the community health worker mainly visited the patients at their homes but occasionally the patients came to the health worker's home.

Figuras y tablas -
Table 3. Interventions comparing family‐administered DOT versus community health worker DOT
Comparison 1. Directly observed versus self‐administered

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cure (negative sputum smear in last month of Rx in patients +ve initially) Show forest plot

5

1645

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.91, 1.27]

2 Cure (by intensity of monitoring in control group) Show forest plot

5

1645

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [1.00, 1.15]

2.1 Monthly monitoring of patients in self administered group

2

900

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.06, 1.25]

2.2 Once every two weeks monitoring of patients in self‐administered group

1

497

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.83, 1.12]

2.3 Weekly monitoring of patients in self‐administered group

2

248

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.68, 1.21]

3 Treatment completion (both with smear sputum test at end and those without) Show forest plot

6

1839

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.96, 1.19]

4 Treatment completion (grouped by frequency of monitoring in the self‐administered therapy group) Show forest plot

6

1839

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.96, 1.19]

4.1 Monthly monitoring of self‐administered treatment

3

1073

Risk Ratio (M‐H, Random, 95% CI)

1.12 [0.95, 1.31]

4.2 Once every two weeks monitoring of self‐administered treatment

1

497

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.87, 1.14]

4.3 Weekly monitoring of self‐administered treatment

2

269

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.74, 1.46]

Figuras y tablas -
Comparison 1. Directly observed versus self‐administered
Comparison 2. Home observed versus clinic observed

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially) Show forest plot

4

1556

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.88, 1.18]

2 Treatment completion (both with smear sputum test at end and those without) Show forest plot

3

1034

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.91, 1.17]

3 Cure (stratified by intensity of observation) Show forest plot

4

1556

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.91, 1.11]

3.1 DOT (Intense supervision of observer)

1

522

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.91, 1.28]

3.2 Routine supervision of DOT

3

1034

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.86, 1.10]

Figuras y tablas -
Comparison 2. Home observed versus clinic observed
Comparison 3. Community observed vs family observed

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially) Show forest plot

2

1493

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.86, 1.21]

2 Treatment completion (both with smear sputum test at end and those without) Show forest plot

2

1493

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.90, 1.22]

Figuras y tablas -
Comparison 3. Community observed vs family observed
Comparison 4. Injecting drug users

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment completion Show forest plot

1

300

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.88, 1.13]

Figuras y tablas -
Comparison 4. Injecting drug users