Guidelines for treatment of drug-susceptible tuberculosis ... · 17 May 2016 17 May 2016 17 May 2016 Results 1677 2278 8 We included randomized controlled trials and cohort studies

TREATMENT OF TUBERCULOSIS

Guidelines for treatment of

drug-susceptible tuberculosis and

patient care

2017 UPDATE

Annex 5 REPORTS OF THE

SYSTEMATIC REVIEWS

TREATMENT OF TUBERCULOSIS

Guidelines for treatment of

drug-susceptible tuberculosis and

patient care

2017 UPDATE

Annex 5 REPORTS OF THE

SYSTEMATIC REVIEWS

Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update

Contents: Web Annex 3: GRADE evidence profiles – Web Annex 4: Evidence-to-decision tables – Annex 5: Reports of the systematic reviews – Annex 6: Essential first-line antituberculosis drugs

ISBN 978-92-4-155000-0

© World Health Organization 2017

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iii

Contents

Abbreviations & acronyms

Report on a systematic review for category II tuberculosis treatmentBackground 1

PIO question 1

Review methods 2

Results 3

Slidesets 5

References 9

Report on a systematic review for adherence interventions in tuberculosis treatmentBackground 10

PICO question 11

Review methods 11

Results 13

Slidesets 28

References 44

Report on a systematic review for decentralized treatment and care for multidrug-resistant tuberculosis patients Executive summary 50

Background 51

Objective of this review 52

Definitions 53

Research question 54

Methods 54

Results 58

Authors conclusions 62

Appendixes 72

References 77

iv

Abbreviations & acronyms

AIDS acquired immunodeficiency syndrome

ART antiretroviral treatment

ATS American Thoracic Society

BMI body mass index

CDC United States Centers for Disease Control and Prevention

DOT directly observed treatment

E Ethambutol

FDC fixed-dose combination

GDG Guideline Development Group

Gfx Gatifloxacin

GRADE Grading of Recommendations Assessment, Development and Evaluation

GTB Global TB Programme

HIV human immunodeficiency virus

IDSA Infectious Diseases Society of America

IRIS Immune Reconstitution Inflammatory Syndrome

KNCV Royal Dutch Tuberculosis Foundation

MDR-TB multidrug-resistant tuberculosis

Mfx Moxifloxacin

NGO non-governmental organization

PICO Patients, Intervention, Comparator and Outcomes

RIF or R Rifampicin

RFP Rifapentine

SAT self-administered treatment or unsupervized treatment

SMS Short Message Service or text message

TB tuberculosis

The Union International Union Against Tuberculosis and Lung Disease

USAID United States Agency for International Development

VOT video-observed treatment

WHO World Health Organization

XDR-TB extensively drug-resistant tuberculosis

ANNEX 5. REPORTS OF THE SYSTEMATIC REVIEWS

1

Report on a systematic review for category II tuberculosis treatmentLelia Chaisson, Cecily Miller, Adithya Cattamanchi & Payam Nahid (project contact and principal investigator)University of California, San Francisco

BackgroundHistorically, WHO has recommended category II treatment regimen (HRZES for two months, HRZE for one month and HRE for 5 months (2HRZES/1HRZE/5HRE))1 for tuberculosis (TB) patients with a previous history of treatment with first-line anti-TB drugs. A systematic review (Menzies D, Benedetti A, Paydar A, Royce S, Madhukar P, Burman W et al. Standardized treatment of active tuberculosis in patients with previous treatment and/or with mono-resistance to isoniazid: a systematic review and meta-analysis. PLoS Med. 2009;6:e1000150) searched the literature from 1965 to 2008 for studies of patients undergoing retreatment with the category II treatment regimen, focusing on patients with mono-resistance to isoniazid, and found suboptimal outcomes and significant variability in failure rates.

This analysis updates this systematic review from 2008 to 2016 and focuses on patient cohorts for whom drug resistance status is unknown. The specific terms of reference were:• to undertake a systematic review and analysis evaluating the following population,

intervention and outcome (PIO) question;• to work in close liaison with WHO and, where necessary, other contributors to the

studies and data in carrying out this work and to invite WHO technical focal points and other significant contributors to be co-authors in subsequent publication of the systematic reviews contracted;

• to deliver the findings in accordance with the agreed timelines, including submitting the report of findings and presenting the findings at the guideline meeting; and

• to sign and comply with the confidentiality agreement with WHO for not releasing or publishing the results of the systematic reviews before the WHO Guideline Review Committee approves the publication of the WHO TB treatment guidelines.

All aspects of the terms of reference have been completed, including this final report.

PIO questionFor patients with a previous history of treatment with first-line anti-TB drugs being considered for retreatment (due to treatment interruption or recurrence) in the absence of isoniazid and rifampicin resistance testing, does empiric treatment with five first-line drugs (2HRZES/1HRZE/5HRE) lead to acceptable outcomes?

1 H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; S: streptomycin.

GUIDELINES FOR TREATMENT OF DRUG-SUSCEPTIBLE TUBERCULOSIS AND PATIENT CARE - 2017 UPDATE

2

Table 1. Description of the PIO

Population Intervention Outcomes: critical

Outcomes: important

TB patients previously treated with first-line drugs (2HRZE/4HR) with unknown resistance to isoniazid and rifampicin

2HRZES/1HRZE/5HRE (category II retreatment regimen)

• Cure• Treatment failure• Relapse• Death

• Acquisition or amplification of drug resistance

• Smear or culture conversion• Drug adverse events

Review methodsThe following protocol was developed before the systematic review began in accordance with the PIO question defined above.

This systematic review was conducted according to the preferred reporting for systematic review and meta-analyses (PRISMA) guidelines, where applicable.

Study selection

We searched the PubMed, Cochrane and Embase databases between 1 January 2008 and 17 May 2016, with no restriction on language, using the search strategy outlined in Table 2.

Table 2. Search protocol

Step Search terms (PubMed) Search terms (Embase) Search terms (Cochrane)1 Tuberculosis[Mesh] tb[exp] tb

2 tb tb tuberculosis

3 tuberculosis tuberculosis[exp] 1-2/OR

4 1-3/OR tuberculosis retreatment

5 Retreatment[Mesh] 1-4/OR relapse

6 retreatment retreatment[exp] previously treated

7 relapse retreatment 4-6/OR

8 previously treated relapse[exp] 3 AND 7

9 5-8/OR relapse

10 4 AND 9 previously treated

11 6-10/OR

12 5 AND 10

Date conducted

17 May 2016 17 May 2016 17 May 2016

Results 1677 2278 8

We included randomized controlled trials and cohort studies enrolling previously treated pulmonary TB patients initiating the WHO category II retreatment regimen due to TB recurrence or treatment interruption. We excluded studies if there were no bacteriological outcomes; if participants were only described as “retreatment” patients, with no reference to the WHO category II regimen; if participants were given modified category II regimens; if drug susceptibility testing was performed in the patient population and the results guided patient management or if it was unclear whether the drug susceptibility testing results guided patient management; if there was insufficient data for analysis (such as the outcomes not being stratified by treatment regimen); or if the publication was not in English.


3

Two reviewers (CRM, LHC) participated in study selection. A single reviewer independently screened titles and abstracts for relevance. We excluded publications from full-text review if they were not about TB or if they definitively met one of the exclusion criteria. A single reviewer independently performed full-text reviews to identify publications for inclusion. A single reviewer independently abstracted data using a standardized form. We abstracted data concerning treatment outcomes, acquisition or amplification of drug resistance and adverse events for patients receiving category II retreatment due to treatment interruption or TB recurrence (Table 1). When possible, we stratified data by reason for retreatment (treatment interruption or TB recurrence). We assessed study quality using applicable criteria from the Newcastle-Ottawa Scale.

Analysis

We determined the proportion of patients receiving the WHO category II retreatment regimen who experienced each outcome for each study and pooled data to calculate medians, interquartile ranges and ranges. When possible, we stratified data by reason for retreatment (treatment interruption or TB recurrence). In addition, we stratified data by country-level multidrug-resistant TB (MDR-TB) prevalence among previously treated TB cases (6.0–11.9% or 12.0–29.9%) based on WHO country estimates.

The initial terms of reference included requests for GRADE evidence profiles, as well as meta-regression, subgroup analysis and assessment of heterogeneity and bias. However, since there were no comparators for analysis, the WHO Guideline Development Group requested that we provide descriptive summaries of the studies reporting outcomes of category II regimens, and no GRADE profiles were developed.

Results

Fig. 1. Study selection


4

Table 3. Papers included

Author Year Country Study populationAnanthakrishnan et al. (1) 2013 India TB patients in 12 districts in Tamilnadu, India

Bhagat & Gattani (2) 2010 India Retreatment cases at DOTS centres in Nanded, India

Hamusse et al. (3) 2014 Ethiopia Smear-positive cases registered 1997–2011 in Arzi Zone, cen-tral Ethiopia

Huang et al. (4) 2015 China Outpatients with sputum smear–positive pulmonary TB at Zhuji Hospital from February 2011 to October 2012, new and retreat-ment

Jones-Lopez et al. (5) 2011 Uganda Smear- and culture-positive inpatient retreatment cases

Joseph et al. (6) 2011 India Category II pulmonary TB patients

McGreevy et al. (7) 2012 Haiti HIV-positive and HIV-negative patients undergoing treatment for recurrent TB with category II

Mehra et al. (8) 2008 India Smear-positive category I treatment failure and relapses

Mpagama et al. (9) 2015 Uganda TB patients

Mukherjee et al. (10) 2009 India Category II patients at TB treatment unit

Mukherjee et al. (11) 2015 India Children re-treated between 2004 and 2012

Mukhopadhyay et al. (12) 2010 India Retreatment pulmonary TB and extrapulmonary TB cases at treatment units in West Bengal, India

Nabukenya-Mudiope et al. (13)

2015 Uganda Retreatment cases from 1 January to 31 December 2010: only 582 patients treated with category II included

Nacef & Saighi (14) 2011 Algeria Category II pulmonary TB retreatment patients

Panigatti et al. (15) 2014 India Children younger than 13 years treated for TB in Karnataka Hospital, Hubli

Prakasha et al. (16) 2012 India Retreatment cases at DOTS centre

Sarpal et al. (17) 2014 India Category II patients registered by the Revised National Tubercu-losis Control Programme from June 2010 to December 2011

Sharma et al. (18) 2008 India Children with pulmonary TB (smear-positive treatment failure, smear-negative non-responders)

Sharma et al. (19) 2014 India People with TB and HIV attending an antiretroviral therapy clinic in northern India between 2005 and 2011

Takarinda et al. (20) 2012 Zimbabwe Adults with TB registered in the district as being previously treated for TB for >1 month

Wahome et al. (21) 2013 Kenya Hospital staff

Yoshiyama et al. (22) 2010 Nepal Retreatment smear-positive TB cases registered at DOTS cen-tres under the National Tuberculosis Programme

The final slide set, stratified by MDR-TB prevalence, accompanies this report. This slide set includes the review methods, included papers and results.


5

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1

WHOcategoryIIretreatmentfortuberculosis

LeliaChaissonCecilyMiller&PayamNahid

WHOGuidelineDevelopmentGroupMeeGng

July2016

PopulaGon,intervenGonandoutcome(PIO)quesGon•  ForpaGentswithaprevioushistoryoftreatmentwithfirstlineanG-TBdrugsbeingconsideredforretreatment(duetotreatmentinterrupGonorrecurrence)intheabsenceofisoniazidandrifampicinresistancetes2ng,doesempirictreatmentwithfivefirst-linedrugs(HRZESfortwomonths,HRZEforonemonthandHREfor5months(2HRZES/1HRZE/5HRE))1leadtoacceptableoutcomes?

1H:isoniazid;R:rifampicin;Z:pyrazinamide;E:ethambutol;S:streptomycin.

Outcomesofinterest

CRITICAL IMPORTANT

Cure AcquisiGonoramplificaGonofdrugresistance

Treatmentfailure Smearorcultureconversionduringtreatment

Relapse Drugadverseeffects

Death

Searchstrategy

•  Databases:

–  PubMed:■  "Tuberculosis"[Mesh]ORtb[AllFields]OR"tuberculosis"[AllFields])AND("Retreatment"[Mesh]OR

retreatmentORrelapseOR"previouslytreated")

–  Cochrane:■  (tbOR"tuberculosis")AND(retreatmentORrelapseOR"previouslytreated")

–  Embase:■  ‘tb'/expORtbOR“tuberculosis”/expOR“tuberculosis”AND(“retreatment”OR“retreatment”/expOR

retreatmentOR“relapse”/expORrelapseOR“previouslytreated”)

•  Dates:1January,2008–17May,2016

StudyselecGon

Inclusioncriteria•  Randomizedcontrolledtrial(RCT)or

cohortstudy•  Enrollingpreviouslytreatedpulmonary

TBpaGentsiniGaGngWHOcategoryIIretreatmentregimenduetoTBrecurrenceortreatmentinterrupGon

Exclusioncriteria•  Nobacteriologicaloutcomes

•  ParGcipantsonlydescribedas“retreatment”paGents,withnoreferencetotheWHOcategoryIIregimen

•  DrugsuscepGbilitytesGng(DST)

performedinthepaGentpopulaGonandguidedthepaGentmanagementorunclearwhetherguidedthepaGentmanagement

•  Insufficientdata(suchasoutcomes

notstraGfiedbytreatmentregimen)•  NotinEnglish

Methods

•  Titleandabstractreviewfollowedbyfull-textreview(LC,CM)

•  DataabstracGon(LC,CM)•  Datasynthesis– DescripGveanalysisoftreatmentoutcomes– StraGfiedanalysis•  CountrymulGdrug-resistantTB(MDR-TB)prevalenceamongretreatedTBpaGents

•  Reasonforretreatment(relapseorrecurrence,treatmentinterrupGon)

Slidesets


6

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2

SystemaGcreviewprocess

3021arGclesidenGfied

217fulltextsreviewed

22arGclesincluded

2804Gtlesandabstractsexcluded

195fulltextsexcluded:3notRCTorcohortstudy9nobacteriologicaloutcomes35incorrectstudypopulaGon(e.g.noretreatmentpaGents,DSTdone)102incorrecttreatmentregimenornodescripGonoftreatmentregimen27withoutsufficientdataonoutcomesofinterest1duplicatedata18couldnotaccess(requestedfromlibrary)

Author,year Country n Studypopula2on

Nacef&Saighi,2011 Algeria 44PulmonaryTBrelapsepaGentsreceivingcategoryIItreatment

Huangetal.,2015 China 23Previouslytreatedsmear-posiGvePTBoutpaGentsreceivingcategoryIItreatment

Hamusseetal.,2014 Ethiopia 984Previouslytreatedsmear-posiGvePTBpaGentsreceivingcategoryIItreatment

McGreevyetal.,2012 HaiG 153PaGentswithrecurrentTBreceivingcategoryIItreatment

Wahomeetal.,2013 Kenya 46 HospitalstaffreceivingcategoryIItreatment

Yoshiyamaetal.,2010 Nepal 242Previouslytreatedsmear-posiGveTBpaGentsregisteredatDOTScentresreceivingcategoryIItreatment

Jones-Lopezetal.,2011 Uganda 288Previouslytreatedsmear-andculture-posiGveinpaGentsreceivingcategoryIItreatment

Mpagamaetal.,2015 Uganda 161PreviouslytreatedTBinpaGentsreceivingcategoryIItreatment

Nabukenya-Mudiopeetal.,2015 Uganda 582

PreviouslytreatedTBpaGentsinregionalreferralhospitalsreceivingcategoryIItreatment

Takarindaetal.,2012 Zimbabwe 135AdultrecurrentTBpaGentsreceivingcategoryIItreatment

Author,year Country n Studypopula2on

Mehraetal.,2008 India 517 Smear-posiGvecategoryIfailuresandrelapsesreceivingcategoryIItreatment

Sharmaetal.,2008 India 115 ChildrenwithpulmonaryTBtreatmentfailuresplacedoncategoryIItreatment

Mukherjeeetal.,2009 India 234 categoryIIpaGentsregisteredatTBtreatmentunit

Bhagat&Garani,2010 India 112 PreviouslytreatedTBpaGentsatDOTScentrereceivingcategoryIItreatment

Mukhopadhyayetal.,2010 India 212 PreviouslytreatedTBtreatmentfailuresplacedoncategoryIItreatment

Josephetal.,2011 India 74 PreviouslytreatedTBpaGentsreceivingcategoryIItreatment

Prakashaetal.,2012 India 9 PreviouslytreatedTBpaGentsregisteredatDOTScentrereceivingcategoryIItreatment

Ananthakrishnanetal.,2013

India 159 PreviouslytreatedTBpaGentsin12districtsreceivingcategoryIItreatment

Panigasetal.,2014 India 4 Previouslytreatedchildren<13receivingcategoryIItreatment

Sarpaletal.,2014 India 545 PaGentsreceivingcategoryIIregisteredinRNTCP

Sharmaetal.,2014 India 23 PreviouslytreatedTB-HIVpaGentsarendingARTclinicreceivingcategoryIItreatment

Mukherjeeetal.,2015 India 125 PreviouslytreatedpediatricpaGentsreceivingcategoryIItreatment

FavourableoutcomesAuthor Country Numberretreated Treatmentsuccess Cure Treatmentcompleted

n % n % n %

Nacef&Saighi Algeria 44 16 36.4 16 36.4 _ _

Huangetal. China 23 8 34.8 _ _ _ _

Hamusseetal. Ethiopia 984 665 67.6 523 53.2 142 14.4

McGreevyetal. HaiG 153 120 78.4 _ _ _ _

Mehraetal. India 517 360 69.6 _ _ _ _

Sharmaetal. India 115 95 82.6 80 69.6 15 13.0

Mukherjeeetal. India 234 160 68.4 _ _ _ _

Bhagat&Garani India 112 _ _ _ _ _ _

Mukhopadhyayetal. India 212 121 57.1 117 55.2 4 1.9

Josephetal. India 74 35 47.3 35 47.3 _ _

Prakashaetal. India 9 8 88.9 _ _ _ _

Ananthakrishnanetal. India 159 104 65.4 66 41.5 38 23.9

Panigasetal. India 3 3 100.0 3 100.0 _ _

Sarpaletal. India 545 444 81.5 283 51.9 161 29.5

Sharmaetal. India 23 12 52.2 _ _ _ _


Wahomeetal. Kenya 46 28 60.9 _ _ _ _

Yoshiyamaetal. Nepal 242 138 57.0 138 57.0 _ _

Jones-Lopezetal. Uganda 288 222 77.1 _ _ _ _

Mpagamaetal. Uganda 161 124 77.0 _ _ _ _

Nabukenya-Mudiope

etal.Uganda 582 322 55.3 _ _ _ _

Takarindaetal. Zimbabwe 135 102 75.6 _ _ _ _

Range 36.4-100.0 36.4-100.0 1.9-29.5

Median 67.6 53.2 14.4

FavourableoutcomesStudiesincountrieswith6.0-11.9%prevalenceofMDR-TBamongpreviouslytreatedTBcases

Author Country

%ofretreatment

pa2entswithMDR-TB

(WHOTBreport)

Number

retreatedTreatmentsuccess Cure Treatmentcompleted

n % n % n %

Nacef&Saighi Algeria 9.1 44 16 36.4 16 36.4 _ _

McGreevy HaiG 11 153 120 78.4 _ _ _ _

Takarinda Zimbabwe 11 135 102 75.6 _ _ _ _

Range 36.4-78.4 36.4

Median 75.6 36.4

Author Country%ofretreatment

pa2entswithMDRTB

Number

retreatedTreatmentsuccess Cure Treatmentcompleted

(WHOTBreport) n % n % n %Hamusseetal. Ethiopia 12 984 665 67.6 523 53.2 142 14.4

Jones-Lopezetal. Uganda 12 288 222 77.1 _ _ _ _

Mpagamaetal. Uganda 12 161 124 77 _ _ _ _

Nabukenya-Mudiope

etal. Uganda 12 582 322 55.3 _ _ _ _

Wahomeetal. Kenya 14 46 28 60.9 _ _ _ _

Mehraetal. India 15 517 360 69.6 _ _ _ _

Sharmaetal. India 15 115 95 82.6 80 69.6 15 13

Mukherjeeetal. India 15 234 160 68.4 _ _ _ _

Bhagat&Garani India 15 112 _ _ _ _ _ _

Mukhopadhyayetal. India 15 212 121 57.1 117 55.2 4 1.9

Josephetal. India 15 74 35 47.3 35 47.3 _ _

Prakashaetal. India 15 9 8 88.9 _ _ _ _

Ananthakrishnanetal.India 15 159 104 65.4 66 41.5 38 23.9

Panigasetal. India 15 3 3 100.0 3 100.0 _ _

Sarpaletal. India 15 545 444 81.5 283 51.9 161 29.5

Sharmaetal. India 15 23 12 52.2 _ _ _ _

Mukherjee India 15 125 80 64 _ _ _ _

Yoshiyamaetal. Nepal 15 242 138 57 138 57 _ _

Huangetal. China 22 23 8 34.8 _ _ _ _

Range 34.8–100.0 41.5–100.0 1.9–29.5

Median 66.5 54.2 14.4

FavourableoutcomesStudiesincountrieswith12.0-29.9%prevalenceofMDRTBamongpreviouslytreatedTBcases


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FavourableoutcomesRetreatmentaKerrelapse

Author Country Numberretreated Treatmentsuccess Cure Treatmentcompleted

n % n % n %


McGreevyetal. HaiG 153 120 78.4 _ _ _ _

Mehraetal. India 390 298 76.4 _ _ _ _


Prakashaetal. India 4 _ _ _ _ _ _

Sarpaletal. India 264 _ _ 205 77.7 8 3.0





Range 68.4–79.6 54.0–77.7 3.0–14.4

Median 76.4 57.8 17.4

FavorableoutcomesRetreatmentaKertreatmentinterrupLon

Author Country Numberretreated Treatmentsuccess Cure Treatmentcompleted

n % n % n %








Range 47.4–79.1 39.4–65.3 1.3–18.2

Median 57.6 47.4 9.8

UnfavorableoutcomesAuthor Country Numberretreated Death Failure Default

n % n % n %

Nacef&Saighi Algeria 44 _ _ 1 2.3 4 9.1

Huangetal. China 23 _ _ _ _ _ _


McGreevyetal. HaiG 153 14 9.2 6 3.9 13 8.5

Mehraetal. India 517 28 5.4 59 11.4 70 13.5

Sharmaetal. India 115 4 3.5 7 6.1 9 7.8

Mukherjeeetal. India 234 14 6.0 31 13.2 26 11.1

Bhagat&Garani India 112 15 13.4 _ _ 24 21.4

Mukhopadhyayetal. India 212 3 1.4 51 24.1 37 17.5

Josephetal. India 74 0 0.0 24 32.4 15 20.3


Ananthakrishnanetal.India 159 21 13.2 3 1.9 _ _

Panigasetal. India 4 0 0.0 0 0.0 0 0.0


Sharmaetal. India 23 _ _ _ _ _ _


Wahomeetal. Kenya 46 _ _ _ _ _ _

Yoshiyamaetal. Nepal 242 3 1.2 13 5.4 17 7.0

Jones-Lopezetal. Uganda 288 38 13.2 18 6.3 _ _

Mpagamaetal. Uganda 161 21 13.0 4 2.5 12 7.5

Nabukenya-Mudiope

etal.Uganda 582 _ _ _ _ _ _

Takarindaetal. Zimbabwe 135 6 4.4 0 0.0 9 6.7

Range 0.0–13.4 0.0–32.4 0.0–25.0

Median 4.9 5.8 9.1

UnfavourableoutcomesStudiesincountrieswith6.0-11.9%prevalenceofMDR-TBamongpreviouslytreatedTBcases

Author Country

%retreatment

pa2entswithMDRTB

(WHOTBreport)

Number

retreatedDeath Failure Default

n % n % n %

Nacef&Saighi Algeria 9.1 44 _ _ 1 2.3 4 9.1

McGreevyetal. HaiG 11 153 14 9.2 6 3.9 13 8.5

Takarindaetal. Zimbabwe 11 135 6 4.4 0 0.0 9 6.7

Range 4.4-9.2 0.0-3.9 6.7-9.1

Median 6.8 2.3 8.5

UnfavourableoutcomesStudiesincountrieswith12.0-29.9%prevalenceofMDR-TBamongpreviouslytreatedTBcases

Author Country%retreatment

pa2entswithMDRTB

Number

retreatedDeath Failure Default

(WHOTBreport) n % n % n %

Hamusseetal. Ethiopia 12 984 115 11.7 15 1.5 189 19.2

Jones-Lopezetal. Uganda 12 288 38 13.2 18 6.3 _ _

Mpagamaetal. Uganda 12 161 21 13 4 2.5 12 7.5

Nabukenya-

Mudiopeetal. Uganda 12 582 _ _ _ _ _ _

Wahomeetal. Kenya 14 46 _ _ _ _ _ _

Mehraetal. India 15 517 28 5.4 59 11.4 70 13.5

Sharmaetal. India 15 115 4 3.5 7 6.1 9 7.8

Mukherjeeetal. India 15 234 14 6 31 13.2 26 11.1

Bhagat&Garani India 15 112 15 13.4 _ _ 24 21.4

Mukhopadhyayet

al. India 15 212 3 1.4 51 24.1 37 17.5

Josephetal. India 15 74 0 0 24 32.4 15 20.3

Prakashaetal. India 15 9 _ _ _ _ _ _

Ananthakrishnanet

al. India 15 159 21 13.2 3 1.9 _ _

Panigasetal. India 15 4 0 0.0 0 0.0 0 0.0

Sarpaletal. India 15 545 23 4.2 46 8.4 32 5.9

Sharmaetal. India 15 23 _ _ _ _ _ _

Mukherjeeetal. India 15 125 0 0 20 16 25 20

Yoshiyamaetal. Nepal 15 242 3 1.2 13 5.4 17 7

Huangetal. China 22 23 _ _ _ _ _ _

Range 0.0–13.4 0.0–32.4 0.0–25.0

Median 4.8 6.3 12.3

UnfavorableoutcomesRetreatmentaKerrelapse

Author Country Numberretreated Death Failure Default

n % n % n %


McGreevyetal. HaiG 153 14 9.2 6 3.9 13 8.5

Mehraetal. India 390 20 5.1 24 6.2 48 12.3




Mukherjeeetal. India 45 _ _ _ _ _ _




Range 1.5–14.7 0.0–8.7 4.9–19.3

Median 5.6 4.8 8.5


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UnfavorableoutcomesRetreatmentaKertreatmentinterrupLon

Author Country Numberretreated Death Failure Default

n % n % n %




Mukherjeeetal. India 24 _ _ _ _ _ _




Range 0.0-15.2 0.0-23.5 8.8-31.6

Median 8.4 8.0 12.0

Relapse&acquisiGonofdrugresistance

Author Country

%retreatment

pa2entswithMDRTB

(WHOTBreport)

Number

retreatedRelapse

Acquisi2onofdrug

resistance

n % n %

Yoshiyamaetal. Nepal 15 242 5 2.1 3 1.2

Discussion


9

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5. Jones-Lopez EC, Ayakaka I, Levin J, Reilly N, Mumbowa F, Dryden-Peterson S et al. Effectiveness of the standard WHO recommended retreatment regimen (category II) for tuberculosis in Kampala, Uganda: a prospective cohort study. PLoS Med. 2011;8:e1000427.

6. Joseph N, Nagaraj K, Bhat J, Babu R, Kotian S, Ranganatha Y et al. Treatment outcomes among new smear positive and retreatment cases of tuberculosis in Mangalore, south India – a descriptive study. Australas Med J. 2011;4:162–7.

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10

Report on a systematic review for adherence interventions in tuberculosis treatment

Narges Alipanah, Leah Jarlsberg, Cecily Miller, Andrew Lechner, Kathy Wai, Payam Nahid (project contact and principal investigator)University of California, San Francisco

BackgroundThe current treatment for drug-susceptible pulmonary tuberculosis (TB), for most types of extrapulmonary TB, and for human immunodeficiency virus (HIV)–associated TB is a six-month multidrug regimen. Ensuring adherence to long-duration treatment regimens is challenging, and incomplete treatment may lead to poor outcomes, including treatment failure, relapse and acquisition of drug resistance. Several adherence strategies have been implemented over the years to improve adherence with therapy. Perhaps the most commonly known such intervention is directly observed therapy (DOT) introduced in the early 1960s, in which a health worker, family member or community member observes the patient taking TB medications (1). Other interventions have included financial incentives, implementing reminder or tracking systems, improving patient and staff education and, most recently, the use of mobile technology for video observed therapy and text message tracking. The resources necessary for such interventions vary, and many centres across the world have been using a combination of these strategies to improve TB treatment outcomes. Here, we set out to determine which of these interventions, alone or in conjunction with a package of interventions, leads to improved TB treatment outcomes.

The specific terms of reference for the current systematic review were as follows:• undertake systematic reviews and analysis evaluating the following population,

intervention, comparator and outcome (PICO) question: Among patients with TB, are any interventions to promote adherence to TB treatment more or less likely to lead to the following outcomes: treatment adherence, conventional treatment outcomes, adverse reactions, acquired drug resistance, patient costs and health service costs?;

• work in close liaison with WHO and, where necessary, other contributors to the studies and data in carrying out this work and invite WHO technical focal points and others who are significant contributors to be co-authors in the subsequent publication of the systematic reviews contracted;

• deliver the findings in accordance with the agreed timelines, including submitting the report of findings and presenting the findings at the guideline meeting; and

• sign and comply with the confidentiality agreement with WHO for not releasing or publishing the results of the systematic reviews before the WHO Guideline Review Committee approves the publication of the WHO TB treatment guideline.


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PICO questionAmong patients with TB, are any interventions to promote adherence to TB treatment more or less likely to lead to the outcomes listed below?

Table 1. Breakdown of the PICO question

Population Intervention Comparator OutcomePatients receiv-ing treatment for drug-susceptible TBPatients on multi-drug-resistant TB (MDR-TB) treatmentChildren (0–14 years old) and adultsTB patients with and without HIV

Any intervention to promote treatment adherence• Supervising treatment

(DOT, video observed therapy)

• Measures to improve treatment adherence (such as medication mon-itors and/or text message or phone call reminders)

• Social support (educa-tional, psychological and material)

• Combinations of the above interventions

Routine prac-ticea

• Adherence to treatment (or treatment interruption due to non-adherence)

• Conventional TB treatment outcomes: cured and completed, failure, relapse, survival or death

• Adverse reactions from TB drugs (severity, type and organ class)

• Cost to the patient (including direct medical costs as well as others such as transport and lost wages due to disability)

• Cost to health services

a Routine practice: regular TB drug pick-up and consultations with physicians or other health-care workers are available when necessary; TB treatment is free of charge; and essential information and health education in relation to TB treatment is provided.

Review methodsA protocol for this systematic review was generated prior to conducting the literature search and conducted in accordance with the preferred reporting for systematic review and meta-analyses (PRISMA) guidelines.

All aspects of the terms of reference have been completed, including this final report.

Study selection

We searched PubMed through 6 February 2016. One reviewer (NA) reviewed titles and abstracts, and multiple reviewers reviewed the full texts. We included all randomized controlled trials, quasi-randomized studies and prospective or retrospective cohort studies that met the inclusion criteria. Articles were excluded if they were conducted on patients with latent TB, did not have a current or historical control group or the article was not published in English. Two non-English articles were included, since a different systematic review previously abstracted data from them. Studies that specifically compared DOT delivered in a hospital setting versus clinic setting were excluded from this review because a different systematic review dedicated to the comparison was being conducted at the time of our review.


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Table 2. Search protocol for adherence interventions in TB

Step Search Terms (Pubmed)1 TB

2 tuberculosis

3 1 OR 2

4 “directly observed therapy”

5 “directly observed treatment”

6 “supervised therapy”

7 “supervised treatment

8 DOT*

9 VOT

10 “video observed”

11 SMS

12 Text messag*

13 phone

14 telephone

15 Patient adherence

16 video

17 Patient participation

18 motivation

19 Decision support techniques

20 Default*

21 Adheren*

22 Supervis*

23 4-22/OR

24 3 AND 23

Date conducted 12/12/2015

Results 6394

Date search repeated 2/6/2016

Final results 6467

A separate search was conducted for video and text message interventions in TB through 28 June 2016 using the search strategy outlined in Table 3.

Table 3. Search protocol for SMS/video interventions

Step Search Terms (Pubmed)1 TB

2 tuberculosis

3 1 OR 2

4 Text message

5 SMS

6 Cell phone

7 Video

8 4–7/OR

9 3 AND 8

Date conducted 28 June 2016

Results 425


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Analysis

The Cochrane risk of bias tool was used to assess the quality of randomized controlled trials (reference), and the Newcastle-Ottawa Scale was used for observational studies (reference). The types of information abstracted from each article included setting, average age of the patients enrolled, type of TB (pulmonary versus extrapulmonary), drug resistance, coinfection with HIV, type of adherence intervention and conventional TB treatment outcomes including cure, success, treatment failure, default or loss to follow-up, adverse reactions and death. The standard WHO definition was used for all outcomes of interest. One reviewer (NA) abstracted all data for analysis. Data were abstracted and analysed using RevMan. If two or more studies reported on similar outcomes, data were pooled using random effects meta-analysis. Heterogeneity was assessed using the chi-square test available in RevMan with P < 0.05 used to determine statistical significance. If more than 15 studies were available for a particular question, we used funnel plots to determine publication bias.

ResultsTables 4–13 summarize the characteristics of the included studies. The complete slide set is provided as a companion to this report and includes a summary of the methods as well as forest plots and GRADE evidence profiles for each comparison.

Fig. 1. PRISMA diagram


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Table 4. Characteristics of the included studies: self-administered therapy as an intervention versus DOT

Authors Year Study design Country

Number of patients

Condition DOT administration

Kamol-ratanakul et al. (2)

1999 RCT Thailand 836 Pulmonary TB (smear +)≥15 years

DailyClinic, community mem-ber, family member

MacIntyre et al. (3)

2003 Quasi-RCT Australia 173 Excluded: MDR-TB, relapse, HIV+≥14 years

DailyFamily member

Tuberculosis Research Centre Chennai (4)

1997 Clinical trial, not randomized

India 825 Pulmonary TB (smear +)Excluded: those who missed >25% of the therapyIncluded: isoniazid and rifampicin mono-resistant≥12 years

Twice weeklyClinic

Walley et al. (5)

2001 RCT Pakistan 497 Pulmonary TB (smear +)≥15 years

DailyClinic, home (health worker or family mem-ber)

Zwarenstein et al. (6)

1998 RCT South Africa

216 Pulmonary TB (smear +)Excluded: MDR-TB, history of antituberculosis treatment >2 weeks≥15 years

DailyClinic

Zwarenstein et al. (7)


156 Pulmonary TB (smear +)Excluded: MDR-TB, history of antituberculosis treatment >2 weeks≥15 years

DailyClinic, home (health worker or family mem-ber)

Tandon et al. (8)

2002 RCT India 400 Pulmonary TB (smear +)Excluded: HIV+≥20 years

Provided by patient attendant or school teacher

Akkslip et al. (9)

1999 Prospective Thailand 779 Pulmonary TB (smear +/–)Extrapulmonary TB

DOT, family member or village volunteer

Balasubra-manian et al. (10)

2000 Retrospec-tive

India 200 NewPulmonary TB (smear +)

DOT by health workersThrice-weekly intensive phaseOnce-weekly continua-tion phase

Mathema et al. (11)

2001 Prospective Nepal 759 Pulmonary TB (smear +/–)Extrapulmonary TB (4%)Adults and children

DOT by health workers, community, or familyIntensive phase only, daily

Ormerod et al. (12)

2002 Mixed United Kingdom

205 Pulmonary TB (smear +/–)Adults

Thrice-weekly regimen

Tsuchida & Koyanagi (13)

2003 Retrospec-tive

Japan 80 Pulmonary TB (smear +)Excluded: DR-TBNew and retreatmentAdults

Hospital until sputum conversionDaily DOT by clinic nurse

Nirupa et al. (14)

2005 Retrospec-tive

India 865 Pulmonary TB (smear +)NewAdults and children

DOT by communi-ty health workers, teachers, community volunteers


15


Number of patients


Daniel (15) 2006 Retrospec-tive

Nigeria 467 Pulmonary TB (Smear +/–)Extrapulmonary TB≥15 years

No info

Okanurak et al. (16)

2007 Prospective Thailand 931 ≥15 years Clinic, family, communi-ty DOT

Abassi & Mansourian (17)

2007 Prospective Islamic Republic of Iran

260 Pulmonary TB (smear +) New

Clinic DOT

Siemi-on-Szcześni-ak & Kuś (18)

2009 Retrospec-tive

Poland 100 Pulmonary TB (smear +/–)New

DOTS (not defined)

Caylà et al. (19)

2009 Prospective Spain 1 490 Pulmonary TB (smear +/–)Extrapulmonary TB≥18 yearsNo drug resistanceTB and HIVNew and retreatment

Provided to those at higher risk of default

Zvavamwe & Ehlers (20)

2009 Prospective Namibia 332 Post-hospital discharge Community or clinic DOTContinuation phase only

Xu et al. (21) 2009 Prospective China 670 Pulmonary TB (smear +)AdultsNew and retreatment

DOT by family member, health worker, or village doctor

Abuaku et al. (22)

2010 Retrospec-tive

China 68 430 Pulmonary TB (smear +/–)Extrapulmonary TBAdults and childrenNew and retreatment

DOTModified DOT (intensive phase only)

Ershova et al. (23)

2014 Retrospec-tive

South Africa

741 Adults and childrenTB and HIV (60%)Pulmonary TB (smear +/–)Extrapulmonary TBNew and retreatment

Full DOT versus partial DOT

Weis et al. (24)

1995 Retrospec-tive

United States

988 Adults and childrenMDR–TBTB and HIV (data only availa-ble for the DOT group)Pulmonary TBExtrapulmonary TB

DOT offered at multiple locations, daily for 2-4 weeks and then twice weekly for 2–4 weeks

Bashar et al. (25)

2001 Retrospec-tive

United States

28 Diabetics versus non-dia-beticsPulmonary TBTB and HIVMDR-TB (100%)Adults and two children

No information

Ollé-Goig & Alvarez (26)

2001 Retrospec-tive

Haiti 281 Pulmonary TB (smear +/–)TB and HIVNew and retreatmentExtrapulmonary TBAdults

First two weeks inpa-tient, rest at home with DOT by health-care workersMeds + food delivered twice weekly

Pungrassami et al. (27)

2002 Prospective Thailand 411 MDR-TBTB and HIVAdults and children

Health-care workers, community member or family member DOT


16


Number of patients


Jasmer et al. (28)

2004 Retrospec-tive

United States

372 Pulmonary TB (culture +)Excluded: extrapulmonary TBTB and HIVAdults and children

DOT plus incentives and enablersHome, clinic or work-place

Cayla et al. (29)

2004 Prospective Spain 1515 Pulmonary TB (smear +)Extrapulmonary TBTB and HIVAdults and children

Provided to those at higher risk of default

Cavalcante et al. (30)

2007 Retrospec-tive

Brazil 1811 Pulmonary TB (smear +/–)Extrapulmonary TBTB and HIVNew and retreatmentAdults

Home or local clinic DOTCommunity health workers

Radil-la-Chavez et al. (31)

2007 Retrospec-tive

Mexico 629 TB and HIVNew and retreatmentAdults and childrenExcluded: extrapulmonary TB

Daily clinic DOT (intensive phase), thrice-weekly continua-tion phase

Anuwatnon-thakate et al. (32)

2008 Prospective Thailand 8031 Pulmonary TB (smear +/–)TB and HIVAdults and childrenNew and retreatment

Health-care workers or family DOTIntensive phase only

Kapella et al. (33)

2009 Retrospec-tive

Thailand 791 Adults and childrenTB and HIVNew and retreatmentPulmonary TB (smear +/–)Extrapulmonary TBMDR-TB

Health-care workers DOT during intensive phase

Vieira & Ribiero (34)

2011 Retrospec-tive

Brazil 218 Pulmonary TB (smear +/–)Extrapulmonary TBNew and retreatmentExcluded: MDR-TB and TB meningoencephalitisAdults and childrenTB and HIV

Clinic DOT thrice-week-ly in the intensive phase and then twice-weekly in the continuation phase

Ong’ang’o et al. (35)

2014 Retrospec-tive

Kenya 2778 Adults and childrenNew and retreatmentPulmonary TB (smear +/–)Extrapulmonary TB (24%)TB and HIV

Community health workers DOT once weekly at home in the intensive phase and once monthly during the continuation phase

Mac et al. (36)

1999 Retrospec-tive

United States

50 Vietnamese≥18 yearsPulmonary TB (smear +/–)Excluded: TB and HIV, ex-trapulmonary TBMDR-TB

DOT (no info provided)

Juan et al. (37)

2006 Mixed Spain 213 Pulmonary TB (smear +/–)Extrapulmonary TBTB and HIV (70%)DR-TBNew and retreatmentAdults and children

Initial two weeks inpa-tientDistrict-based DOT

Chung et al. (38)

2007 Retrospec-tive

Taiwan, China

399 Pulmonary TB (smear +)Excluded: extrapulmonary TB and MDR-TBNew and retreatment

Clinic DOT


17


Number of patients


Yen et al. (39)

2013 Retrospec-tive

Taiwan, China

3 487 ≥18 yearsPulmonary TB (smear +/–)MDR-TBNew and retreatment

Daily DOT at home or workplace

Chien et al. (40)

2013 Retrospec-tive

Taiwan, China

2 160 Pulmonary TB (smear +/–)M/XDR-TBExcluded: TB and HIV

DOTS and DOTS-PLUS

Alvarez-Uria et al. (41)

2014 Retrospec-tive

India 1 460 TB and HIV (100%)Pulmonary TB (smear +/–)Extrapulmonary TB except TB meningitisNew and retreatmentAdults

Inpatient initiallyThrice-weekly DOT at hospital

Das et al. (42)

2014 Retrospec-tive

India 89 NewPulmonary TB (smear +/–)Extrapulmonary TBTB and HIV (100%)Adults

Daily DOT by commu-nity health workers at home

Alwood et al. (43)

1994 Retrospec-tive

United States

78 TB and HIV (100%)Pulmonary TB (smear +/–)AdultsIsoniazid and streptomycin resistant (n = 1)

Daily DOT for 9 months

Table 5. Characteristics of the included studies: DOT offered by provided by family members, community members or lay health workers versus DOT provided by health-care providers


Number of patients


Mathema et al. (11)

2001 Prospec-tive

Nepal 759 Pulmonary TB (smear +/–)Extrapulmonary TB

DOT by health workers, community or familyIntensive phase only, daily

Colvin et al. (44)

2003 Retro-spective

South Africa

1 816 Pulmonary TB (smear +/–)New and retreatmentExtrapulmonary TB

DOT by health clinic, com-munity health workers, lay health workers or tradition-al healersFirst few weeks: inpatient

Singh et al. (45)

2004 Retro-spective

India 617 Pulmonary TB (smear +)New

DOT by community health workers (government facilities) or community volunteers (laypeople)

Nirupa et al. (14)

2005 Retro-spective

India 865 Pulmonary TB (smear +)New

DOT by community health workers, teachers, commu-nity volunteers

Anuwatnon-thakate et al. (32)

2008 Prospec-tive

Thailand 8 031 Pulmonary TB (smear +/–)TB and HIVAdults and childrenNew and retreatment

Health-care workers or family DOTIntensive phase only

Kungkaew et al. (46)

2008 Prospec-tive

Thailand 506 New Pulmonary TB (smear +/–)Adults and childrenTB and HIV

DOT by family members or health-care workers


18


Number of patients


Xu et al. (21) 2009 Prospec-tive

China 670 Pulmonary TB (smear +) DOT by family members, health workers or village doctors

Tripathy et al. (47)

2013 Retro-spective

India 1 769 New Pulmonary TB (smear +)Adults and children

DOT by community volun-teers (community health workers, physicians, alter-native medicine doctors, shopkeepers, teachers) versus institutional pro-viders (TB health visitors, staff nurses, auxiliary nurse midwives)

Wilkinson & Davies (48)

1997 Retro-spective

South Africa

1 890 No informationHigh HIV prevalence

Choice of health-care workers, community health workers or volunteer laypeople; no distinction provided between health-care workers and commu-nity health workers

Table 6. Characteristics of the included studies: DOT offered at home or in the community versus clinic-based


Number of patients


Lwilla et al. (49)

2003 RCT United Republic of Tanzania

522 NewPulmonary TB (smear +)

Community-based versus institution-based DOT

Wandwalo et al. (50)

2004 RCT United Republic of Tanzania

587 Adults and childrenNewPulmonary TB (smear +/–)Extrapulmonary TB

Community (family or former TB patient) versus health clinic DOT

Wright et al. (51)

2004 RCT Swaziland 1 353 Adults and childrenPulmonary TB (smear +/–)Extrapulmonary TBNew and retreatment

DOT by community health workers (not at home) versus family member

Newell et al. (52)

2006 RCT Nepal 907 Pulmonary TB (smear +)≥15 years oldNew

Community-based DOT versus family member DOT

Akkslip et al. (9)

1999 Prospective Thailand 779 Pulmonary TB (smear +) DOT, family member or village volunteer

Banerjee et al. (53)

2000 Prospective Malawi 600 Pulmonary TB (smear +/–)Extrapulmonary TBNew

DOT at home versus health centre versus hospital

Becx-Ble-umink et al. (54)

2001 Prospective Indonesia 2 353 Pulmonary TB (smear +)New

DOT in community versus clinicDOT six times per week by family member during the intensive phase, and five times per two weeks during the continuation phase


19


Number of patients


Cavalcante et al. (30)

2007 Retrospec-tive

Brazil 1 811 Pulmonary TB (smear +/–)TB and HIVExtrapulmonary TB

DOT in community (home or church by community health workers) versus clinic

Dobler et al. (55)

2015 Retrospec-tive

Mongolia 2 181 Pulmonary TB (smear +)≥15 years old

Daily DOT at home by volunteersDOT at cafeteriasClinic DOT

Dudley et al. (56)

2003 Prospective South Africa

2 873 Pulmonary TBExtrapulmonary TB≥15 yearsNew and retreatment

Daily DOT at clinic or community (at community health workers’ home)

Maciel et al. (57)

2010 Prospective Brazil 171 NewTB and HIVPulmonary TB (smear +/–)Extrapulmonary TB

Daily DOT by a domiciliary supervisor at home or by community health workers at a clinic

Miti et al. (58)

2003 Prospective Zambia 168 ≥15 yearsTB and HIV onlyNewPulmonary TB (smear +)

Daily DOT delivered at home + AIDS home care pro-grammeDaily DOT at a clinic

Moalosi et al. (59)

2003 Retrospec-tive

Botswana 633 TB and HIVPulmonary TB (smear +/–)

Daily DOT by family at homeClinic DOT

Niazi & Al-Delaimi (60)

2003 Prospective Iraq 172 NewPulmonary TB (smear +)

Daily home versus clinic DOT

Wares et al. (61)

2001 Prospective Nepal 327 New and retreatmentPulmonary TB (smear +/–)Extrapulmonary TB

Daily DOT via health post, clinic, or hostel

Arora et al. (62)

2003 Prospective India 2 573 Adults and childrenPulmonary TB (smear +/–)Extrapulmonary TB

DOT by community member at patient’s or member’s house versus centre-based DOT

Kironde & Maintjies (63)

2002 Prospective South Africa

505 New and retreatment≥15 yearsPulmonary TB (smear +)

Daily clinic or communi-ty-based DOT

Van Den Boogaard et al. (64)

2009 Retrospec-tive

United Republic of Tanzania

2 769 Adults and childrenNew and retreatmentPulmonary TB (smear +/–)Extrapulmonary TBTB and HIV

Daily community versus clinic DOT

Manders et al. (65)

2001 Prospective Malawi 75 ≥18 yearsPulmonary TB (smear +/–)Extrapulmonary TB

Guardian-based (family) DOT versus health centre–based versus inpatient

Xu et al. (21) 2009 Prospective China 670 Pulmonary TB (smear +) DOT by family member, health worker or village doctor

Akhtar et al. (66)

2011 Prospective Pakistan 582 Pulmonary TB (smear +)≥15 yearsNew and retreatmentExcluded: drug resistant

Clinic DOT five times per week in the intensive phase and then three times per week in the continuation phaseFamily DOT


20

Table 7. Characteristics of the included studies: patient education and counselling in addition to curative therapy versus curative therapy alone


Number of patients


Clark et al. (67)

2007 RCT Turkey 114 NewMDR-TBAdult

Oral and written education via clinical pharmacist before drug collectionIntensive phase: inpatient

Janmeja et al. (68)

2004 RCT India 200 NewPulmonary TB (smear +)Extrapulmonary TBExcluded: MDR-TB

Behavioural psychotherapy at eight drug collection visits

Liefooghe et al. (69)

1999 RCT Pakistan 1 019 NewAdultsPulmonary TB (smear +/–)Extrapulmonary TB

Counselling provided to patients each time they presented for follow-up ap-pointments, also involving social network and family members

Baral et al. (70)

2014 RCT Nepal 156 MDR-TB (100%)Adults

CounsellingCounselling plus financial supportNone

Dick & Lombard (71)

1997 Prospec-tive

South Africa 120 Pulmonary TB (smear +/–)≥15 yearsExcluded: extrapulmo-nary TB, MDR-TBNew and retreatment

Oral and written education via clinical pharmacist before drug collection


21

Table 8. Characteristics of the included studies: incentives and enablers in addition to curative therapy versus curative therapy alone


Number of patients

Condition Intervention

Martins et al. (72)

2009 RCT Timor- Leste

270 NewPulmonary TB (smear +/–)Adults

Daily mid-day food with DOT

Lutge et al. (73)

2013 RCT KwaZu-lu-Natal, South Africa

4 091 New drug-sensitive pulmonary TB, high HIV prevalence

Monthly food voucher on drug collection

Jahnavi & Sudha (74)

2010 RCT India 100 New≥18 yearsPulmonary TB (smear +/–)Extrapulmonary TBWasting (BMI <20)Excluded: HIV

Food supplements and dietary planGeneral advice to increase food intake

Sudarsanam et al. (75)

2011 RCT India 97 >12 yearsTB and HIVNewPulmonary TB (smear +/–)Extrapulmonary TB

Food supplements and multivitamin versus none

Dobler et al. (55)

2015 Retro-spective

Mongolia 2 181 Pulmonary TB (smear +)≥15 years old

Daily DOT at home by volunteersDOT at cafeteriasClinic DOT

Ngamvi-thayapong- Yanai et al. (76)

2013 Retro-spective

Thailand 759 TB and HIVAdults and children

Financial supportFinancial support plus home visitsNone

Zou et al. (77)

2013 Prospec-tive

China 787 New Living subsidy plus trans-port incentive, low socioec-onomic statusLiving subsidy plus trans-port incentive, all patients

Lu et al. (78) 2013 Prospec-tive

China 2 006 ≥15 years oldNewPulmonary TB

Transport subsidies plus living allowance

Wei et al. (79)

2012 Prospec-tive

China 183 Pulmonary TB (smear +/–)No extrapulmonary TB

Transport for allLiving allowance for low-in-come patients

Cantalice Filho (80)

2009 Retro-spective

Brazil 142 TB and HIVPulmonary TB (smear +/–)≥15 years

Monthly baskets of food

Sripad et al. (81)

2014 Mixed Ecuador 191 DR-TB only (including MDR-TB)TB and HIVAdults

Financial bonus after each month of adherence up to 24 months

Tsai et al. (82)

2010 Retro-spective

Taiwan, China

17 061 No information Pay for performance

Bock et al. (83)

2001 Retro-spective

United States

107 History of non-adherenceAdults and childrenTB and HIVIsoniazid mono-resistant

Financial incentive


22

Table 9. Characteristics of the included studies: reminders and tracers in addition to curative therapy versus curative therapy alone


Number of patients


Iribarren et al. (84)

2013 RCT Argentina 37 NewExcluded: DR-TB or HIV≥18 yearsPulmonary TB (smear +)

Patients text daily after taking their medicine and received reminder texts

Krishnaswami et al. (85)

1981 RCT Southern India

150 Pulmonary TB (smear –)Isoniazid mono-resistant (n = 3)

Self-administered therapy, monthly collection; reminder health visit on fourth day of not picking up medicine

Kunawarak et al. (86)

2011 RCT Thailand 61 NewPulmonary TB (smear +)>15 yearsTB and HIVMDR-TB (62%)Excluded XDR-TB

Family DOT plus daily phone call reminder to take medicine

Mohan et al. (87)

2003 RCT Iraq 480 NewPulmonary TB (smear +)

Home visits to patients late for medicine pick-up

Paramasivan et al. (88)

1993 RCT India 200 NewPulmonary TB (smear +)

Sent reminder letter to patients late for medicine pick-up

Tanke & Leirer (89)

1994 Quasi-RCT United States

2 008 Adults and childrenAnyone registered for TB treatment

Automated message reminder before first treatment appointment

Moulding & Caymittes (90)

2002 RCT Haiti 2 002 >15 years oldNewPulmonary TB (smear +)

Medicine monitors with feedbackMedicine monitors without feedbackNone

Bronner et al. (91)

2012 Retrospec-tive

South Africa

405 673 Pulmonary TB (smear +)New and retreatmentTB and HIVMDR-TB

Community health workers traced the pa-tients who interrupted treatment

Snidal et al. (92)

2015 Prospective Uganda 142 >18 yearsPulmonary TB (smear +/–)New and retreatmentTB and HIVExtrapulmonary TB

Computer system to ensure that communi-ty health workers see all patients and keep visit logs

Thomson et al. (93)

2011 Retrospec-tive

Kenya 1 369 TB and HIV (100%)Pulmonary TBAdults and children

Social worker traced the people who missed scheduled clinic appointments

Al-Hajjaj & Al-Khatim (94)

2000 Retrospec-tive

Saudi Arabia

628 New and retreatmentPulmonary TBExtrapulmonary TB

Phone call and then home visit for missed appointments


23

Table 10. Characteristics of the included studies: combination package of adherence interventions versus curative therapy alone


Number of patients

Population Intervention

Khort-wong & Kaewkung-wal (95)

2013 Qua-si-RCT

Thailand 100 Undocumented migrantsNew TB cases>70% smear positive

DOT plus patient education and monthly home visits versus DOT alone

Morisky et al. (96)

1990 RCT United States

88 New≥18 years

Health education and US$ 10 voucher at each monthly visit and US$ 40 if no missed treatment versus monthly clinic follow-up alone

Baral et al. (70)

2014 RCT Nepal 156 MDR-TBAdults

Counselling plus financial incen-tive (US$ 28 per month) for 2–3 weeks versus none

Drabo et al. (97)

2009 RCT Burkina Faso

333 Pulmonary TB (smear +) Food, home visits and psychoso-cial support versus self-adminis-tered therapy

Thiam et al. (98)

2007 RCT Senegal 1 522 AdultsPulmonary TB (smear +)New

Counselling, choice of DOT supporter and reinforcement ac-tivities versus clinic-based DOT

Hsieh et al. (99)

2008 RCT Taiwan, China

96 ≥18 yearsExcluded: extrapulmo-nary TB

DOT in the intensive phase, home visits in the continuation phase and health educationControl: initial ward care and then monthly clinic follow-up

Atkins(100) 2011 Prospec-tive

South Africa

5833 >18 years oldPulmonary TB (smear +/–)Extrapulmonary TBNew and retreatmentTB and HIV (>50%)Excluded: M/XDR-TB

Enhanced DOT with staff train-ing, treatment supporters and counselling versus standard DOT

Farmer et al. (101)

1991 Prospec-tive

Haiti 60 Pulmonary TBExtrapulmonary TBTB and HIV

Daily home visits, monthly reminder visits, food, financial incentive versus self-adminis-tered therapy

Jasmer et al. (102)

2004 Retro-spective

United States

372 Pulmonary TB (culture +)Excluded: extrapulmo-nary TBTB and HIVAdults and children

DOT plus incentives and ena-blers at home, clinic or work-place versus self-administered therapy

Soares et al. (103)

2013 Prospec-tive

Brazil 2 623 Adults and childrenPulmonary TB (smear +/–)Extrapulmonary TBNew and retreatmentTB and HIV

DOT, psychosocial intervention, counselling and education and food incentives versus self-ad-ministered therapy

Yassin et al. (104)

2013 Prospec-tive

Ethiopia 5 090 Pulmonary TB (smear +/–)Extrapulmonary TBAdults and children

Hospital capacity strengthening, staff education, mobile phone for health-care workers, home-based DOT versus clinic- or community-based DOT

Chan et al. (105)

2013 Retro-spective

Taiwan, China

390 MDR-TB (100%)Pulmonary TBNew and retreatmentAdults

Home DOT plus incentives and enablers, optional inpatient component versus hospital and then clinic DOT


24


Number of patients

Population Intervention

Garden et al. (106)

2012 Prospec-tive

Russian Federa-tion

518 AdultsNew and retreatment (77%)Pulmonary TB (smear +/–)

DOT plus food incentive, psycho-social support versus self-ad-ministered therapy

Davidson (107)

1998 Retro-spective

United States

319 Adults and childrenTB and HIVExtrapulmonary TBPulmonary TBMDR-TB

Clinic or home DOT five times per week in the intensive phase, including food coupons and bus tokens, versus self-administered therapy

Table 11. Characteristics of the included studies: psychosocial interventions in addition to curative therapy versus curative therapy alone


Number of patients


Shin et al. (108)

2013 RCT Russian Federation

196 ≥18 years oldTB and HIVNew and retreatment

Brief counselling intervention for alcohol cessation

Álvarez et al. (109)

2003 RCT Mexico 87 ≥15 years oldPulmonary TB

Self-help groups

Demissie et al. (110)

2003 Prospective Ethiopia 128 Adults and childrenPulmonary TB (smear +/–)

TB clubs as a support network

Table 12. Characteristics of the included studies: staff education in addition to curative therapy versus curative therapy alone


Number of patients


Lewin et al. (111)


1 177 ≥14 yearsPulmonary TB (smear +)NewExcluded: MDR-TB

Adherence education for staff

Ritchie et al. (112)

2015 RCT Malawi 178 NewAdults and childrenPulmonary TBExtrapulmonary TBTB and HIV (45%)

Peer training of lay health workersLaminated chart and visual reminder to initiate adherence discussions

Datiko & Lindtjørn (113)

2009 RCT Ethiopia 318 NewPulmonary TB (smear +)Adults and children

Education for health-care workers and laboratory tech-nicians

Safdar et al. (114)

2011 Prospective Pakistan 194 Children (100%)Pulmonary TB (smear +/–)Extrapulmonary TB

Staff educational tool and desktop aid for decision-mak-ing and red flags


25

Table 13. Characteristics of the included studies: mobile health interventions in addition to curative therapy versus curative therapy alone


Number of patients


Iribarren et al. (84)

2013 RCT Argentina 37 New≥18 yearsPulmonary TB (smear +)

Patients text daily after taking their medicine and received reminder texts

Kunawarak et al. (86)

2011 RCT Thailand 61 NewPulmonary TB (smear +)

Family DOT plus a daily phone call reminder to take medicine

Liu et al. (115)

2015 RCT China 4 173 NewPulmonary TB (smear +/–)≥18 years

Text messageMedicine monitorBothControl

Chuck et al. (116)

2016 Prospective United States

390 >18 yearsPulmonary TB (smear +/–)Included drug resistantIncluded TB-HIV

Video DOT versus in-per-son DOT

Broomhead & Mars (117)

2012 Case–con-trol

South Africa

120 Pulmonary TB (smear +)New

Wireless pill box with an alarm system sends text messageDOTS

Wade et al. (118)

2012 Retrospec-tive

Australia 128 Anyone receiving DOT Home videophone DOT versus in-person DOT


26

Table 14.1 Summary of meta-analysis findings of all the included adherence interventions

Self-

adm

inis

tere

d th

era-

py v

ersu

s DO

T (a

ll)

Self-

adm

inis

tere

d th

er-

apy

vers

us D

OT (T

B an

d HI

V)DO

T pr

ovid

er: f

amily

or

com

mun

ity v

ersu

s he

alth

-car

e w

orke

rsDO

T pr

ovid

er: l

ay p

ro-

vide

r ver

sus

heal

th-c

are

wor

kers

DOT

loca

tion:

hom

e or

co

mm

unity

ver

sus

clin

ic

Patie

nt e

duca

tion

vers

us

cura

tive

ther

apy

alon

e

Ince

ntiv

es a

nd e

nabl

ers

vers

us c

urat

ive

ther

apy

alon

eRe

min

ders

and

trac

ers

vers

us c

urat

ive

ther

apy

alon

e

Mortality: cohorts No effecta --b No effect No effect No effect -- êc No effect

Mortality: RCTs No effect -- -- -- No effect No effect No effect No effect

Success: cohorts ê ê No effect No effect No effect -- éd No effect

Success: RCTs ê -- -- -- é No effect é é

Completion: cohorts No effect ê No effect -- No effect -- No effect é

Completion: RCTs No effect -- -- -- é é é No effect

Cure: cohorts ê ê No effect No effect No effect -- é No effect

Cure: RCTs No effect -- -- -- No effect é No effect No effect

Failure: cohorts No effect é No effect No effect No effect -- No effect No effect

Failure: RCTs No effect -- -- -- No effect No effect ê --

Loss to follow up: cohorts

é -- é No effect ê -- No effect No effect

Loss to follow up: RCTs

é -- -- -- No effect No effect ê No effect

Relapse: cohorts No effect No effect -- -- -- -- -- --

Relapse: RCTs No effect -- -- -- -- -- -- --

Adherence: cohorts ê -- ê -- No effect é -- --

Adherence-RCTs No effect -- -- -- -- é -- é

Smear conversion: cohorts

No effect -- -- -- é -- -- --

Smear conversion: RCTs

ê -- -- -- No effect -- é é

Acquisition of drug resistance: cohorts

é -- -- -- -- -- -- ê

Acquisition of drug resistance: RCTs

No effect -- -- -- -- -- No effect --

Unfavourable outcome: cohorts

-- -- -- -- ê -- -- --

a No effect: There is no statistically significant difference in the rate of outcome occurrence between the intervention and control groups.

b -- : No outcome data available for the comparison.c ê: Overall estimate of effect shows a significantly lower rate of outcome occurrence in the intervention

group compared to the control group.d é: Overall estimate of effect shows a significantly higher rate of outcome occurrence in the intervention

group compared to the control group.


27

Table 14.2 Summary of meta-analysis findings of all included adherence interventions

Mix

ed in

terv

entio

ns a

nd

enha

nced

DOT

ver

sus

self-

adm

inis

tere

d th

erap

y

Mix

ed in

terv

entio

ns a

nd

enha

nced

DOT

ver

sus

DOT

Mix

ed c

ase

man

agem

ent a

nd

mix

ed in

terv

entio

ns v

ersu

s se

lf-ad

min

iste

red

ther

apy

Psyc

hoso

cial

inte

rven

tions

ve

rsus

cur

ativ

e th

erap

y al

one

Staf

f edu

catio

n ve

rsus

cu

rativ

e th

erap

y al

one

Phon

e re

min

ders

ver

sus

no

rem

inde

rs

Vide

o DO

T ve

rsus

in-p

erso

n DO

T

Mortality: cohorts No effect No effect -- No effect No effect No effect No effect

Mortality: RCTs -- ê No effect -- No effect -- --

Success: cohorts é é -- -- é -- --

Success: RCTs é é -- No effect No effect No effect --

Completion: cohorts é No effect -- é -- No effect No effect

Completion: RCTs é No effect -- é No effect ê --

Cure: cohorts é No effect -- -- -- é --

Cure: RCTs é é -- No effect No effect é --

Failure: cohorts No effect No effect -- No effect No effect -- --

Failure: RCTs -- No effect No effect ê No effect ê --

Loss to follow-up: cohorts No effect No effect -- ê ê ê --

Loss to follow-up: RCTs -- ê ê No effect No effect -- --

Relapse: cohorts No effect -- -- -- -- -- --

Relapse: RCTs -- -- -- -- -- -- --

Adherence: cohorts -- -- -- -- -- -- --

Adherence: RCTs -- No effect No effect -- -- -- --

Smear conversion: cohorts -- -- -- -- -- é --

Smear conversion: RCTs é -- -- -- -- No effect --

Acquisition of drug resistance: cohorts

No effect -- -- -- -- -- --

Acquisition of drug resistance: RCTs

-- -- -- -- -- -- --

Unfavourable outcome: cohorts

-- -- -- -- -- ê --

Unfavourable outcome: RCTs

-- -- -- -- -- -- --

Poor adherence: cohorts -- -- -- -- -- ê(phone

reminder and med monitor

combined)

--


28

Slidesets

22/02/18

1

Adherenceinterven,onsinTBtreatment

NargesAlipanah,LeahJarlsberg,CecilyMiller,AndrewLechner,KathyWai&PayamNahid

PICOQues/on

•  Amongpa,entswithTB,areanyinterven,onstopromoteadherencetoTBtreatmentmoreorlesslikelytoleadtotheoutcomeslistedbelow?

PICOQues/onPopula,on Interven,on Comparator OutcomePa/entsreceiving

treatmentforDS-TB

Pa/entsreceiving

treatmentforMDR-TB

Children(0–14years

old)andadults

HIV-infectedandHIV-

uninfectedTBpa/ents

Anyinterven/onto

promotetreatment

adherence:

Supervisingtreatment

(DOT,video-observed

treatment)

Measurestoimprove

treatmentadherence

(suchasmedica/on

monitorsand/ortext

messageorphonecall

reminders)

Socialsupport

(educa/onal,

psychological,material)

Combina/onsofthe

aboveinterven/ons

Rou/neprac/ce Adherenceto

treatment(or

treatmentinterrup/on

duetonon-adherence)

Conven/onalTB

treatmentoutcomes:

curedorcompleted,

failure,relapse,survival

ordeath

Adversereac/onsfrom

TBdrugs(severity,type

andorganclass)

Costtothepa/ent

(includingdirect

medicalcostsaswellas

otherssuchastransport

andlostwagesdueto

disability)

Costtohealthservices

Eligibility

•  Studydesigns:

-Randomizedcontrolledtrials(RCTs)-Prospec,veandretrospec,vecohortstudies-Currentorhistoricalcontrol

Outcomesofinterest

CRITICAL IMPORTANT

Adherence

Adversereac/onsfromTBdrugs

Cureorcomple/on Costtothepa/ent

Failure Costtohealthservices

Relapse

Survival(ordeath)

Acquisi/on(amplifica/on)ofdrug

resistance

Losstofollow-up

Searchmethods

•  MEDLINEdatabase

•  Searchthrough2June2016•  Titlesandabstractsreviewedbyonereviewer•  Full-textreviewbymul/plereviewers


29

22/02/18

2

Analysis

•  Dataabstrac/onbyonereviewer•  CochraneriskofbiastoolforRCTs•  Newcastle-O\awaScaleforcohortstudies•  DatasynthesisinRevMan

-Pooles/matesif≥2studies

-Randomeffectsmeta-analysis

Newcastle-O\awaScale

•  9-pointscale:

–  Selec/on(4)

-Representa/venessoftheexposedcohort

-Selec/onofthenon-exposedcohort

-Ascertainmentofexposure

-Demonstra/onthattheoutcomeofinterestwasnotpresentatthestartofthestudy

–  Comparability(2)

-Comparabilityofcohortsbasedondesignoranalysis

–  Outcome(3)

-Assessmentofoutcome

-Lengthoffollow-uplongenoughtoensureoutcomeoccurrence

-Adequacyoffollow-upofcohorts

Adherenceinterven/ons

•  Self-administeredtreatmentversusDOT

•  DOTprovider

•  DOTloca/on

•  Remindersandtracers

•  Incen/vesandenablers

•  Pa/enteduca/onandcounselling

•  Mixedcasemanagement

•  Mobilehealth(textmessaging,video-observedtreatment)

•  Psychosocial

•  Staffeduca/on

Recordsiden/fiedthrough

databasesearching

(n=6467)

Addi/onalrecordsiden/fied

throughothersources

(n=165)

Recordsaderduplicatesremoved

(n=6526)

Recordsscreened

(n=6526)

Recordsexcludedbased

on/tlesandabstracts

(n=5573)

Full-textar/cles

assessedforeligibility

(n=953)

Full-textar/clesexcluded,with

reasons

(n=716)

•  StudynotonTBmedecine•  Unabletodeterminethenumberofpa/ents

•  Thedatareportednotstra/fiedby

popula/onofinterest(notabstractable)

•  Nodatareportedonoutcomesofinterest

•  Nooriginaldata•  Noadherenceinterven/onused

•  Non-specificpopula/on

•  Purelydescrip/vestudy

•  Nocontrolgroup

•  Reviewar/cle•  Protocolforclinicaltrial

•  Ar/clefocusedondecentralizedcare

Studiesincludedin

quan/ta/veanalysis

(n=135)

Ar/clesrequiring

furtherac/on

(n=102)•  Non-Englishlanguage:28

•  Fulltextnotavailable:61

•  Uncertaininterven/onor

outcome:13

>50%HIV+

n=4

>50%

MDR-TB

n=5

Other

n=126

SATvsDOT

Summaryoffindings(1)

Qualityassessment

Numberofpa,ents Effect

Quality ImportanceNumberofstudies Studydesign Riskofbias

Inconsisten

cyIndirectness Imprecision

Other

considera/

ons

Self-administered

therapyDirectlyobserved

therapy(DOT)Rela/ve

(95%CI)Absolute

(95%CI)

Mortality–cohortstudies

19 observa/onalstudies very

seriousavery

seriousbnotserious seriousc none 471/6955(6.8%) 2681/81500(3.3%) notes/mable 20moreper

1000

(from0fewer

to40more)

⨁◯◯◯

VERY

LOW

CRITICAL

Mortality–RCTs

5 randomizedtrials seriousd not

seriousnotserious veryseriousc,e none 27/731(3.7%) 43/961(4.5%) notes/mable 10fewerper

1000

(from30

fewerto10

more)

⨁◯◯◯

VERY

LOW

CRITICAL

Treatmentsuccess–cohortstudies


seriousavery

seriousfnotserious notserious none 3370/5061(66.6%) 10311/13858

(74.4%)RR0.79

(0.72to0.88)156fewerper

1000

(from89

fewerto208

fewer)

⨁◯◯◯

VERY

LOW

CRITICAL

Treatmentsuccess–RCTs


seriousnotserious notserious none 566/775(73.0%) 747/1001(74.6%) RR0.94


1000

(from15

fewerto82

fewer)

⨁⨁⨁◯

MODERA

TE

CRITICAL


30

22/02/18

3


Qualityassessment


Quality ImportanceNumberofstudies

Study

designRiskof

biasInconsistency Indirectness Imprecision

Other

considera/

ons

Self-administered

therapy

Directly

observed

therapy

(DOT)

Rela/ve

(95%CI)Absolute

(95%CI)

Comple,on–cohortstudies

14 observa/o

nalstudiesvery

seriousaveryseriousb notserious seriousc none 1193/2997(39.8%) 2276/86

82

(26.2%)

notes/mable 20moreper

1000

(from40

fewerto80

more)

⨁◯◯◯

VERYLOWCRITICAL

Comple,on–RCTs

5 randomize

dtrialsseriousd notserious notserious seriousc none 139/842(16.5%) 267/1140

(23.4%)RR0.79


1000

(from26

moreto103

fewer)

⨁⨁◯◯

LOWCRITICAL

Cure–cohortstudies

17 observa/o

nalstudiesvery

seriousaveryseriouse notserious notserious strong

associa/o

n

1083/3689(29.4%) 5067/10

676

(47.5%)

RR0.61


1000

(from109

fewerto252

fewer)

⨁◯◯◯

VERYLOWCRITICAL

Cure–RCTs

4 randomize

dtrialsseriousd seriousf notserious seriousc none 432/689(62.7%) 587/914

(64.2%)RR0.98


1000

(from109

fewerto109

more)

⨁◯◯◯

VERYLOWCRITICAL


Qualityassessment Numberofpa,ents Effect

Quality ImportanceNumberof

studies Studydesign Riskofbias Inconsistency IndirectnessImprecisio

nOther

considera/onsSelf-administered

therapyDirectlyobserved

therapy(DOT)Rela/ve

(95%CI)Absolute

(95%CI)

Failure–cohortstudies


seriousaveryseriousb notserious seriousc none 422/4511(9.4%) 519/11802(4.4%) notes/mable 20moreper

1000

(from0fewer

to50more)

⨁◯◯◯

VERYLOWCRITICAL

Failure–RCTs

6 randomizedtrials seriousd notserious notserious seriouse none 21/1036(2.0%) 24/1220(2.0%) notes/mable 0fewerper

1000

(from10more

to10fewer)

⨁⨁◯◯

LOWCRITICAL

Losstofollow-up–cohorts


seriousaveryseriousf notserious not

seriousnone 2590/27540(9.4%) 2544/81897

(3.1%)notes/mable 60moreper

1000

(from20more

to90more)

⨁◯◯◯

VERYLOWCRITICAL

Losstofollow-up–RCTs

4 randomizedtrials seriousd notserious notserious seriousc none 138/689(20.0%) 166/914(18.2%) RR1.28

(0.93to1.76)51moreper

1000

(from13

fewerto138

more)

⨁⨁◯◯

LOWCRITICAL


Qualityassessment


Quality ImportanceNumberofstudies Studydesign Riskofbias Inconsistency Indirectness Imprecision

Other

considera/o

ns

Self-

administered

therapyDOT

Rela/ve

(95%CI)Absolute

(95%CI)

Relapse–cohorts

6 observa/onal

studiesseriousa seriousb notserious seriousc none 103/937

(11.0%)36/99

2

(3.6%)

not

es/mab

le

60moreper

1000

(from30

fewerto150

more)

⨁◯◯◯

VERYLOWCRITICAL

Relapse–RCTs(follow-up:mean24months)

1 randomizedtrials seriousd notserious notserious very

seriousc,enone 15/290(5.2%) 23/25

9

(8.9%)

RR0.58

(0.31to

1.09)

37fewerper

1000

(from8more

to61fewer)

⨁◯◯◯

VERYLOWCRITICAL

Adherence–cohorts

2 observa/onal

studiesnotserious notserious seriousf notserious strong

associa/on961/1392

(69.0%)1634/

1936

(84.4

%)

RR0.83

(0.80to

0.86)

143fewerper

1000

(from118

fewerto169

fewer)

⨁⨁◯◯

LOWCRITICAL

Adherence–RCTs(follow-up:mean6months)

1 randomizedtrials seriousg notserious notserious seriousc none 78/86(90.7%) 84/87

(96.6

%)

RR0.94

(0.87to

1.02)

58fewerper

1000

(from19

moreto126

fewer)

⨁⨁◯◯

LOWCRITICAL



Quality ImportanceNumberofstudies Studydesign Riskofbias Inconsistency Indirectness

Imprecisio

nOther

considera/ons

Self-

administered

therapyDOT

Rela/ve

(95%CI)Absolute

(95%CI)

Smearconversion–cohortstudies

2 observa/onalstudies seriousa notserious notserious seriousb none 49/60(81.7%) 324/407

(79.6%)RR0.92


1000

(from64more

to175fewer)

⨁◯◯◯

VERYLOWCRITICAL

Smearconversion–RCTs

1 randomizedtrials seriousc notserious notserious not

seriousnone 345/422

(81.8%)366/414

(88.4%)RR0.92


1000

(from18

fewerto115

fewer)

⨁⨁⨁◯

MODERATECRITICAL

Acquisi,onofdrugresistance


seriousdveryseriouse notserious seriousb none 202/2644

(7.6%)71/3284

(2.2%)notes/mable 50fewerper

1000

(from0fewer

to90fewer)

⨁◯◯◯

VERYLOWCRITICAL

Conclusion

•  Theratesoftreatmentsuccess,cure,adherenceandsputumconversionwerelowerandtherateoflosstofollow-upattwomonthswashigherwithself-administeredtherapycomparedwithDOT.

Self-administeredtherapyversusDOTinpa,entswithTB

andHIV


31

22/02/18

4



Quality ImportanceNumberofstudies Studydesign Riskofbias Inconsistency

Indirectnes

sImprecision

Other

considera/ons

Self-

administered

therapyDOT

Rela/ve

(95%CI)Absolute

(95%CI)


3 observa/onalstudies seriousa notserious not

seriousseriousb none 27/181

(14.9%)13/193

(6.7%)RR2.74


1000

(from34more

to269more)

⨁◯◯◯

VERYLOWCRITICAL

Success–cohortstudies


seriousnotserious strongassocia/on 45/158

(28.5%)710/865

(82.1%)RR0.41


1000

(from337

fewerto583

fewer)

⨁⨁◯◯

LOWCRITICAL



seriousseriousc none 1/39(2.6%) 11/44

(25.0%)RR0.10


1000

(from60fewer

to248fewer)

⨁◯◯◯

VERYLOWCRITICAL



seriousnotserious strongassocia/on 35/151

(23.2%)85/145

(58.6%)RR0.40


1000

(from264

fewerto416

fewer)

⨁⨁◯◯

LOWCRITICAL


Qualityassessment



Indirectne

ssImprecisio

nOther

considera/ons

Self-

administered

therapyDOT

Rela/ve

(95%CI)Absolute

(95%CI)



seriousnot

seriousstrong

associa/on71/112(63.4%) 20/101

(19.8%)RR3.20

(2.11to

4.86)

436moreper

1000

(from220

moreto764

more)

⨁⨁◯◯

LOWCRITICAL

Default–cohortstudies

2 observa/onalstudies seriousa seriousb not

seriousseriousc none 229/1156

(19.8%)66/387

(17.1%)RR1.94

(0.52to

7.17)

160moreper

1000

(from82

fewerto1000

more)

⨁◯◯◯

VERYLOWCRITICAL

Relapse–cohortstudies


seriousseriousc none 2/112(1.8%) 2/101(2.0%) RR0.90

(0.13to

6.28)

2fewerper

1000

(from17

fewerto105

more)

⨁◯◯◯

VERYLOWCRITICAL

Conclusions

•  Theratesoftreatmentsuccess,comple/on

andcurewerelowerandtherateof

treatmentfailurewashigherwithself-

administeredtherapyamongTBpa/entswith

HIV.

Self-administeredtherapyversus

DOTinpa/entswithMDR-TB

Findings–MDR-TB

•  Basharetal.,Chest,2001•  Retrospec/vecohortstudy,1987–1997•  BellevueHospital,NewYorkCity•  Pa/entswithTBandtype2diabetesversusTBalone,regardlessofHIVstatus

•  Primaryobjec/ve:comparisonofratesofMDR-TB

•  Secondaryobjec/ve:outcomesinthe28pa/ents

withMDR-TB

Findings–MDR-TB

•  n=28•  11self-administeredtherapy,17DOT

•  Self-administeredtherapyversusDOT

•  Mortality:RR6.18(95%CI:0.79,48.30)

•  Comple/on:RR0.42(95%CI:0.15,1.18)

•  Noncompliance(notdefined):RR2.32(95%CI:0.46,

11.72)

•  6/17pa/entsinDOTunderwentlungresec/on•  Pa/entsallhadtype2diabetes


32

22/02/18

5

DOTprovidertypes


Qualityassessment



Indirectn

essImprecisio

nOther

considera/onsdifferentDOT

providersstandard

providersRela/ve

(95%CI)Absolute

(95%CI)

Mortality–familyDOTversushealth-careworkers


seriousnot

seriousnone 589/4774

(12.3%)281/2357

(11.9%)RR1.05


1000

(from11

fewerto25

more)

⨁◯◯◯

VERYLOWCRITICAL

Mortality–layproviderversushealth-careworkers


seriousseriousb none 113/2875(3.9%) 135/2599(5.2%) RR0.73


1000

(from7more

to28fewer)

⨁◯◯◯

VERYLOWCRITICAL

Success–familyversushealth-careworkers



(66.2%)1705/2357

(72.3%)RR0.85


1000

(from43more

to239fewer)

⨁◯◯◯

VERYLOWCRITICAL

Success–layproviderversushealth-careworkers

3 observa/onalstudies seriousa seriousc not


(85.0%)1658/2173

(76.3%)RR1.09


1000

(from53

fewerto206

more)

⨁◯◯◯

VERYLOWCRITICAL


Qualityassessment



Inconsisten

cyIndirectness Imprecision Otherconsidera/ons

DOT

providerPlacebo

Rela/ve

(95%CI)Absolute

(95%CI)


3 observa/onalstudies seriousa not

seriousnotserious notserious none 2513/6

513

(38.6%)

879/2409

(36.5%)RR0.97

(0.93to

1.02)

11fewerper

1000

(from7more

to26fewer)

⨁◯◯◯

VERYLOWCRITICAL

Cure–familyversushealth-careworkers

2 observa/onalstudies seriousa seriousb notserious seriousc none 1944/4

774

(40.7%)

1115/2357

(47.3%)RR0.52

(0.16to

1.66)

227fewerper

1000

(from312

moreto397

fewer)

⨁◯◯◯

VERYLOWCRITICAL

Cure–layproviderversushealth-careworkers


(88.9%)1292/1736

(74.4%)RR1.09

(0.81to

1.47)

67moreper

1000

(from141

fewerto350

more)

⨁◯◯◯

VERYLOWCRITICAL




Other

considera/onsDifferentDOT

providersStandard

providersRela/ve

(95%CI)Absolute

(95%CI)

Failure–familyversushealth-careworkers

2 observa/onalstudies seriousa notserious notserious seriousb none 74/4774

(1.6%)20/2357

(0.8%)notes/mable 10moreper

1000

(from0fewer

to10more)

⨁◯◯◯

VERY

LOW

CRITICAL

Failure–layproviderversushealth-careworkers

3 observa/onalstudies seriousa seriousc notserious very

seriousb,dnone 38/1411

(2.7%)94/2173

(4.3%)RR0.47


1000

(from13more

to36fewer)

⨁◯◯◯

VERY

LOW

CRITICAL


Qualityassessment



Indirectne

ssImprecision

Other

considera/onsDifferentDOT

providersStandard

providersRela/ve

(95%CI)Absolute

(95%CI)

Losstofollow-up–familyversushealth-careworkers


seriousnotserious none 403/4774

(8.4%)128/2357

(5.4%)RR1.48


1000

(from11more

to44more)

⨁◯◯◯

VERYLOWCRITICAL

Losstofollow-up–cohortstudies


seriousseriousc none 129/1411

(9.1%)218/2173

(10.0%)RR0.75


1000

(from32more

to58fewer)

⨁◯◯◯

VERYLOWCRITICAL

Adherence–cohortstudies

1 observa/onalstudies notserious notserious not

seriousnotserious none 95/117(81.2%) 302/320

(94.4%)RR0.86


1000

(from57

fewerto198

fewer)

⨁⨁◯◯

LOWCRITICAL

Conclusion

•  Theperformanceoffamilyorlayproviders

wassimilartothatofins/tu/onalproviders

formostoutcomesofinterest.

•  Therateoflosstofollow-upwashigherandtherateofadherencewaslowerwithfamily

andlayDOTproviders.


33

22/02/18

6

DOTloca/on




Inconsisten

cy

Indirectnes

s

Imprecisio

n

Other

considera/on

s

DOTatdifferent

loca/ons

Clinicorrou/ne

care

Rela/ve

(95%CI)

Absolute

(95%CI)

Mortality–cohorts(homeorcommunityversusclinic)


serious

seriousc none 195/4148(4.7%) 263/5793(4.5%) notes/mable 0fewerper

1000

(from10

fewerto20

more)

⨁◯◯◯

VERYLOW

CRITICAL

Mortality–RCTs(communityversusclinic)

2 randomizedtrials seriousd seriousb not

serious

seriousc none 29/481(6.0%) 69/628(11.0%) RR0.36

(0.06to2.33)

70fewerper

1000

(from103

fewerto146

more)

⨁◯◯◯

VERYLOW

CRITICAL

Success–cohorts(homeorcommunityversusclinic)


serious

not

serious

none 4464/5654

(79.0%)

7384/9340

(79.1%)

RR1.10

(1.06to1.14)

79moreper

1000

(from47more

to111more)

⨁◯◯◯

VERYLOW

CRITICAL

Success–RCTs(homeorcommunityversusclinic)

2 randomizedtrials notserious not

serious

not

serious

not

serious

none 540/618(87.4%) 736/876(84.0%) RR1.04

(1.00to1.09)

34moreper

1000

(from0fewer

to76more)

⨁⨁⨁⨁

HIGH

CRITICAL

Comple,on–cohortstudies(homeorcommunityversusclinic)


serious

seriousc none 657/3336

(19.7%)

810/4754

(17.0%)

RR0.93

(0.56to1.55)

12fewerper

1000

(from75

fewerto94

more)

⨁◯◯◯

VERYLOW

CRITICAL


Qualityassessment



Imprecisi

on

Other

considera/on

sDOTloca/on Placebo

Rela/ve

(95%CI)Absolute

(95%CI)

Comple,on–cohortstudies(homeorcommunityversusclinic)


(19.7%)810/4754

(17.0%)RR0.93


1000

(from75

fewerto94

more)

⨁◯◯◯

VERYLOWCRITICAL

Comple,on–RCTs(communityversusclinic)

1 randomizedtrials notserious notserious notserious seriousd none 14/143(9.8%) 6/179(3.4%) RR2.92


1000

(from5more

to215more)

⨁⨁⨁◯

MODERATECRITICAL

Cure–cohortstudies(homeorcommunityversusclinic)


(61.3%)3933/5912

(66.5%)RR1.11


1000

(from7fewer

to160more)

⨁◯◯◯

VERYLOWCRITICAL

Cure–RCTs(homeorcommunityversusclinic)

2 randomizedtrials seriouse notserious notserious seriousc none 228/364(62.6%) 289/480(60.2%) RR1.01


1000

(from48

fewerto72

more)

⨁⨁◯◯

LOWCRITICAL


Qualityassessment



Other

considera/on

sDOTloca/on Placebo

Rela/ve

(95%CI)Absolute

(95%CI)

Failure–cohortstudies(homeorcommunityversusclinic)


(1.1%)185/4762


1000

(from30fewer

to0fewer)

⨁◯◯◯

VERYLOWCRITICAL

Failure–RCTs(homeversuscommunity)

1 randomizedtrials notserious notserious notserious very

seriousc,dnone 1/662(0.2%) 1/664(0.2%) RR1.00


1000

(from1fewer

to23more)

⨁⨁◯◯

LOWCRITICAL

Failure–RCTs(communityversusclinic)

1 randomizedtrials seriouse notserious notserious very

seriousc,dnone 2/221(0.9%) 4/301(1.3%) RR0.68


1000

(from12fewer

to36more)

⨁◯◯◯

VERYLOWCRITICAL


Qualityassessment



Other

considera/

ons

DOTatdifferent

loca/onsClinicorrou/ne

careRela/ve

(95%CI)Absolute

(95%CI)

Losstofollow-up–cohorts(homeorcommunityversusclinic)

9 observa/onalstudies seriousa seriousb notserious

notserious none 445/4089

(10.9%)641/5681

(11.3%)RR0.59


1000

(from14fewer

to69fewer)

⨁◯◯◯

VERYLOWCRITICAL

Losstofollow-up–RCTs(homeorcommunityversusclinic)

2 randomizedtrials seriousc seriousb notserious seriousd none 92/481(19.1%) 84/628(13.4%) RR1.04


1000

(from88fewer

to293more)

⨁◯◯◯

VERYLOWCRITICAL

Adherence–cohortstudies(homeorcommunityversusclinic)

2 observa/onalstudies seriousa notserious seriouse seriousd none 126/152

(82.9%)336/360

(93.3%)RR0.93


1000

(from112

moreto215

fewer)

⨁◯◯◯

VERYLOWCRITICAL




Inconsisten

cyIndirectness

Imprecisio

nOther

considera/onsDOTloca/on Placebo

Rela/ve

(95%CI)Absolute

(95%CI)

Sputumconversion(secondmonth)–cohortstudies(homeorcommunityversusclinic)

5 observa/onalstudies seriousa seriousb notserious not


(91.8%)2369/2737

(86.6%)RR1.15


1000

(from17more

to251more)

⨁◯◯◯

VERYLOWCRITICAL

Sputumconversion(secondmonth)–RCTs(homeorcommunityversusclinic)

1 randomizedtrials seriousc not

seriousnotserious seriousd none 168/221(76.0%) 209/301(69.4%) RR1.09


1000

(from7fewer

to153more)

⨁⨁◯◯

LOWCRITICAL

Unfavourableoutcome(communityversusclinic)


seriousseriouse not

seriousstrong

associa/on309/1646

(18.8%)332/1123

(29.6%)RR0.63


1000

(from80fewer

to133fewer)

⨁◯◯◯

VERYLOW


34

22/02/18

7

Conclusion

•  Theratesoftreatmentsuccess,comple/on

andsputumconversionwerehigherwithDOT

athomeorinthecommunity.

•  Theratesoflosstofollow-uporunfavourableoutcomewerelowerwithDOTathomeorina

communityseong.

Pa/enteduca/onand

counselling


Qualityassessment



Inconsistenc

y

Indirect

nessImprecision

Other

considera/o

ns

Pa/ent

educa/onand

counselling

PlaceboRela/ve

(95%CI)

Absolute

(95%CI)

Mortality–RCTs

2 randomized

trials

seriousa notserious not

serious

very

seriousb,c

none 17/537(3.2%) 24/596

(4.0%)

RR0.83

(0.34to

2.05)

7fewerper

1000

(from27

fewerto42

more)

⨁◯◯◯

VERYLOW

CRITICAL

Treatmentsuccess

2 randomized

trials

seriousd seriouse not

serious

seriousb none 321/604(53.1%) 262/615

(42.6%)

RR1.40

(0.90to

2.17)

170more

per1000

(from43

fewerto498

more)

⨁◯◯◯

VERYLOW

CRITICAL

Treatmentcomple,on

1 randomized

trials

seriousd notserious not

serious

notserious strong

associa/on

72/100(72.0%) 42/100

(42.0%)

RR1.71

(1.32to

2.22)

298more

per1000

(from134

moreto512

more)

⨁⨁⨁⨁

HIGH

CRITICAL




Inconsist

encyIndirectn

essImprecisio

nOtherconsidera/ons

Addi/onalpa/ent

educa/onand

counsellingRou/necare

Rela/ve

(95%CI)Absolute

(95%CI)

Cure

1 randomizedtrials seriousa not

seriousnot

seriousnot

seriousverystrongassocia/on 28/33(84.8%) 32/81

(39.5%)RR2.15


1000

(from229

moreto759

more)

⨁⨁⨁⨁

HIGHCRITICAL

Failure

1 randomizedtrials seriousa not

seriousnot

seriousvery

seriousb,cnone 2/33(6.1%) 4/81(4.9%) RR1.23


1000

(from38fewer

to266more)

⨁◯◯◯

VERYLOWCRITICAL

Losstofollow-up

3 randomizedtrials seriousa,d seriouse not

seriousseriousb none 254/637(39.9%) 344/696

(49.4%)RR0.49


1000

(from84more

to390fewer)

⨁◯◯◯

VERYLOWCRITICAL


Qualityassessment



Other

consider

a/ons

Pa/enteduca/on

andcounsellingPlacebo

Rela/ve

(95%CI)Absolute

(95%CI)

Adherence–RCT

1 randomizedtrials seriousa notserious notserious notserious none 30/56(53.6%) 17/58

(29.3%)RR1.83

(1.14to

2.92)

243moreper

1000

(from41more

to563more)

⨁⨁⨁◯

MODERATECRITICAL

Adherence–cohortstudies

1 observa/onalstudies notserious notserious notserious notserious none 57/60(95.0%) 47/60

(78.3%)RR1.21

(1.05to

1.40)

164moreper

1000

(from39more

to313more)

⨁⨁◯◯

LOWCRITICAL

Conclusions

•  Theratesoftreatmentcomple/on,cureand

adherencewerehigherwithpa/enteduca/on

andcounsellinginterven/ons.


35

22/02/18

8

Incen/vesandenablers


Qualityassessment



Imprecisio

nOther

considera/onsIncen/vesand

enablersNone

Rela/ve

(95%CI)Absolute

(95%CI)


3 observa/onalstudies seriousa seriousb notserious seriousc none 37/482(7.7%) 219/2101

(10.4%)RR0.51


1000

(from30

fewerto66

fewer)

⨁◯◯◯

VERYLOWCRITICAL

Mortality–RCTs

2 randomizedtrials notserious notserious notserious seriousd none 151/2157(7.0%) 139/2034


1000

(from40

fewerto30

more)

⨁⨁⨁◯

MODERATECRITICAL


4 observa/onalstudies seriousa seriousb notserious not


(72.0%)2021/2999

(67.4%)RR1.25


1000

(from61more

to283more)

⨁◯◯◯

VERYLOWCRITICAL


3 randomizedtrials seriouse notserious notserious not


(76.5%)1543/2162

(71.4%)RR1.07


1000

(from21more

to79more)

⨁⨁⨁◯

MODERATECRITICAL



Quality ImportanceNumber

ofstudies

StudydesignRiskof

biasInconsistency

Indirectn

essImprecision

Other


enablersNone

Rela/ve

(95%CI)Absolute

(95%CI)

Treatmentcomple,on–cohortstudies

3 observa/ona

lstudiesseriousa

seriousb not

seriousseriousc none 206/345(59.7%) 185/158

6(11.7%)RR1.25

(0.85to

1.83)

29more

per1000

(from17

fewerto

97more)

⨁◯◯◯

VERY

LOW

CRITICAL

Treatmentcomple,on–RCTs

2 randomized

trialsnot

seriousnotserious not

seriousnotserious none 960/2157

(44.5%)735/203

4(36.1%)RR1.23

(1.15to

1.31)

83more

per1000

(from54

moreto

112more)

⨁⨁⨁⨁

HIGHCRITICAL


Qualityassessment



Indirectnes

sImprecision

Other


enablersNone

Rela/ve

(95%CI)Absolute

(95%CI)


2 observa/onalstudies seriousa notserious notserious not

seriousstrong

associa/on173/191

(90.6%)1158/1509

(76.7%)RR1.24


1000

(from138

moreto230

more)

⨁⨁◯◯

LOWCRITICAL

Cure–RCTs

1 randomizedtrials notserious notserious notserious seriousb none 695/2107

(33.0%)708/1984

(35.7%)RR0.92


1000

(from4more

to54fewer)

⨁⨁⨁◯

MODERATECRITICAL




Indirectnes

sImprecision

Other

considera/

ons

Incen/ves

and

enablersNone

Rela/ve

(95%CI)Absolute

(95%CI)

Treatmentfailure–cohortstudies

2 observa/onalstudies seriousa notserious notserious seriousb none 2/309

(0.6%)141/2008


1000

(from120

fewerto20

more)

⨁◯◯◯

VERYLOWCRITICAL

Treatmentfailure–RCTs

1 randomizedtrials notserious notserious notserious seriousb none 79/2107

(3.7%)113/1984

(5.7%)RR0.66


1000

(from7fewer

to28fewer)

⨁⨁⨁◯

MODERATECRITICAL


QualityassessmentNumberofpa,ents Effect

Quality Importance

Numberofstudies Studydesign Riskofbias Inconsistency Indirectness

Imprecisio

nOther


enablersNone

Rela/ve

(95%CI)Absolute

(95%CI)


5 observa/onal

studiesseriousa seriousb notserious not


(10.6%)236/2326


1000

(from130

fewerto40

more)

⨁◯◯◯

VERYLOWCRITICAL


1 randomizedtrials notserious notserious notserious not

seriousnone 158/2107(7.5%) 202/1984

(10.2%)RR0.74


1000

(from10

fewerto41

fewer)

⨁⨁⨁⨁

HIGHCRITICAL


36

22/02/18

9




Indirectn

essImprecision

Other

considera/on

s

Incen/vesand

enablersNone

Rela/ve

(95%CI)Absolute

(95%CI)

Acquisi,onofresistance

1 randomizedtrials notserious notserious not

seriousveryseriousa,b none 1/2107(0.0%) 3/1984

(0.2%)RR0.31


1000

(from1fewer

to3more)

⨁⨁◯◯

LOWCRITICAL

Sputumconversionrate–RCTs


seriousnotserious none 35/36(97.2%) 29/36

(80.6%)RR1.21


1000

(from16more

to346more)

⨁⨁⨁⨁

HIGHCRITICAL

Conclusions

•  Theratesofmortality,treatmentfailureand

losstofollow-upwerelowerwithincen/ves

andenablers.

•  Theratesoftreatmentsuccess,comple/on,

cureandsputumconversionwerehigherwith

incen/vesandenablers.

Remindersandtracers




Other

considera/onsRemindersand

tracersNone

Rela/ve

(95%CI)Absolute

(95%CI)


3 observa/on

alstudiesseriousa notserious notserious seriousb none 16375/182194

(9.0%)18044/22463

1(8.0%)notes/mable 20fewerper

1000

(from70

fewerto30

more)

⨁◯◯◯

VERYLOWCRITICAL

Mortality–RCTs

1 randomized

trialsnotserious notserious notserious very

seriousb,cnone 3/240(1.3%) 8/240(3.3%) RR0.38


1000

(from13more

to30fewer)

⨁⨁◯◯

LOWCRITICAL


3 observa/on

alstudiesseriousa seriousd notserious seriousb none 129645/18219

4(71.2%)171637/2246

31(76.4%)RR1.03


1000

(from84

fewerto153

more)

⨁◯◯◯

VERYLOWCRITICAL


4 randomized

trialsseriouse seriousd notserious notserious none 361/389

(92.8%)303/389

(77.9%)RR1.12


1000

(from8more

to203more)

⨁⨁◯◯

LOWCRITICAL


Qualityassessment



Inconsisten


Other

considera/onsReminders

andtracersNone

Rela/ve

(95%CI)Absolute

(95%CI)

Treatmentcomple,on–cohortstudies

1 observa/onalstudies notserious notserious notserious notserious none 20579/1812

83(11.4%)19697/22

4390

(8.8%)

RR1.29


1000

(from24more

to28more)

⨁⨁◯◯

LOWCRITICAL

Treatmentcomple,on–RCTs

2 randomizedtrials seriousa seriousb notserious seriousc none 59/94

(62.8%)115/158


1000

(from310

fewerto190

more)

⨁◯◯◯

VERYLOWCRITICAL


2 observa/onalstudies seriousd seriousb notserious very

seriouscnone 108459/181

319(59.8%)151810/2

24496

(67.6%)

RR1.28


1000

(from277

fewerto1000

more)

⨁◯◯◯

VERYLOWCRITICAL


3 observa/onalstudies seriousd notserious notserious notserious none 4208/18219

4(2.3%)4687/224


1000

(from0fewer

to0fewer)

⨁◯◯◯

VERYLOWCRITICAL


Qualityassessment



Other

considera/onsRemindersand

tracersNone

Rela/ve

(95%CI)Absolute

(95%CI)


4 observa/onal

studiesseriousa seriousb notserious seriousc none 20935/182822

(11.5%)18637/2252


1000

(from150

fewerto40

more)

⨁◯◯◯

VERYLOWCRITICAL


2 randomized

trialsnotserious notserious notserious veryseriousc,d none 7/304(2.3%) 42/367

(11.4%)RR0.23


1000

(from66more

to111fewer)

⨁⨁◯◯

LOWCRITICAL

Adherence

2 randomized

trialsseriouse notserious notserious notserious none 361/547

(66.0%)94/200

(47.0%)RR1.41


1000

(from66more

to357more)

⨁⨁⨁◯

MODERATECRITICAL


37

22/02/18

10




Inconsisten

cyIndirectness

Imprecisi

on

Other

considera/on

s

Reminders

andtracersNone

Rela/ve

(95%CI)Absolute

(95%CI)

Sputumandcultureconversionat2months

2 randomizedtrials seriousa notserious notserious not

seriousnone 209/247

(84.6%)166/248

(66.9%)RR1.26


1000

(from94more

to268more)

⨁⨁⨁◯

MODERATECRITICAL

Developmentofdrugresistance–cohortstudies

1 observa/onalstudies notserious notserious notserious not


83(0.3%)1452/22439

0(0.6%)RR0.50


1000

(from3fewer

to4fewer)

⨁⨁◯◯

LOWCRITICAL

Conclusion

•  Theratesoftreatmentsuccess,comple/on,

adherenceandsputumconversionwere

higherwithremindersandtracers.

•  Therateofdrugresistancedevelopmentwas

lowerwithremindersandtracers.

Mixedinterven/ons


Qualityassessment



Inconsisten


Other

considera/on

s

Mixedcase

management

interven/onsnone

Rela/ve

(95%CI)Absolute

(95%CI)

Mortality–cohortstudies(enhancedDOTversusself-administeredtherapy)

4 observa/onalstudies seriousa seriousb notserious very

seriousc,dnone 64/2063(3.1%) 64/1311


1000

(from130

fewerto30

more)

⨁◯◯◯

VERYLOWCRITICAL

Mortality–cohortstudies(enhancedDOTversusDOT)

2 observa/onalstudies seriousa seriousb notserious seriousc none 285/6411(4.4%) 575/1173

9(4.9%)RR0.93


1000

(from17more

to18fewer)

⨁◯◯◯

VERYLOWCRITICAL

Mortality–RCTs(mixedinterven,onsversusself-administeredtherapy)

2 randomizedtrials seriouse not

seriousnotserious very

seriousc,dnone 15/219(6.8%) 19/236

(8.1%)RR0.88


1000

(from45

fewerto60

more)

⨁◯◯◯

VERYLOWCRITICAL

Mortality–RCTs(enhancedDOTversusDOT)

1 randomizedtrials seriouse not

seriousnotserious very

seriousc,dnone 12/778(1.5%) 25/744

(3.4%)RR0.46


1000

(from3fewer

to26fewer)

⨁◯◯◯

VERYLOWCRITICAL




Other

considera/on

s

Mixedcase

management

interven/onsNone

Rela/ve

(95%CI)Absolute

(95%CI)

Treatmentsuccess–cohortstudies(enhancedDOTversusself-administeredtherapy)

2 observa/on

alstudiesseriousa notserious notserious not

seriousnone 1607/1920(83.7%) 747/1075

(69.5%)RR1.22


1000

(from111

moreto188

more)

⨁◯◯◯

VERYLOWCRITICAL

Treatmentsuccess–cohortstudies(enhancedDOTversusDOT)

3 observa/on

alstudiesnotserious seriousb notserious not

seriousnone 5371/6611(81.2%) 8546/11929

(71.6%)RR1.27


1000

(from64more

to351more)

⨁◯◯◯

VERYLOWCRITICAL

Treatmentsuccess–RCTs(enhancedDOTversusself-administeredtherapy)

1 randomized

trialsseriousc notserious notserious not

seriousnone 30/32(93.8%) 22/32

(68.8%)RR1.36


1000

(from41more

to516more)

⨁⨁⨁◯

MODERATECRITICAL

Treatmentsuccess–RCTs(enhancedDOTversusDOT)

2 randomized

trialsseriousc notserious notserious not

seriousnone 720/828(87.0%) 594/794

(74.8%)RR1.16


1000

(from82more

to165more)

⨁⨁⨁◯

MODERATECRITICAL


Qualityassessment



Inconsis

tencyIndirectness

Imprecisio

n

Other

considera

/ons

Mixedcase

management

interven/onsNone

Rela/ve

(95%CI)Absolute

(95%CI)

Treatmentcomple,on–cohortstudies(enhancedDOTversusself-administeredtherapy)



seriousnone 97/179(54.2%) 177/

582(30.4%)RR1.84

(1.52to

2.21)

255moreper

1000

(from158

moreto368

more)

⨁◯◯◯

VERYLOWCRITICAL

Treatmentcomple,on–cohortstudies(enhancedDOTversusDOT)

2 observa/onalstudies notserious seriousb notserious seriousc none 2407/6411(37.5%) 4823/1173

9(41.1%)RR0.85

(0.52to

1.38)

62fewerper

1000

(from156

moreto197

fewer)

⨁◯◯◯

VERYLOWCRITICAL

Treatmentcomple,on–RCTs(enhancedDOTversusself-administeredtherapy)



seriousnone 31/32(96.9%) 22/32

(68.8%)RR1.41

(1.11to

1.79)

282moreper

1000

(from76more

to543more)

⨁⨁⨁◯

MODERATECRITICAL

Treatmentcomple,on–RCTs(enhancedDOTversusDOT)


seriousnotserious seriousc none 47/828(5.7%) 56/794

(7.1%)RR0.83

(0.58to

1.19)

12fewerper

1000

(from13more

to30fewer)

⨁⨁◯◯

LOWCRITICAL


38

22/02/18

11




Inconsiste

ncyIndirectness

Imprecisio

n

Other

considera/o

ns

Mixed

case

managem

ent

interven/

ons

NoneRela/ve

(95%CI)

Absolute

(95%CI)

Cure–cohortstudies(enhancedDOTversusDOT)

2 observa/onal

studies

not

serious

seriousa notserious seriousb none 2803/56

37

(49.7%)

3640/10

725

(33.9%)

RR1.41

(0.67to

2.96)

139moreper

1000

(from112

fewerto665

more)

⨁◯◯◯

VERYLOW

CRITICAL

Cure–RCTs(enhancedDOTversusDOT)


serious

notserious not

serious

none 649/778

(83.4%)

520/744

(69.9%)

RR1.19

(1.13to

1.26)

133moreper

1000

(from91

moreto182

more)

⨁⨁⨁◯

MODERATE

CRITICAL


Qualityassessment



Inconsisten


Other

considera/ons

Mixed

case

manage

ment

interven

/ons

NoneRela/ve

(95%CI)Absolute

(95%CI)

Cure–cohortstudies(enhancedDOTversusself-administeredtherapy)


9

(91.6%)

179/253

(70.8%)RR1.42


1000

(from14more

to700more)

⨁◯◯◯

VERYLOWCRITICAL

Cure–RCTs(enhancedDOTversusself-administeredtherapy)

1 randomizedtrials seriousd notserious notserious notserious none 30/32

(93.8%)22/32

(68.8%)RR1.36


1000

(from41more

to516more)

⨁⨁⨁◯

MODERATECRITICAL

Cure–RCTs(mixedcasemanagementversusself-administeredtherapy)

2 randomizedtrials seriousd notserious notserious notserious none 169/21

5

(78.6%)

160/236

(67.8%)RR1.15


1000

(from20more

to197more)

⨁⨁⨁◯

MODERATECRITICAL


Qualityassessment



Impreci

sion

Other

conside

ra/ons

Mixedcase

management

interven/ons

NoneRela/ve

(95%CI)

Absolute

(95%CI)

Failure–cohortstudies(enhancedDOTversusDOT)

2 observa/onal

studies

notserious notserious notserious very

seriousa,b

none 34/6017(0.6%) 93/11268

(0.8%)

RR0.64

(0.23to1.77)

3fewerper

1000

(from6fewer

to6more)

⨁◯◯◯

VERYLOW

CRITICAL

Failure–cohortstudies(enhancedDOTversusself-administeredtherapy)

2 observa/onal

studies

seriousc notserious notserious seriousd

none 2/1920(0.1%) 4/1075(0.4%) notes/mable 0fewerper

1000

(from20

fewerto10

more)

⨁◯◯◯

VERYLOW

CRITICAL

Failure–RCTs(mixedcasemanagementversusself-administeredtherapy)


seriousa,d

none 2/42(4.8%) 4/81(4.9%) RR0.96

(0.18to5.05)

2fewerper

1000

(from40

fewerto200

more)

⨁◯◯◯

VERYLOW

CRITICAL

Failure–RCTs(enhancedDOTversusDOT)


seriousa,d

none 12/778(1.5%) 6/744(0.8%) RR1.91

(0.72to5.07)

7moreper

1000

(from2fewer

to33more)

⨁◯◯◯

VERYLOW

CRITICAL


Qualityassessment



Inconsiste

ncyIndirectness Imprecision

Other

considera/ons

Mixedcase

management

interven/ons

NoneRela/ve

(95%CI)

Absolute

(95%CI)

Losstofollow-up–cohortstudies(enhancedDOTversusDOT)

2 observa/onal

studies

notserious seriousa notserious seriousb none 673/6411

(10.5%)

1962/11739

(16.7%)

RR0.47

(0.14to

1.61)

89fewerper

1000

(from102

moreto144

fewer)

⨁◯◯◯

VERYLOW

CRITICAL

Losstofollow-up–RCTs(enhancedDOTversusDOT)


serious

notserious notserious none 52/828

(6.3%)

142/794(17.9%) RR0.38

(0.25to

0.57)

111fewerper

1000

(from77

fewerto134

fewer)

⨁⨁⨁◯

MODERATE

CRITICAL

Losstofollow-up–cohortstudies(enhancedDOTversusself-administeredtherapy)

4 observa/onal

studies

seriousd seriousa notserious seriouse none 150/2099

(7.1%)

445/1657

(26.9%)

RR0.61

(0.32to

1.14)

105fewerper

1000

(from38

moreto183

fewer)

⨁◯◯◯

VERYLOW

CRITICAL

Losstofollow-up–RCTs(mixedcasemanagementversusself-administeredtherapy)


serious

notserious seriousf none 23/219

(10.5%)

44/236(18.6%) RR0.58

(0.36to

0.93)

78fewerper

1000

(from13

fewerto119

fewer)

⨁⨁◯◯

LOW

CRITICAL


Qualityassessment



Inconsist

encyIndirectness

Imprecis

ionOther

considera/ons

Mixedcase

management

interven/onsNone

Rela/ve

(95%CI)Absolute

(95%CI)

Relapse–cohortstudies(enhancedDOTversusself-administeredtherapy)


seriousnotserious seriousb none 0/149(0.0%) 3/223(1.3%) notes/mable 10moreper

1000

(from30more

to10fewer)

⨁◯◯◯

VERYLOWCRITICAL

Adherence(enhancedDOTversusDOT)


seriousnotserious seriousd none 40/50(80.0%) 38/50

(76.0%)RR1.05


1000

(from114

fewerto228

more)

⨁⨁◯◯

LOWCRITICAL

Adherence(mixedcasemanagementversusself-administeredtherapy)


seriousnotserious seriouse none 29/41(70.7%) 24/42

(57.1%)RR1.24


1000

(from63fewer

to411more)

⨁⨁◯◯

LOWCRITICAL


Qualityassessment



Imprecisio

n

Other

considera/on

s

Mixedcase

management

interven/onsNone

Rela/ve

(95%CI)Absolute

(95%CI)

Sputumsmearconversionrate(secondmonth)–RCTs(enhancedDOTversusself-administeredtherapy)

1 randomizedtrials seriousa notserious notserious seriousb none 28/32(87.5%) 17/32

(53.1%)RR1.65


1000

(from85more

to712more)

⨁⨁◯◯

LOWCRITICAL

Acquireddrugresistance–cohortstudies(enhancedDOTversusself-administeredtherapy)

1 observa/onalstudies seriousc notserious notserious seriousd,e none 0/149(0.0%) 2/223(0.9%) notes/mable 10moreper

1000

(from30more

to10fewer)

⨁◯◯◯

VERYLOWCRITICAL


39

22/02/18

12

Conclusions

•  TheratesoftreatmentsuccessandcurewerehigherwithenhancedDOTinterven/onsversusself-administeredtherapyorDOTalone.

•  Theratesoftreatmentcomple/onandtwo-monthsputumconversionwerehigherwithenhancedDOTinterven/onsversusself-administeredtherapy.

•  Theratesofmortalityandlosstofollow-upwerelowerwithenhancedDOTinterven/onsversusDOTalone.

•  Therateoflosstofollow-upwaslowerwithmixedcasemanagementinterven/onsversusself-administeredtherapy.

Psychological


Qualityassessment



Inconsiste

ncyIndirectness Imprecision

Other

considera/o

ns

Psychol

ogical

interve

n/ons

NoneRela/ve

(95%CI)

Absolute

(95%CI)


1 observa/onal

studies

seriousa not

serious

notserious very

seriousb,c

none 11/64

(17.2%)

6/64(9.4%) RR1.83

(0.72to

4.66)

78moreper

1000

(from26

fewerto343

more)

⨁◯◯◯

VERYLOW

CRITICAL

Success–RCTs(alcoholcessa,oncounselling)


serious

notserious seriousb none 80/92

(87.0%)

83/104

(79.8%)

RR1.09

(0.96to

1.23)

72moreper

1000

(from32

fewerto184

more)

⨁⨁⨁◯

MODERATE

CRITICAL

Treatmentcomple,on–cohortstudies(supportgroups)

1 observa/onal

studies

seriousa not

serious


(68.8%)

30/64

(46.9%)

RR1.47

(1.08to

2.00)

220moreper

1000

(from38

moreto469

more)

⨁◯◯◯

VERYLOW

CRITICAL

Treatmentcomple,on–RCTs(supportgroups)


serious


(97.7%)

35/43

(81.4%)

RR1.20

(1.03to

1.39)

163moreper

1000

(from24

moreto317

more)

⨁⨁⨁⨁

HIGH

CRITICAL


Qualityassessment



Indirectnes

sImprecis

ionOther

considera/onsPsychological

interven/onsNone

Rela/ve

(95%CI)Absolute

(95%CI)

Cure–RCTs(supportgroups)


seriousseriousa none 40/43(93.0%) 35/43

(81.4%)RR1.14


1000

(from24

fewerto285

more)

⨁⨁⨁◯

MODERATECRITICAL

Failure–cohortstudies(supportgroups)

1 observa/onalstudies seriousb notserious not

seriousvery

seriousa,c

none 0/64(0.0%) 1/64(1.6%) notes/mable 20fewerper

1000

(from60

fewerto30

more)

⨁◯◯◯

VERYLOWCRITICAL

Failure–RCTs(supportgroups)


seriousvery

seriousa,c

none 0/43(0.0%) 5/43(11.6%) notes/mable 120moreper

1000

(from220

moreto10

more)

⨁⨁◯◯

LOWCRITICAL




Other

considera/ons

Psychol

ogical

interve

n/ons

NoneRela/ve

(95%CI)Absolute

(95%CI)

Losstofollow-up–cohortstudies(supportgroups)

1 observa/onalstudies seriousa notserious notserious seriousb strong

associa/on8/64

(12.5%

)

26/64

(40.6%)RR0.31


1000

(from150

fewerto345

fewer)

⨁◯◯◯

VERYLOWCRITICAL

Losstofollow-up–RCTs(supportgroups)


seriousb,cnone 1/43

(2.3%)2/43(4.7%) RR0.50


1000

(from44fewer

to200more)

⨁⨁◯◯

LOWCRITICAL

Conclusions

•  Psychologicalinterven/ons(supportgroups)wereassociatedwithahigherrateof

treatmentcomple/onandlowerrateof

treatmentfailureandlosstofollow-up.


40

22/02/18

13

Staffeduca/on


Qualityassessment



Inconsisten


Other

considera/o

nsStaffeduca/on None

Rela/ve

(95%CI)Absolute

(95%CI)



seriousnotserious seriousb none 0/54(0.0%) 0/101(0.0%) notes/mable 0fewerper

1000

(from30

moreto30

fewer)

⨁◯◯◯

VERYLOWCRITICAL

Mortality–RCTs


seriousnotserious veryseriousc,d none 20/630(3.2%) 33/657

(5.0%)RR0.76

(0.44to1.31)12fewer

per1000

(from16

moreto28

fewer)

⨁⨁◯◯

LOWCRITICAL



seriousnotserious notserious none 50/54(92.6%) 70/101

(69.3%)RR1.34

(1.15to1.55)236more

per1000

(from104

moreto381

more)

⨁◯◯◯

VERYLOWCRITICAL



seriousnotserious seriousc none 586/860

(68.1%)472/745

(63.4%)RR1.03


1000

(from32

fewerto76

more)

⨁⨁⨁◯

MODERATECRITICAL


Qualityassessment



Imprecis

ionOther

considera/onsStaff

educa/onNone

Rela/ve

(95%CI)Absolute

(95%CI)

Comple,on–RCTs

2 randomizedtrials notserious notserious notserious seriousa none 46/260

(17.7%)52/168

(31.0%)RR0.91

(0.63to

1.31)

28fewerper

1000

(from96more

to115fewer)

⨁⨁⨁

MODERATECRITICAL

Cure–RCTs

3 randomizedtrials notserious seriousb notserious seriousa none 446/860

(51.9%)338/745

(45.4%)RR1.08

(0.86to

1.36)

36moreper

1000

(from64

fewerto163

more)

⨁⨁

LOWCRITICAL

Treatmentfailure–cohortstudies

1 observa/onalstudies seriousc notserious notserious seriousd none 0/54(0.0%) 0/101(0.0%) not

es/mable0fewerper

1000

(from30more

to30fewer)

⨁

VERYLOWCRITICAL

Treatmentfailure–RCTs

2 randomizedtrials notserious notserious notserious seriouse none 10/830

(1.2%)6/665(0.9%) not

es/mable0fewerper

1000

(from10

fewerto20

more)

⨁⨁⨁

MODERATECRITICAL


Qualityassessment



Inconsisten

cyIndirectness

Impre

cisionOther

considera/onsStaffeduca/on None

Rela/ve

(95%CI)Absolute

(95%CI)


1 observa/onalstudies seriousa notserious notserious serio

usbnone 0/54(0.0%) 18/101


1000

(from260

fewerto100

fewer)

⨁

VERYLOWCRITICAL



serio

usb,c

none 17/260(6.5%) 13/168

(7.7%)RR0.74


1000

(from38more

to50fewer)

⨁⨁

LOWCRITICAL

Conclusion

•  Staffeduca/oninterven/onswereassociatedwithahigherrateoftreatmentsuccessand

lowerrateoflosstofollow-up. Mobilehealth


41

22/02/18

14




Indire

ctnes

sImprecision Otherconsidera/ons

Mobile

health

interven/on

s

NoneRela/ve

(95%CI)Absolute

(95%CI)

Mortality–cohortstudies(VOTversusin-personDOT)

1 observa/onal

studiesseriousa notserious not

serio

us

veryseriousb,c none 1/61(1.6%) 3/329(0.9%) RR1.80


1000

(from7fewer

to146more)

⨁

VERYLOWCRITICAL

Treatmentsuccess–RCTs(phonereminders)

2 randomizedtrials seriousd notserious not

serio

us

seriousb none 66/68

(97.1%)60/68

(88.2%)RR1.06


1000

(from115

fewerto265

more)

⨁⨁

LOWCRITICAL

Comple,on–cohortstudies(VOTversusin-personDOT)

2 observa/onal

studiesseriousa notserious not

serio

us

seriousb none 77/119

(64.7%)283/399

(70.9%)RR1.17


1000

(from149

fewerto511

more)f

⨁

VERYLOWCRITICAL

Comple,on–RCTs(phonereminders)

1 randomizedtrials seriouse notserious not

serio

us

seriousc none 0/30(0.0%) 6/31(19.4%) notes/mable 190fewerper

1000

(from340

fewerto50

fewer)

⨁⨁

LOWCRITICAL




Other

conside

ra/ons

Mobilehealth

interven/onsNone

Rela/ve

(95%CI)Absolute

(95%CI)

Cure–cohortstudies(phonereminder)

1 observa/onalstudies seriousa notserious notserious seriousb strong

associa

/on

18/24(75.0%) 31/96

(32.3%)RR2.32


1000

(from194

moreto762

more)

⨁

VERYLOWCRITICAL

Cure–RCTs(phonereminders)

1 randomizedtrials seriousc notserious notserious seriousb,d none 49/49(100.0%) 29/50

(58.0%)RR1.71


1000

(from203

moreto679

more)

⨁⨁

LOWCRITICAL

Failure(phonereminders)

1 randomizedtrials seriousc notserious notserious seriousb none 0/49(0.0%) 6/50(12.0%) notes/mable 120fewerper

1000

(from220

fewerto20

fewer)

⨁⨁

LOWCRITICAL


Qualityassessment



Other

considera/ons

Mobile

health

interven/o

ns

NoneRela/ve

(95%CI)Absolute

(95%CI)

Sputum/cultureconversionat2months–cohortstudies(phonereminders)

1 observa/onalstudies seriousa notserious notserious seriousb,c none 15/24

(62.5%)37/96

(38.5%)RR1.62


1000

(from35more

to547more)

⨁

VERYLOWCRITICAL

Sputum/cultureconversionattwomonths–RCTs(phonereminders)

1 randomizedtrials seriousd notserious notserious very

seriousb,cnone 5/7

(71.4%)6/8(75.0%) RR0.95


1000

(from368

fewerto570

more)

⨁

VERYLOWCRITICAL


Qualityassessment



Indirectnes

sImprecisi

onOther

considera/onsMobilehealth

interven/onsNone

Rela/ve

(95%CI)Absolute

(95%CI)

Losstofollow-up(phonereminders)


seriousnot

seriousnone 41/954(4.3%) 112/1057

(10.6%)RR0.41


1000

(from46fewer

to75fewer)

⨁⨁

LOWCRITICAL

Losstofollow-up(medica,onmonitor)


seriousnot

seriousnone 59/946(6.2%) 112/1057

(10.6%)RR0.59


1000

(from21fewer

to60fewer)

⨁⨁

LOWCRITICAL

Losstofollow-up(combinedmedica,onmonitorandphonereminders)


seriousnot

seriousnone 89/982(9.1%) 112/1057

(10.6%)RR0.86


1000

(from12more

to36fewer)

⨁⨁

LOWCRITICAL




Imprecisio

n

Other

considera/on

s

Mobilehealth

interven/onsNone

Rela/ve

(95%CI)Absolute

(95%CI)

Pooroutcome(phonereminders)


seriousnone 53/966(5.5%) 121/1066

(11.4%)RR0.48

(0.35to

0.66)

59fewerper

1000

(from39

fewerto74

fewer)

⨁⨁

LOWCRITICAL

Pooroutcome(medica,onmonitor)


seriousnone 68/955(7.1%) 121/1066

(11.4%)RR0.63

(0.47to

0.83)

42fewerper

1000

(from19

fewerto60

fewer)

⨁⨁

LOWCRITICAL

Pooroutcome(combinedmedica,onmonitorandphonereminders)


seriousnone 99/992(10.0%) 121/1066

(11.4%)RR0.88

(0.68to

1.13)

14fewerper

1000

(from15more

to36fewer)

⨁⨁

LOWCRITICAL


Qualityassessment



Other

considera/onsMobilehealth

interven/onsNone

Rela/ve

(95%CI)Absolute

(95%CI)

Pooradherence(phonereminders)

1 observa/onalstudies notserious notserious seriousa notserious none 1518/5284

(28.7%)1834/6013

(30.5%)RR0.94

(0.89to

1.00)

18fewerper

1000

(from0fewer

to34fewer)

⨁

VERYLOW

Pooradherence(medica,onmonitor)


(17.4%)1834/6013

(30.5%)RR0.57

(0.53to

0.61)

131fewerper

1000

(from119

fewerto143

fewer)

⨁

VERYLOW

Pooradherence(phonereminderandmedica,onmonitor)


(17.0%)1834/6013

(30.5%)RR0.56

(0.52to

0.60)

134fewerper

1000

(from122

fewerto146

fewer)

⨁

VERYLOW


42

22/02/18

15

Conclusions

•  Phonereminderswereassociatedwithhigher

ratesofcureandsputumconversionand

lowerratesoftreatmentfailure,lossto

follow-upandpooroutcome.

•  Therateofpooradherencewaslowerwithcombinedphonereminderandmedicine

monitoringinterven/ons.

Liuetal.–studydesign•  PLoSOne,2015

•  RCT,clusterrandomized

•  Inclusioncriteria:

-Newpa/ents

->18years

•  Interven/on:

-Textmessagereminder

-Medicinemonitorboxreminder

-Both

•  Control:

-Self-administeredtherapy,familyDOTorhealth-careworkerDOT(in

accordancewithpa/entpreference)

•  Outcomes:

-Numberofmisseddosesbasedonpillcount

-Pooradherence=percentageofpa/ent-monthsinwhich>20%ofdoseswere

missed

Liuetal–Results Liuetal.–Results

Liuetal.–studydesign•  PLoSOne,2015•  RCT,pragma,cclusterrandomized•  Inclusioncriteria:

-Newpa,ents->18years

•  Interven,on:-Textmessagereminder-Medicinemonitorboxreminder-Both

•  Control:-Self-administeredtherapy,familyDOTorhealth-careworkerDOT(in accordancewithpa,entpreference)

•  Outcomes:-Numberofmisseddosesbasedonpillcount-Pooradherence=percentageofpa,ent-monthsinwhich>20%ofdosesweremissed

Liuetal.–results


43

22/02/18

16

Liuetal.–results Conclusions

•  Mobilehealthinterven/onswereassociated

withhigherratesofcureandsputum

conversionandalowerrateoftreatment

failure.

•  Combinedmedicinemonitorpillboxandtext

messagereminderswereassociatedwitha

higherrateoftreatmentadherence.


44

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Report on a systematic review for decentralized treatment and care for multidrug-resistant tuberculosis patients

Jennifer Ho1,2,3, Anthony Byrne1,2,4,5 & Greg J. Fox1,2,6

1 National Health and Medical Research Council, Centre of Research Excellence in Tuberculosis Control, University of Sydney, Australia

2 Woolcock Institute of Medical Research, Sydney, Australia3 South Western Sydney Clinical School, University of New South Wales, Sydney, Australia4 Socios En Salud Sucursal, Partners in Health, Lima, Peru5 St Vincent’s and Blacktown Hospitals, Sydney Australia6 Central Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia


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Executive summaryBackgroundMultidrug-resistant tuberculosis (MDR-TB) poses a major threat to the control of TB worldwide. Management of MDR-TB is complex and prolonged and has traditionally been provided in centralized, specialized treatment centres. However, such treatment centres are insufficient to meet the needs of the large and growing burden of MDR-TB patients in most settings. Decentralized treatment typically uses facilities close to the patient’s residential location (including home-based care) and trained personnel in the community to administer and monitor treatment, thereby overcoming the resource limitations in centralized, specialized facilities. This review summarizes the evidence for the use of decentralized treatment and care for patients with MDR-TB.

MethodsWe performed a comprehensive database search for relevant studies on decentralized treatment and care for patients with MDR-TB that compared treatment outcomes, treatment adherence and the cost of health services to centralized treatment facilities. For outcome measures that had sufficient studies, meta-analysis was performed to obtain pooled relative risk (RR) estimates.

ResultsEight studies comprising 4493 patients with MDR-TB were eligible for inclusion. Two studies modelled cost–effectiveness; the remaining six cohort studies reported on treatment outcomes and/or the cost of health care. The pooled RR estimates for decentralized versus centralized care for the outcomes of treatment success, loss to follow-up, death and treatment failure were: 1.13 (95% CI 1.01–1.27), 0.66 (95% CI 0.38–1.13), 1.01 (95% CI 0.67–1.52) and 1.07 (95% CI 0.48–2.40), respectively. The studies for each pooled estimate had considerable heterogeneity.

ConclusionsTreatment success for MDR-TB patients improved when they were treated in a decentralized compared with centralized setting. Further studies, in a range of different settings, are required to improve the evidence base for recommending decentralized care for patients with MDR-TB.


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BackgroundMultidrug-resistant tuberculosis (MDR-TB) (resistance to both rifampicin and isoniazid) poses a major threat to the control of TB worldwide. In 2014, there were an estimated 480 000 new cases of MDR-TB worldwide and about 190 000 deaths from MDR-TB (1). An estimated 9.7% of the people with MDR-TB have extensively drug-resistant TB (XDR-TB) (MDR-TB that is also resistant to a second-line injectable drug and a fluoroquinolone). Of all MDR-TB cases from the 2012 cohort, only 50% completed treatment, 16% died, 16% were lost to follow-up and treatment failed for 10% (1). Recommended therapy for MDR-TB requires a combination of second-line drugs that are more costly, less efficacious and more toxic and must be taken for much longer than first-line TB therapy (2). Historically, MDR-TB treatment has been provided through specialized, centralized programmes and involved prolonged inpatient care (3). This approach is based on the view that treatment adherence, the management of adverse events and infection control may be superior in the hospital setting compared with the community (4,5). However, prolonged treatment in centralized facilities is impractical in resource-limited settings, with a substantial number of patients having MDR-TB. Paradoxically, the reliance on centralized treatment for MDR-TB may inadvertently increase the transmission of this infection by delaying treatment commencement until inpatient beds become available. In addition, centralized approaches have been associated with poorer rates of retention in care (6). Decentralized care for treating drug-susceptible TB is well established, with treatment outcomes shown to be at least as good as hospital-based approaches (7–9). This review aims to evaluate the existing evidence for decentralized care to treat MDR-TB.

Current WHO policy

WHO currently says that “patients with MDR-TB should be treated using mainly ambulatory care, rather than models of care based principally on hospitalization” (10). These recommendations are conditional, reflecting the very-low-quality evidence on which they were based. Two published systematic reviews have compared treatment outcomes for hospital and ambulatory-based management of MDR-TB, reporting similar treatment outcomes for centralized and decentralized approaches (11,12). However, an important limitation of both these reviews was the inclusion of studies without an appropriate comparator group (a control group provided standard centralized care). The review by Weiss et al. (12) compared the pooled treatment outcomes of a community-based MDR-TB management intervention to pooled treatment outcomes from other previously published systematic reviews. Just one of the 41 studies included in one or both of these reviews directly compared hospital and ambulatory MDR-TB care (13). The approach used in these systematic reviews likely results in substantial bias – since the control and intervention populations were largely drawn from different study populations. Where possible, direct comparisons should be used to draw conclusions about complex health system interventions (14). More robust evidence is therefore required to evaluate the effect of decentralized care on treatment outcomes compared with standard centralized treatment.


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Objective of this reviewThe objective of this review is to examine the effect of decentralized treatment and care on treatment outcomes among patients with MDR-TB. This review addresses some of the limitations of previous systematic reviews on this topic (11,12) by including studies that directly compare decentralized and centralized MDR-TB treatment models in the same study setting. This review will contribute to revised WHO guidelines for treating drug-resistant TB.

Table 1 provides information about previous related systematic reviews and how these differ from this current review.

Table 1. Summary of related systematic reviews on treatment outcomes for MDR-TB and/or decentralized care for TB

Review Objective Main study findings How this review differs from ours

Studies of DS-TBKarumbi et al. (15) (2015)(Cochrane review)

Compared treatment outcomes using DOT versus SAT

Found no difference in treatment outcomes for:• DOT versus SAT• home versus health facility DOT• family member versus community health worker provider

Did not focus on MDR-TB

Wright et al. (16) (2015)

Compared treatment outcomes for community-based and clinic-based DOT

Greater treatment success for community versus clinic-based DOT


Kangovi et al. (17) (2009)

Compared treatment outcomes using community-based DOT programmes that do and do not offer financial rewards

No difference in treatment outcomes with and without financial rewards


Studies of MDR-TBYin et al. (18) (2016)

Compared treatment success with DOT to SAT for MDR-TB

Greater treatment success for DOT over the entire treatment courseNo difference found between health facility– and home-based DOT

Did not specifically focus on decentralized versus centralized treatmentThe only outcome measured was treatment success

Toczek et al. (6) (2012)

Identified strategies for reducing treatment default in DR-TB

Lower default rates for patients for which community health workers provided care and DOT was given for the entire treatment course

Did not specifically focus on decentralized versus centralized treatmentThe only outcome measured was treatment default

Orenstein et al. (19) (2009)

Identified factors associated with improved treatment outcomes in MDR-TB

Improved treatment success with at least 18 months of treatment and DOT for entire course

Did not compare decentralized and centralized treatment

Johnston et al. (20) (2009)

Identified factors associated with poor treatment outcomes in MDR-TB

Factors associated with lower success rates were: male, alcohol abuse, low BMI, smear positive at diagnosis, fluoroquinolone resistance.

Did not compare decentralized and centralized treatment


53

Review Objective Main study findings How this review differs from ours

Fitzpatrick et al. (21) (2012)

Summarized evidence regarding the cost- effectiveness of MDR-TB treatment.

Treatment for MDR-TB can be cost effective in low- and middle income countries

Did not compare decentralized and centralized treatment.

Weiss et al. (12) (2014)

Reviewed treatment outcomes from community based MDR-TB treatment programs

Treatment outcomes of community based MDR-TB treatment were similar to pooled outcomes in published systematic reviews of MDR-TB treatment

Only one included study had a control group.The control group was derived from published systematic reviews on MDR-TB (i.e. different studies)

Bassili et al. (11) (2013)

Compared treatment outcomes using ambulatory versus hospital-based MDR-TB treatment

No difference in treatment success between the ambulatory and hospital-based treatment.

Included studies reported either hospital or ambulatory treatment. They did not directly compare outcomes from these two treatment interventions

DS-TB: drug-susceptible tuberculosis; DOT: directly observed therapy; SAT: self-administered therapy; MDR-TB: multidrug-resistant tuberculosis; DR-TB: drug-resistant tuberculosis; BMI: body mass index.

DefinitionsThe following definitions are modified from the 2012 WHO guidelines for the programmatic management of MDR-TB (10). In this review, centralized versus decentralized treatment is defined according to (a) the location of treatment; and/or (b) community-based personnel delivering the treatment. This acknowledges the potential impact of the distance between the treatment facility and patients’ residential location on treatment outcomes and cost as well as the limited personnel available to provide treatment and care in centralized, specialized settings.

• Decentralized MDR-TB treatment and careThis refers to treatment and care located in the local community in which the patient resides. This includes treatment delivery based at community health centres, clinics, religious and other community venues as well as in the patient’s home or workplace. The entire treatment period typically occurs in the ambulatory setting or, alternatively, there is a brief period of hospitalization in a centralized facility (less than one month) that occurs in the intensive phase to observe initial response to therapy and to manage severe medication side-effects or other comorbid conditions. Decentralized care is delivered primarily by trained volunteers (including family members), community nurses or non-specialized doctors.

• Specialized and centralized MDR-TB treatment and careThis includes treatment and care in a centralized and/or specialized hospital. Centralized care is usually provided by doctors and nurses with specialist training in managing MDR-TB. It also includes treatment and care provided by centralized outpatient clinics: outpatient facilities located at or near to the site of the specialized, centralized facility.


54

Additional definitions• Directly observed therapy (DOT)

A treatment programme in which a health worker, community volunteer or family member routinely observes participants taking their anti-tuberculosis drugs (15).

• Treatment outcomes MDR-TB treatment outcomes were defined according to standard WHO definitions (10).

Research questionIs decentralized treatment and care for MDR-TB patients more or less likely to lead to the following outcomes: treatment adherence, improved treatment outcomes, adverse reactions, acquired drug resistance, reduced patient costs and health service costs compared with treatment and care provided solely by specialized drug-resistant TB (DR-TB) treatment centres? (WHO PICO question 2)

PICO framework

The PICO framework for this research question is as follows.

• Population: all patients commencing treatment for MDR-TB.

• Intervention: decentralized treatment and care, provided by non-specialized or periphery health centres, community health workers, community volunteers or treatment supporters. Treatment and care includes: DOT and patient support; administration of injectable antibiotics during the intensive phase; specialist care for comorbidities (such as human immunodeficiency virus (HIV) infection, diabetes, chronic lung diseases or other conditions such as auditory function, renal function, liver function, nervous system function and vision).

• Comparator: treatment and care provided solely by centralized and/or specialized DR-TB centres or teams.

• Outcomes: adherence to treatment (or treatment interruption due to non-adherence); conventional TB treatment outcomes: cured and completed, failure, relapse, survival or death; adverse reactions from TB drugs (severity, type and organ class); acquisition (amplification) of drug resistance; cost to the patient (including direct medical costs as well as others such as transport and lost wages due to disability); and cost to health services.

MethodsThis systematic review was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses: guidance for reporting of systematic reviews and meta-analyses) (22).

Search terms

The authors developed and agreed on the comprehensive search terms in consultation with WHO counterparts. Table 2 lists the search terms.


55

Table 2: Search terms applied using the Medline search engine

Area MeSH headings Free textPopulation Tuberculosis,

Multidrug-Resistant [MeSH]

((tuberculosis OR TB) AND (multidrug-resistan* OR multidrug resistan* OR multi-drug resistan* OR “drug resistan*” OR drug-resistan* OR multiresistan* OR "multi resistan*" OR “rifampicin resistan*” OR “extensively drug-resistan*” OR “extensively-drug resistan*” OR "extensively resistan*" OR MDR OR XDR OR TDR)) OR MDRTB OR XDRTB OR TDRTB OR MDR-TB OR XDR-TB OR TDR-TB OR “MDR TB” OR “XDR TB” OR “TDR TB”

Intervention (directly observed OR DOT OR DOTS OR DOTS-Plus OR cb-DOTS OR treatment) AND (community OR outpatient OR public participation OR community-based OR decentralized OR non-specialized OR periph* health centres OR home-based OR ambulatory ORclinic OR community OR community health worker OR CHW OR volunteer*)

Population terms were combined using the Boolean operator “OR”. Intervention terms were combined using “OR”. Population and intervention term groupings were then combined using “AND”. The search strategy did not include comparator and outcome terms, since sufficiently few hits were achieved using only the population and intervention terms. By sifting for comparator and outcome during the manual sift, the likelihood of missing a potentially relevant paper was reduced.

Search sources and limits

We searched electronic health-care databases and evidence-based reviews and hand searched the grey literature. The search terms in Table 2 were adapted to the requirements of each database (see Appendix 1).

Table 3 lists the sources searched to identify relevant literature. Each search was limited to publications from 1995 onwards, since this is the time frame in which DOT for TB has been widely used. The searches were not restricted by language, publication type or study design.

Table 3: Information sources searched to identify relevant literature

Category SourcesHealth-care databases Medline

EmbaseLILACSWeb of ScienceGoogle Scholar

Evidence-based reviews Cochrane Library (includes CENTRAL, DARE, HTA, CDSR)

Grey literature OpenSIGLEInternational Union of Tuberculosis and Lung Disease conference electronic abstract database

Unpublished studies ClinicalTrials.govWHO portal of clinical trialsConsultation with expert in the field


56

Eligibility criteria for studies

The following inclusion and exclusion criteria were applied to the searches.

Inclusion criteria• Types of participants

Studies recruiting individuals of all ages with MDR-TB. » Given the limited availability of microbiological confirmation of MDR-TB in

some settings, MDR-TB was defined as microbiological (phenotypic or genotypic) evidence of MDR-TB or a clinical diagnosis of MDR-TB.

» Studies including individuals with XDR-TB or totally drug resistant (TDR-TB) were included.

• Types of interventions Studies including any of the following interventions (or any similar intervention but named differently): decentralized treatment and care provided by non-specialized or peripheral health centres, by community workers, community volunteers or treatment supporters. » Treatment and care includes: DOT and patient support, injection during the

intensive phase, and specialist care for comorbidities (such as HIV, diabetes, chronic lung diseases or other conditions such as auditory function, renal function, liver function, nervous system function and vision).

» No restrictions were placed on the timing of the intervention within the treatment period, such as whether the intervention occurred in the intensive phase or continuation phase or throughout the treatment period.

• Types of studies The following study types were included: randomized controlled trials, prospective cohorts, retrospective cohorts, case–control studies including at least 10 patients or modelling studies.

• Types of comparators Treatment and care provided solely by specialist DR-TB centres or teams.

• Types of outcome measures Studies including one or more of the following outcome measures: adherence to treatment (or treatment interruption due to non-adherence); conventional TB treatment outcomes: cured and completed, failure, relapse, survival or death; adverse reactions from TB drugs (severity, type and organ class); acquisition (amplification) of drug resistance; cost to the patient (including direct medical costs as well as others such as transport and lost wages due to disability); and the cost to health services.

Exclusion criteria• Any study that did not report one or more of the above-stated outcomes of interest.

• Any study reporting solely on primary outcomes of interest without a control or comparator group.

• Narrative reviews and commentaries or editorials.

• Fewer than 10 subjects enrolled in the intervention arm.


57

For studies reported in a language other than English, an individual fluent in that language was consulted for interpretation and translation.

For studies for which only an abstract was available, the study authors were contacted to obtain additional study information. Contactable, consenting authors were asked to complete a data collection form, specifically designed for this review, to obtain relevant study data.

Study selection and data extraction

In the first stage of study selection, two reviewers (JH and AB) independently screened the titles and abstracts of papers identified from the above search for suitability for subsequent full-text review.

In the second stage of study selection, two reviewers (JH and AB) independently reviewed full-text papers identified from the first stage. A standardized extraction form was developed and pilot tested. Two reviewers (JH and GF) independently extracted the data from the papers selected for final inclusion. Data were compared, and unresolved disagreements in study selection or extraction were resolved consensus. Additional searches of reference lists of all included articles, of all articles citing included articles and of review articles related to the research question were also conducted, to identify any further articles eligible for inclusion. For studies reporting interim findings in one paper and then more completely in a subsequent paper, the latter was selected for inclusion. Study authors were contacted to clarify or obtain missing data where necessary.

The data extracted included: study design; study objective; study population characteristics (sample size, method of diagnosing MDR-TB, HIV prevalence and comorbidities); details of intervention (organization initiating decentralized care, method of selecting the intervention group, time period in which the intervention occurred, treatment regimen, nature of DOT, provider and location of treatment, duration and timing of decentralized treatment and additional support provided); details of the control group (derived from the same population and/or same time period); and the event numbers for each outcome measure (as detailed above under “types of interventions” in the inclusion criteria).

Study quality assessment

The risk of bias was assessed using the Newcastle Ottawa Scale for assessing the quality of nonrandomized studies (23) and the GRADE methods (24).

Analysis

A meta-analysis of relative risk and 95% confidence intervals for each treatment outcome, where sufficient studies (three or more) were identified, comparing the intervention to the comparator group, was carried out using a generalized linear mixed model with study as a random effect, using RevMan 5.2. Forest plots summarized the data for individual trials. The outcomes were estimated as pooled proportions using the exact binomial method (25). For each comparison, an I2 statistic was calculated to evaluate heterogeneity between


58

studies (26,27). When there were sufficient studies (five or more with the same end-point) (28), publication bias was assessed by funnel plot. When available, costs were converted to US dollars in 2015, based on published World Bank conversion rates. When insufficient studies were available to perform meta-analysis or when substantial heterogeneity precluded meta-analysis, we presented a table of findings of the individual included studies. Statistical analysis was performed using SAS 9.3 (Cary, NC, USA). Forest plots of proportions were created using R version 3.2.5. The overall study outcomes were assessed using the GRADE methods and summarized using GRADEPro software.

Results

Search results

The database search identified 1818 non-duplicate records. An additional six records were identified from searching conference abstracts (two) and the bibliography lists of relevant papers (four). The titles and abstracts of 1824 records were reviewed, identifying 41 articles for full-text review. Of these, 33 did not meet the inclusion criteria (see Fig. 1 and Appendix 2 for the reasons for exclusion), leaving eight eligible studies (one unpublished) for inclusion (13, 29–35). Fig. 1 shows the flow of search results and selection of eligible studies. The search was performed in January 2016.

Fig. 1. Diagram of search results for eligible studies included in the review of decentralized care of MDR-TB compared with centralized care

Records identified through database searching of Medline, EMBASE,

Cochrane Library, LILACS, Web of Science after duplicates removed

(n = 1818)

Additional records identified through other sources: grey literature, bibliography lists, unpublished studies, conference abstracts,

experts in the field (n = 6)

Studies included in review (n = 8)

Full-text articles assessed for

eligibility (n = 41)

Records excluded (n = 1783)

Relevant abstracts from conferences

when authors could be

contacted and provided more detailed study

information (n = 1)

Records screened: title and abstract(n = 1824)

– Full-text articles excluded, with reasons (n = 33)– No control group (n = 16)– Did not include outcomes of interest (n = 2)– Review article (n = 7)– Did not include intervention of interest (n = 2)– Conference abstract subsequently published

(n = 1)– Conference abstract where authors could not

be contacted for further information (n = 2)– Article with only interim results and/or

published elsewhere (n = 2)– Sample size <10 (n = 1)


59

Findings

Table 3 presents the key characteristics of the eight included studies. Of these studies, which included 4493 patients with MDR-TB, two were performed in high-income countries: Taiwan, China and the United States. The remainder were from low- and middle-income countries: Nigeria, the Philippines and South Africa and Swaziland. Two studies modelled cost–effectiveness, and the remaining six were cohort studies and reported on treatment outcomes (six) and/or cost of health care (one). Of the studies reporting on treatment outcomes, five evaluated treatment success, four loss to follow-up, four death and three treatment failure. There were no randomized controlled trials evaluating decentralized MDR-TB treatment and care. Decentralized care described in the different studies included both home-based and decentralized clinic-based care. In one study, decentralized care occurred in a rural hospital (32). In all except for one study, centralized care occurred in a specialized hospital. The (unpublished) study by Kerschberger (35) compared home-based DOT by trained community volunteers to a control cohort of clinic-based care by nurses. Based on a consensus of reviewers, this study was judged to be eligible for inclusion since the intervention provided decentralized care aiming to overcome the limitations of the existing treatment programme, which was clinic-based care. Most decentralized and centralized management approaches used DOT. Importantly, patient selection for decentralized care was not randomized in any of the included cohort studies. Instead, treatment allocation was based on patient factors likely to make centralized care more difficult or less successful, such as residential location far from a centralized facility. No studies reported on treatment adherence, the acquisition of drug resistance or treatment costs for individual patients.

Pooled treatment outcome estimates

Table 4 shows the results of the pooled estimates for treatment outcomes. Five studies evaluated treatment success. The pooled RR from these five studies showed improved treatment success with decentralized versus centralized treatment: pooled RR = 1.13 (95% CI 1.01–1.27). The pooled proportions of studies evaluating treatment success for decentralized and centralized care were 67.3% (95% CI: 53.8–78.5%) and 61.0% (95% CI: 49.0–71.7%), respectively. The pooled analysis of the four studies evaluating loss to follow-up for MDR-TB patients showed a trend towards reduced loss to follow-up with decentralized versus centralized care: pooled RR = 0.66 (95% CI 0.38–1.13). The pooled proportions of studies evaluating loss to follow-up for decentralized and centralized care were 11.9% (95% CI: 5.7–23.3%) and 18.0% (95% CI: 9.3–31.8%), respectively. The pooled RR from the four studies that evaluated death with decentralized versus centralized treatment was 1.01 (95% CI: 0.67–1.52). The pooled proportions of studies evaluating death for decentralized and centralized care were 17.8% (95% CI: 15.9–19.9%) and 18.6% (95% CI: 14.5–23.6%), respectively. The three studies evaluating treatment failure resulted in a pooled RR of 1.07 (95% CI 0.48–2.40) for decentralized versus centralized care. The pooled proportions of studies evaluating treatment failure for decentralized and centralized care were 4.2% (95% CI: 1.4–11.9%) and 4.3% (95% CI: 2.3–8.1%), respectively. The studies had considerable heterogeneity. Fig. 2 shows forest plots of these four outcome measures


60

for decentralized versus centralized MDR-TB treatment and care. Fig. 3 shows a forest plot of proportions for treatment success. Given the small number of eligible studies, we did not formally assess publication bias.

Sensitivity analysis (analysis excluding Narita et al.) for treatment outcomes

Of the studies eligible for review inclusion, the study by Narita et al. (13) differs from the other studies with respect to: the income level of the country (high income versus predominantly low income), the years in which the intervention was conducted (1990s versus 2000s), the small sample size and the method of selection into the intervention and control groups (patients were selected for specialized TB hospital care if treatment was failing or they were non-adherent) (Table 3). The results for treatment success and death for this study differ significantly from the other studies and have wide confidence intervals (forest plots in Fig. 2 and 3). Due to the marked heterogeneity of this study compared to the other included studies, we compared the pooled proportions and relative risk estimates of the studies reporting on treatment success and death, with and without inclusion of the Narita et al. study (Table 5).These estimates did not differ significantly whether this study was or was not included in the analysis. The study by Narita et al. did not report treatment failure or loss to follow-up.

Treatment costs

Of the eight studies eligible for inclusion, three (two modelling (33,34) and one cohort study (35)) reported treatment costs. Table 6 compares the treatment cost to the health-care system for one MDR-TB patient in the decentralized and centralized settings. The two modelling studies showed significant cost savings using a decentralized versus centralized model, whereas the study by Kerschberger (35) showed similar treatment costs for both treatment models.

Methodological quality of the included studies

Tables 4 and 7 shows the risk of bias assessment for the six included studies (excluding modelling studies). In all studies, a non-random method was used to select the intervention and control cohorts. In four of the six studies, the patients were chosen for decentralized treatment based on patient factors, such as residential location, socioeconomic factors and risk factors for loss to follow-up. In the remaining two studies, treatment of the intervention and control groups occurred consecutively (not concurrently), reflecting the implementation of a new decentralized treatment programme. Heterogeneity (inconsistency) was observed for all treatment outcomes, as indicated by the high I2 values (from 74% to 88%) for pooled RR estimates. For all treatment outcomes, except for treatment success, there was wide variance in the point estimates (Fig. 2). The risk of bias and heterogeneity factors reduced the overall quality of the evidence (rated as very low) for all treatment outcomes (Table 4).


61

Uncontrolled studies

Table 8 shows a summary of the key characteristics for the studies evaluating treatment outcomes using decentralized care for MDR-TB, which do not have a control group. Our search found 16 such studies in which decentralized treatment alone, without direct comparison to centralized treatment, was evaluated. Although these studies did not meet the eligibility criteria for inclusion, this summary has been included to provide additional information to the studies eligible for inclusion and includes all the more recent studies compared with the last systematic review on this subject (12). We excluded one study (36) from the pooled analysis that reported on the treatment outcomes of MDR-TB patients treated in a field hospital after an earthquake, since this unique study setting is not representative of routine programmatic conditions.

(i) Treatment outcomesTable 9 shows the event frequency and pooled proportion estimates for the studies that reported on treatment outcomes. Included in this table for comparison are the pooled proportions for the studies in this review that did include a control group and also data from an individual patient data meta-analysis (9153 patients from 32 observation studies) of MDR-TB treatment outcomes (37). The latter serves as a comparison of the pooled results from the uncontrolled studies of MDR-TB treatment, in a decentralized setting, with a “control” group: studies evaluating MDR-TB treatment in a non-specific setting (this may include both decentralized and centralized care models). Fig. 4 shows the forest plots of the proportions of treatment success for the studies evaluating decentralized care for MDR-TB without a control group.

(ii) Adverse events from TB medicationsNo studies that evaluated adverse events associated with TB medications were eligible for inclusion (including a control group). Of the 16 uncontrolled studies, nine studies reported on adverse drug events. Table 10 shows the adverse event frequency (any adverse event, severe adverse event or any adverse event requiring discontinuation of therapy) and pooled proportion estimates for these studies.

Strengths and weaknesses of this review

The results of this review are based on comprehensive database and other information source searching. This review had strict eligibility criteria, which only permitted studies directly comparing intervention and control cohorts from the same study population to be included. This substantially reduced the risk of bias due to indirectness and is a defining feature of this review compared with other systematic reviews on this subject. However, including only studies with both an intervention and control group reduced the final number of included studies and potentially reduced the precision of the estimates. In addition, data were absent for several a priori outcomes of interest. The included studies also had substantial heterogeneity . This likely reflects the important differences between the study settings and the specific interventions used in each setting. We addressed the limitation of the small number of eligible studies by presenting additional data from studies on decentralized care for MDR-TB that did not include a control group.


62

Authors conclusionsIn conclusion, this review demonstrated that treatment success for MDR-TB patients improved with decentralized care. Loss to follow-up was also reduced with decentralized models of care, although the confidence limits crossed the null. These two groups did not differ in the rates of death or treatment failure.

These findings are consistent with previous systematic reviews (11,12). Given the diversity of each setting in which MDR-TB patients are managed (such as cultural and socioeconomic differences and the availability of infrastructure and personnel), heterogeneity of decentralized care among studies is to be expected. This underpins the importance of further research in various settings. Since national TB programmes from TB-endemic countries throughout the world increasingly adopt decentralized approaches for managing patients with MDR-TB, programme interventions and outcomes should be carefully and thoroughly reported (such as by using before-and-after or stepped-wedge study designs) so that the benefit of such interventions can be accurately determined and reported.

Finally, although a decentralized approach to managing MDR-TB may improve treatment outcomes at the level of the population, the management of each patient with MDR-TB should be tailored, when possible, to the individual’s requirements and circumstances. Clinicians and health services need to tailor policies to optimize treatment outcomes and minimize socioeconomic hardship. Thus, TB treatment programmes should aim to combine the available treatment models to serve the needs of all patients.

Declaration of interests

The review authors have no financial involvement with any organization or entity with a financial interest in, or financial conflict with, the subject matter or materials discussed in the review.

Acknowledgements

The authors acknowledge Linh Nhat Nguyen (WHO) for support with this review and the United States Agency for International Development for funding.


63

Table 4. Key characteristics of included studies in systematic review of decentralized versus centralized treatment for MDR-TB

Auth

or, y

ear a

nd

coun

try

Stud

y de

sign

Year

of i

nter

vent

ion

Sam

ple

size

: int

er-

vent

ion,

con

trol

HIV

prev

alen

ce in

th

e st

udy

popu

latio

n

Desc

riptio

n of

the

cont

rol a

rm

Desc

riptio

n of

the

inte

rven

tion

arm

Met

hod

of s

elec

ting

the

inte

rven

tion

grou

p Ti

min

g of

inte

r-ve

ntio

n w

ithin

TB

trea

tmen

tIn

terv

entio

n an

d co

ntro

l: co

ncur

rent

or

con

secu

tive

Outc

omes

m

easu

red

Loveday et al. (12) 2015South Africa (KwaZu-lu-Natal)

Pro-spective cohort

2008–2010

736, 813

75% Treatment in central specialized TB hospital

Treatment in rural hospital followed by outpatient DOT (home or clinic based) by health workers

Based on residential location

Intensive phase

Concur-rent

Treatment successDeathLoss to follow-upTreatment failure

Chan et al. (29) 2013Taiwan, China

Retro-spective cohort

2007–2008

290, 361

0.9% Hospi-tal and outpatient clinics

Home based DOT by “observ-ers” and nurses

Time period

Entire duration of treatment

Consec-utive

Treatment success

Kerschberger (35) 2016Swaziland

Retro-spective cohort

2008–2013

157, 298

81% Clin-ic-based care (patients visited nearest health fa-cility daily)

Home-based DOT by trained community volunteers

Based on residential location and socio-economic status

Intensive phase

Concur-rent

Treatment successDeathLoss to follow-upTreatment failure Cost to health care

Narita et al. (13) 2001United States of America (Florida)

Retro-spective cohort study

1994–1997

31, 39 44% Treatment in special-ized TB hospital

Outpatient ther-apy (DOT and/or SAT)

Selected for control if: treat-ment was failing, needed treatment of other medical condition, non-ad-herent


Concur-rent

Treatment completionDeath

Gler et al. (31) 2012Philippines


2003–2006

167, 416

Not stated

Treatment in central hospital

Communi-ty-based DOT by trained health-care workers

Time period

After spu-tum culture conversion

Consec-utive

Loss to follow-up

Cox et al. (30) 2014South Africa (Khayelitsha)


2008–2010

512, 206

72% Hospi-tal-based care

Communi-ty-based care integrated into existing primary care TB and HIV services

Based on residential location


Consec-utive

Treatment successDeathLoss to follow-upTreatment failure

Musa et al. (33) 2015Nigeria

Mod-elling study

NA NA Not stated

Hospi-tal-based care

Home-based DOT by trained health-care providers

Random selection

Intensive phase

NA Cost to health care

Sinanovic et al. (34) 2015South Africa (Khayelitsha)

Mod-elling study

NA 467 total 72% Fully hos-pitalized model (stay in hospital until culture conversion)

One fully decen-tralized model (in primary health care clin-ics); two partly decentralized models

NA Entire duration of treatment

NA Cost to health care

DOT: directly observed therapy; TB: tuberculosis; HIV: human immunodeficiency virus; SAT: self-administered therapy; MDR-TB: multidrug-resistant; TB; NA = not applicable.Intensive phase defined by inclusion of an injectable antibiotic in the treatment regimen.


64

Table 5. GRADE table of included studies in systematic review of decentralized versus centralized treatment for MDR-TB, showing pooled estimates for treatment outcomes and quality assessment of studies

Quality assessment Number of patients

Effect estimate

Quality Impor-tance

Num

ber o

f stu

dies

Desi

gn

Lim

itatio

nsa

Inco

nsis

tenc

yb

Indi

rect

ness

c

Impr

ecis

iond

Othe

r

Dece

ntra

lized

car

eNu

mbe

r of e

vent

s/nu

mbe

r of

pat

ient

s (p

oole

d pr

opor

-tio

n, 9

5% C

I)

Cent

raliz

ed c

are

Num

ber o

f eve

nts/

num

ber

of p

atie

nts

(poo

led

prop

or-

tion,

95%

CI)

Rela

tive

risk

(95%

CI)

Abso

lute

risk

(95%

CI)

Treatment success versus treatment failure, death or loss to follow-up

5 Obser-vational studies

Serious con-cerns

No con-cerns

No con-cerns

No con-cerns

None 1035/1695(0.67, 0.54 – 0.79)

979/1710(0.61, 0.49–0.72)

1.13 (1.01–1.27)

74 more per 1000 (from 6 more to 155 more)

⨁◯◯◯VERY LOW

Critical

Loss to follow-up versus treatment success, treatment failure or death


Serious con-cerns

Seri-ous con-cerns

No con-cerns

No con-cerns

None 278/1549(0.12, 0.06– 0.23)

384/1727(0.18, 0.09–0.32)

0.66 (0.38–1.13)

76 few-er per 1000 (from 29 more to 138 fewer)


Critical

Death versus treatment success, treatment failure or loss to follow-up


Serious con-cerns

Seri-ous con-cerns

No con-cerns

No con-cerns

None 250/1405(0.18, 0.16– 0.20)

232/1349(0.19, 0.15–0.24)

1.01 (0.67–1.52)

2 more per 1000 (from 57 fewer to 91 more)


Critical

Treatment failure versus treatment success, death or loss to follow-up


Serious con-cerns

Seri-ous con-cerns

No con-cerns

No con-cerns

None 90/1382(0.04, 0.01– 0.12)

55/1311(0.04, 0.02–0.08)

1.07 (0.48–2.40)

3 more per 1000 (from 22 fewer to 59 more)


Critical

a Limitations: all the studies were observational studies. The method of allocating patients to intervention and control groups was not randomized.

b Inconsistency: based on estimated I2.c Indirectness: the study interventions and outcomes were directly relevant to the objective of this review.d Imprecision: based on 95% confidence intervals.


65

Fig. 2

Forest plot of treatment success for decentralized versus centralized MDR-TB treatment and care

Forest plot of loss to follow-up for decentralized versus centralized MDR-TB treatment and care

Forest plot of death for decentralized versus centralized MDR-TB treatment and care

Forest plot of treatment failure for decentralized versus centralized MDR-TB treatment and care


66

Fig. 3. Forest plots of proportions for treatment success

(i) Decentralized treatment and care (intervention)

(ii) Centralized treatment and care (control)

Table 6. Comparison of pooled proportion and relative risk estimates for studies evaluating treatment success and death, including and excluding Narita et al. (13)

(a) Treatment success

Studies included in the analysis

Studies (n)

Pooled proportion (95% CI) de-centralized care

I 2

Pooled proportion (95% CI) centralized care

I 2

Pooled relative risk (95% CI) decentralized versus centralized care

I 2

Narita et al. included

5 0.67 (0.54–0.79)

97.4% 0.61 (0.49–0.72)

93.4% 1.13 (1.01–1.27) 74%

Narita et al. excluded

4 0.68 (0.52–0.63)

98.1% 0.57 (0.47–0.66)

92.8% 1.17 (1.05–1.30) 71%

(b) Death

Studies included in the analysis

Studies (n)

Pooled proportion (95% CI) de-centralized care

I 2

Pooled proportion (95% CI) centralized care

I 2

Pooled relative risk (95% CI) decentralized versus centralized care

I 2

Narita et al. included

4 0.18 (0.16–0.20)

49.5% 0.19 (0.15–0.24) 82.3% 1.01 (0.67–1.52) 77%

Narita et al. excluded

3 0.18 (0.16–0.20)

0.0% 0.19 (0.14–0.24) 88.3% 0.91 (0.59-1.42) 82%


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Table 7. Treatment cost to the health-care system for one MDR-TB patient in the decentralized and centralized care settings (in US dollars)

Study Study design Country

Description of decentralized care

Cost of de-centralized care

Description of centralized care

Cost of centralized care

Musa et al. (33) 2015

Modelling Nigeria Home-based care for the entire duration of treatment

US$ 1 535 Hospital-based care for the intensive phase and then home-based care for the continuation phase

US$ 2 095

Sinanovic et al. (34) 2015

Modelling South Africa

Primary health-care clinic for the entire duration of treatment

US$ 7 753 Hospital-based care for the intensive phase (until the four-month culture conversion) and then clinic-based care

US$ 13 432

Kerschberger (35) 2016

Retrospective cohort

Swaziland Home-based care for the entire duration of treatment

US$ 13 361 Clinic-based care for the intensive phase and then home-based care for the continuation phase

US$ 13 006

Table 8. Risk of bias assessment (23) of the included studies (excluding modelling studies)

Study Selection (max = 4)

Comparability (max = 2)

Outcome (max = 3)

Total scorea

(max = 9)Loveday et al. (32) 3 0 3 6

Chan et al. (29) 4 1 3 8

Kerschberger (35) 3 0 3 6

Narita et al. (13) 2 0 3 5

Gler et al. (31) 4 1 3 8

Cox et al. (30) 3 0 3 6

a A higher score is associated with a lower risk of bias


68

Table 9. Key characteristics of the 16 studies on decentralized treatment and care for MDR-TB patients, without a comparator group

Author, year, country

Study design

Number receiving interven-tion

HIV preva-lence

Description of the intervention

Outcome measures reported

Overall findings and conclusion

Brust et al. (38) 2013South Africa (KwaZulu-Natal)

Prospective cohort

91 81% Home-based care: nurses, community health workers and family supporters trained to administer injections, provide adherence support and monitor for adverse reactions

Adverse events Among people coinfected with MDR-TB and HIV, adverse events to medications were common but most mild. Those receiving antiretroviral therapy did not experience more adverse events. Coinfected patients can be treated safely in a home-based setting

Brust et al. (39) 2012South Africa (KwaZulu-Natal)

Prospective cohort

80 82% Home-based care: nurses, community health workers, and family supporters trained to administer injections, provide adherence support and monitor for adverse reactions

Treatment outcomes Integrated, home-based treatment for MDR-TB and HIV may improve treatment outcomes in rural, resource-limited and high-HIV-prevalence settings

Burgos et al. (4) 2005United States of America (San Francisco)

Retrospec-tive cohort

48 23% DOT was provided in the field by unlicensed public health personnel or at the clinic by an assigned nurse

Treatment outcomesAdverse eventsHealth-care costs

Treatment of MDR-TB among HIV-negative people as outpatients is feasible and associated with high cure rates and lower cost than in other published studies. People living with HIV had very poor treatment outcomes

Cavanaugh et al. (40) 2016 Bangladesh


77 0% Home-based DOT by trained paraprofessionals who administer medications (including injections) and monitor for adverse events

Adverse events (documentation versus patient interview recollection)

The programme appears to be feasible and clinically effective, but monitoring of adverse events is inadequate

Charles et al. (36) 2014Haiti


110 25% Field hospital established after the hospital was destroyed in the earthquake for managing MDR-TB patients in Port-au-Prince

Treatment outcomes Good outcomes for MDR-TB patients in the field hospital setting despite the adverse conditions

Drobac et al. (41) 2005Peru (Lima)


38 6% Community-based DOTS for children with MDR-TB

Treatment outcomesAdverse events

The percentage cured in this community-based treatment programme (94%) was at least as high as any reported for a referral hospital setting and was higher than that for adults enrolled in the DOTS programme in Peru

Furin et al. (42) 2001Peru (Lima)


60 1.7% Community-based DOTS

Adverse events In young patients with little comorbid disease, MDR-TB treatment rarely caused life-threatening adverse effects. Common side-effects may be managed successfully on an outpatient basis

Isaakidis et al. (43) 2012India (Mumbai)

Prospective cohort

67 100% Community-based programme for treating patients with HIV and MDR-TB co-infection

Adverse events Adverse events occurred frequently in this MDR-TB and HIV cohort but not more frequently than in non-HIV patients on similar TB medications. Most adverse events can be successfully managed on an outpatient basis through a community-based treatment programme

Isaakidis et al. (44) 2011India (Mumbai)

Prospective cohort

58 100% Outpatient care for patients coinfected with HIV and MDR-TB involving public–private antiretroviral therapy centres and a network of community NGOs

Treatment outcomes Encouraging rates of survival, cure and culture conversion were found with this treatment programme


69

Author, year, country

Study design

Number receiving interven-tion

HIV preva-lence

Description of the intervention

Outcome measures reported

Overall findings and conclusion

Malla et al. (45) 2009Nepal

Prospective cohort

175 Not stated

DOT on an ambulatory basis through a decentralized network of clinics

Treatment outcomes There were high MDR-TB cure rates in this ambulatory-based treatment programme

Mitnick et al. (46) 2003Peru (Lima)


75 1.3% Community-based DOT


There were high MDR-TB cure rates in this community-based treatment programme

Mohr et al. (47) 2015South Africa (Khayelitsha)


853 71% Community-based treatment for DR-TB in the patient’s nearest primary care clinic

The impact of HIV and other factors on DR-TB treatment outcomes

Response to DR-TB treatment did not differ with HIV infection in a programmatic setting with access to antiretroviral therapy

Satti et al. (48) 2012Lesotho


19 74% Community-based treatment for children with MDR-TB


MDR-TB and MDR-TB and HIV coinfection among children can be successfully treated using a combination of social support, close monitoring by community health workers and clinicians and inpatient care when needed

Seung et al. (5) 2009Lesotho


76 74% Community-based DOT that included social and nutritional support


This program was successful in reducing mortality in MDR-TB patients

Thomas et al. (49) 2007India (Chennai)

Prospective cohort

66 Not stated

MDR-TB management under field conditions where DOTS programme has been implemented

FeasibilityTreatment outcomesAdverse events

The treatment outcomes in this programme were suboptimal. The main challenge was identifying providers close to a patient’s residential location who were able to administer injections and managing drug adverse events

Vaghela et al. (50) 2015India (Delhi)

Prospective cohort

113 Not stated

Home based MDR-TB treatment and care with counselling support

Treatment outcomes Home-based care with counselling support is an important intervention in managing MDR-TB patients

MDR-TB: multidrug-resistant TB; HIV: human immunodeficiency virus; AE: adverse event; DOT: directly observed therapy; DOTS: directly observed therapy, short course; NGO: nongovernmental organization; TB: tuberculosis; DR-TB: drug-resistant TB

Table 10. Event frequency and pooled proportion estimates for treatment outcomes of studies without a comparator group, evaluating decentralized treatment and care for MDR-TB patients. Included for comparison, are studies that do include a comparator group and a meta-analysis of MDR-TB treatment outcome in a non-specific setting (37)

a) Treatment success (versus death, treatment failure and loss to follow-up)

MDR-TB treatment model

Studies (n) Events Total Propor-

tion (%) Lower 95% CI Upper 95% CI I 2

Decentralizeda (no control)

13 955 1570 76.1% 62.7% 85.9% 97.0%

Decentralizedb 5 1035 1695 67.3% 53.8% 78.5% 97.4%

Centralizedb 5 979 1710 61.0% 49.0% 71.7% 93.4%

Non-specificc 15 NR 4637 64% 52% 76% NR

a Studies that do not include a control group of decentralized care for MDR-TB.b Studies that have both an intervention and control group of decentralized care for MDR-TB.c An individual patient data meta-analysis of TB treatment outcomes for MDR-TB in a non-specific setting

(this may include both decentralized and centralized treatment models) (37).


70

b) Death (versus treatment success, treatment failure and loss to follow-up)





13 228 1570 11.8% 7.3% 18.3% 84.1%

Decentralizedb 4 250 1405 17.8% 15.9% 19.9% 49.5%

Centralizedb 4 232 1349 18.6% 14.0% 23.6% 82.3%




c) Treatment failure (versus treatment success, death and loss to follow-up)





12 85 1526 3.0% 1.3% 6.5% 90.4%

Decentralizedb 3 90 1382 4.2% 1.4% 11.9% 93.7%

Centralizedb 3 55 1311 4.3% 2.3% 8.1% 87.0%




d) Loss to follow-up (versus treatment success, treatment failure and death)





13 300 1570 6.1% 2.9% 12.4% 98.2%

Decentralizedb 4 278 1549 11.9% 5.7% 17.8% 98.1%

Centralizedb 4 384 1727 18.0% 9.3% 31.8% 97.0%





71

Fig. 4. Forest plots of the proportions of treatment success for the studies evaluating decentralized care for MDR-TB without a control group

Table 10. Event frequency and pooled proportion estimates for studies evaluating decentralized care for MDR-TB, reporting on adverse events from TB medications


Studies (n) Outcome Events Total Proportion

(%)Lower 95% CI

Upper 95% CI I 2


9 Any adverse events

410 521 86.3% 65.0% 95.6% 94.4%


3 Severe adverse events

47 175 22.2% 7.4% 50.5% 92.1%


8 Adverse events requiring

discontinuation of therapy

76 445 7.4% 1.9% 25.0% 95.6%

a Studies that do not include a control group of decentralized care for MDR-TB


72

Appendixes

Appendix 1. Search terms used and reference retrieval success

MedlineURL: http://www.ncbi.nlm.nih.gov/pubmedSearch date: January 20161) Tuberculosis, Multidrug-Resistant [MeSH]

OR ((tuberculosis OR TB) AND (multidrug-resistan* OR multidrug resistan* OR multi-drug resistan* OR “drug resistan*” OR drug-resistan* OR multiresistan* OR “multi resistan*” OR “rifampicin resistan*” OR “extensively drug-resistan*” OR “extensively-drug resistan*” OR “extensively resistan*” OR MDR OR XDR OR TDR))ORmdrtb OR xdr tb OR mdrtb OR mdr-tb OR xdr-tb OR tdr-tb OR “MDR TB” OR “XDR TB” OR “TDR TB”

AND2) (“directly observed” OR DOT OR DOTS OR DOTS-Plus OR cb-DOTS OR treatment

OR “patient support”) AND (community OR outpatient OR “public participation” OR community-based OR

decentralized OR non-specialized OR “periph* health centres” OR home-based OR ambulatory OR clinic OR “community health worker” OR CHW OR volunteer)

1030 search results returned à titles and abstracts reviewed à 24 identified for full-text review

EmbaseURL: http://www.embase.comSearch date: January 20161. Multidrug resistant tuberculosis.sh2. (tuberculosis or TB).af3. (multidrug-resistan* or multidrug resistan* or multi-drug resistan* or drug resistan*

or drug-resistan* or multiresistan* or multi resistan* or rifampicin resistan* or extensively drug-resistan* or extensively-drug resistan* or extensively resistan* or MDR or XDR or TDR).af

4. 2 and 35. (MDRTB or XDRTB or TDRTB or MDR-TB or XDR-TB or TDR-TB or MDR TB or

XDR TB or TDR TB).af6. 1 or 4 or 57. (directly observed OR DOT OR DOTS OR DOTS-Plus OR cb-DOTS OR treatment

OR patient support).af8. (community OR outpatient OR public participation OR community-based OR

decentralized OR non-specialized OR periph* health centres OR home-based OR ambulatory OR clinic OR community health worker OR CHW OR volunteer).af.

http://www.embase.com


73

9. 7 AND 810. 6 AND 91109 search results returned à titles and abstracts reviewed à 18 identified for full text

review à 10 relevant repeat studies from Medline search found (no additional studies found) and two relevant conference abstracts found

Cochrane Library including: Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA) and Cochrane Database of Systematic Reviews (CDSR)URL: http://onlinelibrary.wiley.com/cochranelibrary/searchSearch date: January 20161. MeSH descriptor: [Tuberculosis, Multidrug-Resistant] explode all trees OR2. ((tuberculosis OR TB) AND (multidrug-resistan* OR “multidrug resistan*” OR multi-

drug resistan* OR “drug resistan*” OR drug-resistan* OR multiresistan* OR “multi resistan*” OR “rifampicin resistan*” OR “extensively drug-resistan*” OR “extensively-drug resistan*” OR “extensively resistan*” OR MDR OR XDR OR TDR) ) OR (MDRTB OR XDRTB OR TDRTB OR MDR-TB OR XDR-TB OR TDR-TB OR “MDR TB” OR “XDR TB” OR “TDR TB”)

3. #1 OR #24. (“directly observed” OR DOT OR DOTS OR DOTS-Plus OR cb-DOTS OR treatment

OR “patient support”) AND (community OR outpatient OR “public participation” OR community-based OR decentralized OR non-specialized OR “peripheral health centres” OR home-based OR ambulatory OR clinic OR “community health worker” OR CHW OR volunteer)

5. #3 AND #4

13 search results returned à no relevant reviews found

WHO portal of clinical trialsURL: http://apps.who.int/trialsearchSearch date: January 2016multi-drug resistant tuberculosis OR multidrug resistant tuberculosis OR multi drug resistant tuberculosis AND treatment (status=ALL)

64 records for 53 trials returned à no relevant studies found

http://apps.who.int/trialsearch/


74

LILACSURL: http://lilacs.bvsalud.org/enSearch date: January 2016((MH: tuberculosis OR TB) AND (multidrug-resistan$ OR “multidrug resistan$” OR “multi-drug resistan$” OR “drug resistan$” OR drug-resistan$ OR multiresistan$ OR “multi resistan$” OR “rifampicin resistan$” OR “extensively drug-resistan$” OR “extensively-drug resistan$” OR “extensively resistan$” OR MDR OR XDR OR TDR)) OR MDRTB OR XDRTB OR TDRTB OR MDR-TB OR XDR-TB OR TDR-TB OR “MDR TB” OR “XDR TB” OR “TDR TB”AND(MH: “directly observed” OR DOT OR DOTS OR DOTS-Plus OR cb-DOTS OR treatment OR “patient support”) AND (community OR outpatient OR “public participation” OR community-based OR decentralized OR non-specialized OR “periph$ health centres” OR home-based OR ambulatory OR clinic OR “community health worker” OR CHW OR volunteer)7 search results returned à no relevant studies identified

Web of ScienceURL: http://wokinfo.com/Search date: January 2016((Multidrug-Resistant Tuberculosis) OR ((tuberculosis OR TB) AND ((multidrug-resistan*) OR (multidrug resistan*) OR (multi-drug resistan*) OR (drug resistan*) OR (drug-resistan*) OR (multiresistan*) OR (multi resistan*) OR (rifampicin resistan*) OR (extensively drug-resistan*) OR (extensively-drug resistan*) OR (extensively resistan*) OR MDR OR XDR OR TDR) ) OR (MDRTB OR XDRTB OR TDRTB OR MDR-TB OR XDR-TB OR TDR-TB OR (MDR TB) OR (XDR TB) OR (TDR TB))) AND ((directly observed OR DOT OR DOTS OR DOTS-Plus OR cb-DOTS OR treatment OR patient support) AND (community OR outpatient OR public participation OR community-based OR decentralized OR non-specialized OR peripheral health centres OR home-based OR ambulatory OR clinic OR community health worker OR CHW OR volunteer))753 search results returned à titles and abstracts reviewed à 19 relevant studies identified à No studies in addition to those from Medline identified

http://lilacs.bvsalud.org/en/


75

OpenSIGLEURL: http://www.opengrey.eu/searchSearch date: January 2016Multidrug-Resistant Tuberculosis OR ((tuberculosis OR TB) AND ((multidrug-resistan*) OR (multidrug resistan*) OR (multi-drug resistan*) OR (drug resistan*) OR multiresistan* OR (multi resistan*) OR MDR OR XDR) OR MDRTB OR XDRTB OR MDR-TB OR XDR-TBNo search terms used for intervention or outcomes.76 search results returned à No relevant studies found

Google ScholarURL: https://scholar.google.comSearch date: January 2016multidrug resistant tuberculosis; community treatmentFirst 10 pages screened – five relevant studies identified. No studies in addition to those from Medline identified

International Union of Tuberculosis and Lung Disease conference electronic abstract database URL: http://www.theunion.org/what-we-do/journals/ijtld/conference-abstract- booksSearch date: January 2016 Manual searching of pdfs from the past 10 years (2006–2015) for abstracts related to MDR-TB and decentralized treatmentTwo relevant abstracts found à Author of one abstract contacted to obtain further information. Unable to contact the authors from the other abstract.

ClinicalTrials.govURL: https://clinicaltrials.gov/ct2/homeSearch date: January 2016multi drug resistant tuberculosis OR multi-drug resistant tuberculosis OR MDR TB OR MDR-TB90 studies found à title and abstract reviewed à no relevant studies foundReview of reference lists from related review papers and from relevant papers identified from the database search à One additional study identified

http://www.opengrey.eu/search/

http://www.theunion.org/what-we-do/journals/ijtld/conference-abstract-books

http://www.theunion.org/what-we-do/journals/ijtld/conference-abstract-books

https://clinicaltrials.gov/ct2/home


76

Appendix 2. Full-text papers reviewed but excluded from review inclusion and reasons for exclusion

Reason for exclusion References excluded from main analysis (n = 33)

No comparator group included in study (4,5,36,38–50)

Did not include the outcomes of interest (51,52)

Review article (not an original study) (6,11,12,15–17,21)

Did not include the intervention of interest (53,54)

Conference abstract: subsequently published (55)

Conference abstract: author could not be contacted for further study information (56)

Study published elsewhere (57,58)

Sample size <10 participants (59)


77

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