Operational research on implementation of tuberculosis guidelines in
Mozambique
Brouwer, M.A.
Publication date
2015
Document Version
Final published version
Link to publication
Citation for published version (APA):
Brouwer, M. A. (2015). Operational research on implementation of tuberculosis guidelines in
Mozambique.
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Operational!research!on!
implementation!of!tuberculosis!
guidelines!in!Mozambique!
! ! Miranda!Brouwer! ! !! ! ! ! ! ! ! ! ! ! ! ! ! ! ! Operational!research!on!implementation!of!tuberculosis!guidelines!in!Mozambique! Miranda!Brouwer! Thesis!University!of!Amsterdam!with!summary!in!English!and!Dutch! ! ISBN:!978H94H6259H700H6! ! ©!2015,!M.A.!Brouwer,!Tilburg,!The!Netherlands;!mbrouwer@phtbconsult.org! ! All!rights!reserved.!No!part!of!this!publication!may!be!reproduced!in!any!form!or!by!any!means,!without! prior!written!permission!of!the!author.! !
The! printing! and! distribution! of! this! thesis! was! financially! supported! by! PHTB! Consult,! Tilburg,! The! Netherlands.!
!
Cover!design:!Esther!Roodhuizen! Photo!credits:!PA!&!MA!Productions!
Operational!research!on!implementation!of!tuberculosis!
guidelines!in!Mozambique!
! ! ACADEMISCH!PROEFSCHRIFT! ! ! ter!verkrijging!van!de!graad!van!doctor! aan!de!Universiteit!van!Amsterdam! op!gezag!van!de!Rector!Magnificus! prof.!dr.!D.C.!van!den!Boom! ten!overstaan!van!een!door!het!College!voor!Promoties!ingestelde!commissie,!! in!het!openbaar!te!verdedigen!in!de!Agnietenkapel! op!woensdag!16!september!2015,!te!12.00!uur! ! ! ! door!! Maria!Antonia!Brouwer! geboren!te!Winschoten! !!
!
!
Promotor:!! Prof.!dr.!F.G.J.!Cobelens!! Universiteit!van!Amsterdam!
!
Co9promotor:! Dr.!F.C.M.!van!Leth! Universiteit!van!Amsterdam!
!
Overige!leden:! Prof.!dr.!M.P.!Grobusch! Universiteit!van!Amsterdam!
! Prof.!dr.!J.W.!Groothoff!! Rijksuniversiteit!Groningen! ! Dr.!A.H.!van!’t!Hoog! Universiteit!van!Amsterdam! ! Prof.!dr.!M.!Prins! Universiteit!van!Amsterdam! ! Prof.!dr.!P.J.!Sterk!! Universiteit!van!Amsterdam! ! Prof.!dr.!A.!Verbon!! Erasmus!Universiteit!Rotterdam! ! Faculteit!der!Geneeskunde! ! !
!
!
!
For!my!mother,!in!loving!memory!
1.! General!introduction!
1!
2.! The!effect!of!tuberculosis!and!antiretroviral!treatment!on!CD4+!cell!count!
response!in!HIV@positive!tuberculosis!patients!in!Mozambique!
11!
3.! Are!routine!tuberculosis!programme!data!suitable!to!report!on!antiretroviral!
therapy!use!of!HIV@infected!tuberculosis!patients?!
21!
4.! Benchmarking!to!assess!potential!under@diagnosis!of!smear@negative!and!extra@
pulmonary!tuberculosis.!A!case!study!from!Mozambique!
31!
5.! Health!care!workers’!challenges!in!the!implementation!of!tuberculosis!infection!
prevention!and!control!measures!in!Mozambique!
41!
6.! Implementation!of!tuberculosis!infection!prevention!and!control!in!Mozambican!
health!care!facilities!
53!
7.! Assessing!ventilation!of!health!facilities!using!a!vaneometer.!
65!
8.! General!discussion!
75!
9.! Summary!
85!
10.! Samenvatting!
89!
Acknowledgements!
93!
Portfolio!
!
97!
Affiliations!and!contributions!of!co@authors!
101!
About!the!author!
103!
!
1. General+introduction+
!
Tuberculosis! (TB)! and! Human! Immunodeficiency! virus! (HIV)! infections! remain! considerable! public! health! challenges!for!many!countries.!Worldwide,!the!number!of!new!HIV!infections!is!declining.1!This!also!applies!
to!subHSaharan!Africa!though!in!2012!still!70%!of!the!world’s!new!infections!occurred!in!this!region.!Of!all! new! infections! in! subHSaharan! Africa,! almost! 50%! occur! in! Southern! Africa.! In! Mozambique! alone,! an! estimated!120,000!new!HIV!infections!occurred!in!2012.!
For!TB,!twentyHtwo!high!burden!countries!represent!80%!of!the!world’s!TB!cases.2!In!terms!of!estimated!
incidence! and! prevalence,! Southern! Africa! bears! the! heaviest! TB! burden:! of! the! five! countries! with! the! highest!estimated!TB!incidence,!four!are!in!Southern!Africa.!According!to!the!2014!Global!TB!report,!the! incidence!ranges!from!552!per!100,000!population!in!Mozambique!and!Zimbabwe!to!1,382!in!Swaziland.2! HIV!is!one!of!the!strongest!risk!factors!for!developing!TB!and!has!been!the!driving!force!for!the!TB!incidence! in!the!region.3! The!Directly!Observed!Treatment,!Short!course!(DOTS)!strategy!has!guided!global!TB!control!efforts!since! 1993.4!The!strategy!consist!of!several!pillars!including!short!course!chemotherapy,!direct!observation!of!the! intake!of!the!medication!during!the!first!two!months,!notification!and!evaluation!of!reported!patients,!and! ensuring!the!availability!of!medicines!at!all!times.!It!became!part!of!the!Stop!TB!Strategy!in!2006,!which!also! included!components!to!address!the!TB/HIV!challenge.5!Policies!and!guidelines!describe!in!more!detail!the!
interventions! and! activities! to! carry! out! the! strategy.! The! purpose! of! guidelines! in! general! is! to! improve! patient!care!and!assist!in!medical!decisionHmaking.6!Since!2009,!the!World!Health!Organization!(WHO)!uses!
an!elaborate!guideline!development!process,!which!includes!a!systematic!review!of!the!available!evidence! and! an! assessment! of! the! quality! of! that! evidence.7! The! review! and! quality! assessment! result! in!
recommendations.!To!finalize!the!formal!guideline!process,!there!is!a!need!to!disseminate,!implement!and! evaluate!these!recommendations.!! Most!countries’!strategic!TB!plans!to!guide!TB!control!at!country!level!reflect!the!Stop!TB!Strategy.!The!TB! national!strategic!plan!2008H2012!for!Mozambique!included!most!of!its!elements.8!TB!manuals!of!countries! present!the!translation!and!adaptation!of!these!global!strategies!and!guidelines!to!the!local!setting.!It!is! mainly!these!TB!manuals!that!guide!the!implementation!and!use!of!TB!control!interventions!at!the!various! levels!of!the!health!care!system.!! The!translation!of!international!policy!and!guidelines!into!national!practice!constitutes!a!major!challenge.9! Reasons!may!be!that!relevant!factors!for!effective!guideline!production!as!described!by!Thomson!et!al!are! not!taken!into!account.6!These!relevant!factors!are:!the!development!group,!the!development!itself!and!the! presentation!of!the!guidelines,!dissemination,!implementation!and!evaluation.!! ! Guideline+development+group+ The!development!of!guidelines!is!usually!a!team!effort.!Key!affected!groups,!including!representatives!from! users,!should!participate!in!the!development!process.10!The!team!should!have!the!necessary!skills,!such!as!
scientific! and! group! leadership,! to! develop! the! guideline.6! The! team! composition! may! influence!
implementation! and! adherence! to! the! guidelines.! A! study! evaluating! adherence! to! TB! contact! tracing! guidelines,! concluded! that! representation! of! the! endHusers! in! the! guideline! development! process! could! improve!adherence!to!these!guidelines.11!
Guideline+development+and+presentation+
The! WHO! handbook! for! guidelines! development! prescribes! a! format! for! WHO! guidelines:! an! executive! summary,! a! main! body! and! appendices.7! The! handbook! recommends! 1,! 3! and! 25! pages! respectively! as!
lengths!for!these!sections.!Thomson!et!al!suggest!that!the!proposed!use!determines!the!guideline!format.6!
A!study!in!Uganda!evaluated!how!factors!related!to!the!guideline!development!process!influenced!health! care!service!delivery.12!Presentation!of!the!evaluated!guidelines!was!mostly!in!the!form!of!booklets,!even!
though! staff! at! the! service! delivery! level! often! preferred! charts! because! of! the! easy! language! and! illustrative!diagrams.!!
!
Dissemination+
Dissemination! of! guidelines! means! making! the! guidelines! available! to! those! that! should! use! them.! This! implies! that! the! intended! users! are! clear.! In! the! Uganda! study,! many! guidelines! were! for! health! care! workers!without!specifying!the!level!and!the!qualification!of!these!workers.12!Also,!dissemination!did!not! occur!systematically!to!all!relevant!levels.!Dissemination!approaches!include!through!professional!bodies,! continuing!medical!education!efforts,!and!relevant!journals!13.!The!most!common!approach!in!subHSaharan! Africa!is!training!of!health!care!workers.!Health!care!workers!attend!workshops!where!they!receive!a!copy! of!the!guidelines14!which!they!perceive!as!their!personal!copies.!This!limits!availability!to!other!health!care! workers!and!at!the!facility!if!the!health!care!worker!transfers!to!another!facility.! ! Implementation+
Implementation! often! involves! a! change! in! practice! which! could! be! achieved! through! addressing! the! knowledge,!attitudes!and!practices!of!the!professionals!involved.6!This!may!not!be!sufficient.!A!variety!of!
organisational! aspects! such! as! revision! of! professional! roles,! multidisciplinary! teams,! integrated! care,! knowledge! and! quality! management! contribute! to! achieve! the! desired! change.15! Shifting! tasks! from!
medical! doctors! to! nonHdoctor! clinicians! is! an! example! of! the! revision! of! professional! roles.! Due! to! the! shortage!of!medical!doctors,!Mozambique!evaluated!the!quality!of!care!of!nonHdoctor!clinicians!for!HIVH infected! patients.16! The! nonHdoctor! clinicians! received! a! 14Hday! training! course! on! care! for! HIVHinfected!
patients.! The! study! found! that! in! most! clinical! encounters! with! patients! they! did! not! adhere! to! the! guidelines!as!taught!in!the!course.!!
Another! example! where! the! organisation! of! an! intervention! did! not! lead! to! the! desired! improvements! comes!from!Malawi!in!the!early!days!of!TB/HIV!collaboration.!Initiation!of!antiretroviral!therapy!(ART)!in!coH infected!TB!patients!was!postponed!until!they!completed!two!months!of!TB!treatment.17!This!resulted!in!
more!difficulties!to!achieve!the!required!change!in!practice,!which!was!the!provision!of!ART.!The!reason! was!that!most!patients!had!returned!to!their!communities!where!few!if!any!HIV!treatment!services!were! available.!After!returning!to!their!communities!and!feeling!better!on!TB!treatment,!patients!were!less!likely! to! return! to! the! hospital! for! ART.! Had! initiation! of! ART! been! integrated! in! the! first! two! months! of! TB! treatment! while! the! patients! still! attended! the! hospital! and! felt! more! ill,! ART! coverage! may! have! been! higher.!!
Other! factors! relevant! for! implementation! are! support! and! leadership,! and! alignment! with! existing! roles! and! tasks.18! Despite! the! embracing! of! operational! or! implementation! research,! there! seems! to! be!
inadequate!attention!for!implementation.19!
Evaluation++
Newly!emerging!evidence!necessitates!the!revision!of!guidelines!periodically.!The!guideline!development! process!includes!evaluation!that!should!also!inform!the!revision!of!the!guidelines.6!This!does!not!seem!to!
happen! systematically,! nor! is! it! clear! who! should! do! the! evaluation! and! how.! The! WHO! handbook! for! guideline!development!includes!only!half!a!page!on!evaluation!and!monitoring!compared!to!7!pages!on!the! assessment! of! the! evidence.7! The! half! page! provides! very! little! practical! information! on! carrying! out! an!
evaluation.!!
Recommendations! made! in! guidelines! should! have! an! effect! or! outcome.7! Therefore! guidelines! should! include! measurable! indicators! to! monitor! the! outcome! of! the! guideline.! However,! measuring! outcomes! alone!is!not!sufficient!and!it!is!necessary!to!take!into!account!all!parts!of!the!development!process.6!If!the! dissemination!process!occurred!inadequately,!one!would!not!expect!improved!outcomes.!To!interpret!the! outcome!indicators,!baseline!information!or!a!reference!value!for!the!indicator!is!needed.! + Research+questions+ + The!overall!objective!of!this!thesis!is!to!assess!how!guideline!implementation!and!evaluation!contribute!to! health! care! decisionHmaking! and! to! assess! what! critical! factors! contribute! to! successful! or! unsuccessful! implementation! of! TB! control! guidelines! through! case! studies! mainly! conducted! in! Mozambique.! We! specifically! evaluate! two! components! of! the! guideline! development! process! as! outlined! above,! i.e.! implementing!guidelines!and!evaluation!of!guidelines.!
The!central!research!questions!of!this!thesis!are:!
1. How! can! assessment! of! guideline! implementation! and! its! evaluation! contribute! to! health! care! decisionHmaking?! Guidelines!support!health!care!decisionHmaking!at!both!patient!and!health!care!service!delivery!level.!To!do! so!effectively,!health!care!workers!and!decisionHmakers!should!use!guidelines!and!monitor!their!outcomes.! If!this!occurs!either!not!or!incompletely,!the!decisionHmaking!process!lacks!crucial!information.!This!could! lead!to!poor!or!no!decisionHmaking.!In!this!thesis!we!evaluate!outcomes!described!in!guidelines!with!the! aim!to!inform!health!care!decisionHmaking.! 2. Which!factors!are!critical!for!failure!or!success!in!guideline!implementation?!
Improved! health! care! is! one! of! the! objectives! of! guidelines,! however,! implementation! of! these! is! often! challenging.!If!the!desired!outcomes!of!guidelines!are!not!achieved,!assessment!of!the!reasons!for!this!need! exploration.!It!seems!logical!to!evaluate!guideline!implementation!or!the!guideline!itself,!though!this!does! not!happen!systematically.!In!this!thesis!we!assess!various!aspects!of!guideline!implementation!to!identify! factors!that!contribute!to!failure!and!success!of!the!implementation.! ! Guidelines+assessed+ +
To! address! these! questions,! the! thesis! focuses! on! guideline! implementation! and! evaluation! in! a! local! context.!It!looks!at!several!guidelines!developed!in!the!first!decade!of!the!21st!century!when!it!became!clear!
willingness! to! provide! care! to! HIVHinfected! individuals! together! with! availability! of! funding! created! opportunities!that!did!not!exist!before.!!
Studies! had! found! that! many! HIVHinfected! patients! died! of! TB! and! that! provision! of! coHtrimoxazole! preventive!therapy!reduced!the!mortality!for!coHinfected!TB!patients.22!Other!studies!identified!TB!clinics!as!
a!good!entry!point!for!testing!for!and!diagnosing!HIV!infection.23!Centres!for!voluntary!HIV!testing!proved!
good!places!to!screen!for!TB.24!Isoniazid!preventive!therapy!proved!to!protect!HIVHinfected!individuals!from!
TB!although!the!effect!was!limited!to!a!few!years.25!!
HIV! and! multiHdrug! resistant! TB! (MDRHTB)! placed! infection! control! back! on! the! agenda.26! HIVHinfected!
people!have!a!vulnerability!to!develop!TB!disease!soon!after!they!acquire!infection!with!HIV.27!MDRHTB!has!
poorer!treatment!outcomes!compared!to!drugHsensitive!TB,!and!is!much!more!costly!to!treat.!An!outbreak! of!MDRH!and!extensively!drug!resistant!(XDR)!TB!in!South!Africa!identified!nosocomial!transmission!as!the! most! important! cause! for! the! outbreak! that! had! a! high! mortality! in! the! mainly! HIVHinfected! patients.28!
Mozambique!has!the!combined!challenge!of!an!high!HIV!prevalence29!and!a!relatively!high!percentage!of!
new!TB!patients!having!MDRHTB!(3.5%).30!MDRHTB!is!more!frequent!in!HIVHinfected!people.30,31!
Several! of! these! developments! contributed! to! the! development! of! the! interim! policy! for! TB/HIV! collaborative!activities!in!2004.32!The!policy!recommends!sets!of!activities!for!collaboration!in!health!care!
facilities!to!decrease!the!burden!of!TB!in!people!living!with!HIV!(PLHIV),!and!to!decrease!the!burden!of!HIV! in!TB!patients.!Intensified!case!finding,!the!provision!of!isoniazid!preventive!therapy!and!infection!control!in! health!care!and!congregate!settings!are!the!activities!to!decrease!the!burden!of!TB!in!PLHIV.!HIV!testing! and! counselling,! HIV! prevention! methods,! coHtrimoxazole! preventive! therapy,! HIV! care! and! support,! and! provision!of!antiHretroviral!therapy!(ART)!are!the!activities!to!reduce!to!burden!of!HIV!in!TB!patients.!! The!WHO!also!published!guidelines!on!the!diagnosis!of!smearHnegative!and!extrapulmonary!TB,33!and!on!
infection!control!in!health!care!facilities.34!SmearHnegative!and!extrapulmonary!TB!occur!more!frequently!in!
HIVHinfected! people! and! are! a! diagnostic! challenge! in! settings! depending! mainly! on! smear! microscopy.35!!!
Several!studies!found!substantially!higher!notification!rates!of!TB!among!health!care!workers!in!comparison! with!the!general!population.!Nursing!students!in!Zimbabwe!had!a!much!higher!prevalence!of!TB!infection! compared!to!polytechnic!school!students.36!Hospital!staff!in!Kenya!had!high!TB!notification!rates!and!the!
risk! for! TB! disease! was! higher! for! staff! members! that! spend! more! hours! with! patients.37! These! studies!
illustrated!clearly!that!infection!control!needs!strengthening.! !
Research+setting++ +
The! studies! of! this! thesis! took! place! in! Mozambique.! The! country! notified! an! increasing! number! of! TB! patients!since!1990!and!reached!almost!50,000!cases!in!2012!(Figure!1).38!The!estimated!incidence!in!2011!
of! 551! per! 100,000! would! result! in! almost! 139,000! cases,! suggesting! that! many! TB! cases! remain! undiagnosed.38!!
Mozambique! also! faces! a! substantial! HIV! epidemic.! A! national! population! prevalence! survey! in! 2009! showed! that! nationwide! 11.5%! of! the! adult! population! was! infected! with! HIV.29! Prevalence! within! the!
country! showed! a! large! variation! from! 3.7%! in! Niassa! province! to! 25.1%! in! Gaza! province.! Furthermore,! prevalence!was!higher!in!women!compared!to!men,!and!in!urban!areas!compared!to!rural!areas.!Many!TB! patients! in! Mozambique! are! coHinfected! with! HIV:! in! 2013,! 91%! of! notified! TB! patients! knew! their! HIVH! status!and!56%!were!HIV!positive.2!
!
Figure'1'Incident'TB'notifications'in'Mozambique'1990;2012'
!
Mozambique!became!independent!from!Portugal!in!1975.!Soon!thereafter!the!country!entered!into!a!civil! war! that! lasted! until! the! Peace! Agreement! in! 1992.39! Conflict! situations! contribute! to! (re)! emergence! of!
infectious! diseases! through! various! mechanisms.40! Conflict! situations! may! lead! to! a! breakdown! of! the!
health! care! infrastructure! including! disruption! of! disease! control! programmes! and! reduced! practice! of! infection! control.! It! also! leads! to! inadequate! disease! surveillance! and! increased! movement! of! the! population.!Access!of!the!population!to!health!care!services!and!of!the!health!care!services!to!reach!out!to! the!population!for!interventions!may!be!reduced.!In!the!prolonged!civil!war,!many!of!these!mechanisms! also!affected!Mozambique’s!infrastructure.!Roads,!schools!and!health!care!facilities!were!destructed!and! became!dysfunctional.41!
The! National! TB! Control! Programme! (Programa' Nacional' de' Controlo' de' TB)! has! directed! TB! control! in! Mozambique! since! the! 1980s.! Mozambique! practised! the! DOTS! strategy! already! before! it! became! the! global!policy9!because!of!the!international!support!advising!implementation!of!short!course!chemotherapy,!
direct!observation!of!the!intake!of!the!medication!during!the!first!two!months,!evaluation,!notification!and! ensuring!availability!of!medicines.42!The!country!succeeded!full!implementation!of!the!strategy!only!in!2000!
because!the!war!limited!geographical!expansion.!
Mozambique! adopted! the! interim! policy! for! TB/HIV! collaborative! activities32,! the! guidelines! on! the!
diagnosis! of! smearHnegative! and! extrapulmonary! TB33! and! on! infection! control! in! health! care! facilities34!
mainly!through!translation!into!Portuguese.!Routine!supervisory!visits!to!districts!and!health!care!facilities! in!Mozambique!identified!several!gaps!and!challenges!related!to!the!use!of!these!guidelines.!Health!care! workers!in!health!care!facilities!and!at!district!level!did!not!always!know!how!to!use!the!guidelines.!There! was!no!system!in!place!to!assess!their!implementation.!Although!health!care!facilities!and!districts!collect!a! substantial! amount! of! data! on! a! monthly! or! quarterly! basis,! they! did! not! use! the! data! to! evaluate! their! performance.! Also,! countries! including! Mozambique! spend! a! substantial! amount! of! resources! on! the! process! of! guideline! development! and! implementation.! Therefore! an! evaluation! of! guideline! implementation!at!health!care!facility!and!district!level!seemed!warranted.!! 0! 10000! 20000! 30000! 40000! 50000! 60000! 1990! 1991! 1992! 1993! 1994! 1995! 1996! 1997! 1998! 1999! 2000! 2001! 2002! 2003! 2004! 2005! 2006! 2007! 2008! 2009! 2010! 2011! 2012!
The!studies!took!place!in!three!provinces!in!central!Mozambique:!Manica,!Sofala!and!Tete!(Figure!2).!!
!
! Legend:!! Sm+!=!smearFpositive!pulmonary!tuberculosis! AF!=!all!forms!of!tuberculosis! TB!data!concern!number!of!notifications!of!the!year!2007!and!are!from!the!national!TB!control!programme.!The!population!data!come!from!the! same!source.!!
Figure'2'The'three'provinces'of'Mozambique'where'the'research'took'place' ! At!the!start!of!the!studies!in!2007,!these!three!provinces!had!a!population!of!4.7!million,!representing!23%! of!the!country’s!population.!They!notified!4,399!sputum!smearFpositive!TB!cases!and!9,399!all!forms!of!TB! cases!(National!TB!Programme!data).!This!was!24!and!25%!of!the!country’s!total!notification,!respectively.! The!HIV!prevalence!in!the!provinces!was!15.3%!in!Manica,!15.5%!in!Sofala!and!7%!in!Tete!Province.29!The! Ministry! of! Health! provides! guidelines! for! TB! and! HIV! control! activities! in! the! country! through! the! National! TB! Programme! and! the! National! Aids! Control! Programme! (Programa' Nacional' de' Controlo' das'
ITS/HIV/SIDA).! The! National! TB! Programme! and! the! National! Aids! Control! Programme! distribute! the!
guidelines!through!the!provincial!and!district!health!offices!to!the!health!care!facilities.!Supervision!occurs! from!one!level!to!the!next.!Data!flow!moves!the!other!direction:!from!health!care!facilities!to!the!district! that!prepares!an!aggregated!report!for!the!province.!Similarly,!the!provinces!prepare!an!aggregated!report! for!the!national!level.!Review!meetings!take!place!at!the!various!levels!to!discuss!progress.!! All!districts!keep!a!TB!register!with!nominal!TB!notifications.!Larger!health!care!facilities!also!maintain!a!TB! register,!but!smaller!ones!do!report!the!TB!notifications!to!the!district!where!these!enter!into!the!district! register.! !
Specific'research'questions' ' In!order!to!answer!the!central!research!questions!of!1)!How!can!assessment!of!guideline!implementation! and!its!evaluation!contribute!to!health!care!decision<making?!and!2)!Which!factors!are!critical!for!failure!or! success!in!guideline!implementation?,!we!formulated!specific!research!questions.!! The!specific!research!questions!are:!
1. How! can! routinely! available! TB! and! HIV! programme! data! facilitate! evaluation! of! guideline! implementation!and!assist!in!decision<making?!
The!evaluation!of!the!guideline!on!ART!use!in!chapter!2!investigates!whether! the!TB!programme!misses! opportunities! for! ART! initiation! because! of! non<availability! of! laboratory! results.! In! chapter! 3! we! assess! whether!routinely!available!data!are!a!good!source!for!evaluating!implementation!of!the!use!of!ART!in!co< infected! TB! patients! using! completeness! and! correctness! of! data! as! the! outcome! measure.! Chapter! 4! evaluates!the!possibility!to!assess!potential!under<diagnosis!of!some!forms!of!tuberculosis!with!routinely! available!data!on!TB!cases!and!HIV!prevalence.! 2. What!can!we!learn!from!users!about!the!implementation!of!guidelines?! Chapter!5!describes!how!health!care!workers!use!the!guideline!on!TB!infection!prevention!and!control.!We! evaluate!how!they!use!the!measures!as!outlined!in!this!guideline!to!reduce!their!occupational!TB!infection! risk.!Furthermore,!it!describes!the!challenges!health!care!workers!face!in!their!work!practice!while!using! these!guidelines.!! 3. What!is!the!implementation!status!of!current!tuberculosis!guidelines!in!Mozambique?!
In! chapter! 6! we! evaluate! the! level! of! implementation! of! selected! TB! infection! prevention! and! control! measures! in! health! care! facilities.! In! chapter! 7! we! assess! a! specific! part! of! the! guideline! on! TB! infection! prevention!and!control:!the!assessment!of!ventilation!in!rooms!in!health!care!facilities.!We!assess!how!to! conduct!measurement!of!air!velocity,!an!essential!component!in!ventilation!assessment.!!
! !
References'
1.!! Joint!United!Nations!Programme!on!HIV/AIDS!(UNAIDS).!UNAIDS!report!on!the!Global!AIDS!epidemic.!2013!Nov.!! 2.!! World!Health!Organization.!Global!tuberculosis!report.!2014.!!
3.!! Corbett! EL,! Marston! B,! Churchyard! GJ,! De! Cock! KM.! Tuberculosis! in! sub<Saharan! Africa:! opportunities,! challenges,!and!change!in!the!era!of!antiretroviral!treatment.!Lancet.!2006!Mar!18;!367:!926–37.!! 4.!! World!Health!Organization.!Framework!for!effective!tuberculosis!control.!1994.!! 5.!! World!Health!Organization,!Stop!TB!Partnership.!THE!STOP!TB!STRATEGY.!WHO/HTM/STB/2006.37.!2006.!! 6.!! Thomson!R,!Lavender!M,!Madhok!R.!How!to!ensure!that!guidelines!are!effective.!BMJ.!1995!Jul!22;!311(6999):! 237–42.!! 7.!! World!Health!Organization.!WHO!Handbook!for!Guideline!Development.!2012.!! 8.!! Ministério!de!Saúde,!Programa!Nacional!de!Controlo!da!Tuberculose.!Plano!estratégico!nacional!de!controlo!da! Tuberculose!em!Mocambique!2008<2012.!2007.!! 9.!! Cliff!J,!Walt!G,!Nhatave!I.!What’s!in!a!name?!Policy!transfer!in!Mozambique:!DOTS!for!tuberculosis!and!syndromic! management!for!sexually!transmitted!infections.!J!Public!Health!Policy.!2004;!25(1):!38–55.!!
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11.!! Mulder! C,! Harting! J,! Jansen! N,! Borgdorff! MW,! van! Leth! F.! Adherence! by! Dutch! public! health! nurses! to! the! national!guidelines!for!tuberculosis!contact!investigation.!PloS!One.!2012;!7(11):!e49649.!! 12.!! Nabyonga!Orem!J,!Bataringaya!Wavamunno!J,!Bakeera!SK,!Criel!B.!Do!guidelines!influence!the!implementation!of! health!programs?!<!Uganda’s!experience.!Implement!Sci!IS.!2012;!7:!98.!! 13.!! Grol!R,!Grimshaw!J.!From!best!evidence!to!best!practice:!effective!implementation!of!change!in!patients’!care.! Lancet.!2003!Oct!11;!362!(9391):!1225–30.!! 14.!! Baker!U,!Tomson!G,!Somé!M,!Kouyaté!B,!Williams!J,!Mpembeni!R,!et!al.!“How!to!know!what!you!need!to!do”:!a! cross<country!comparison!of!maternal!health!guidelines!in!Burkina!Faso,!Ghana!and!Tanzania.!Implement!Sci!IS.! 2012!Apr!13;!7:!31.!! 15.!! Wensing!M,!Wollersheim!H,!Grol!R.!Organizational!interventions!to!implement!improvements!in!patient!care:!a! structured!review!of!reviews.!Implement!Sci!IS.!2006;!1:!2.!!
16.!! Brentlinger! PE,! Assan! A,! Mudender! F,! Ghee! AE,! Vallejo! Torres! J,! Martínez! Martínez! P,! et! al.! Task! shifting! in! Mozambique:!cross<sectional!evaluation!of!non<physician!clinicians’!performance!in!HIV/AIDS!care.!Hum!Resour! Health.!2010;!8:!23.!!
17.!! Friedland! G,! Harries! A,! Coetzee! D.! Implementation! issues! in! tuberculosis/HIV! program! collaboration! and! integration:!3!case!studies.!J!Infect!Dis.!2007!Aug!15;!196!Suppl!1:!S114–23.!!
18.!! Leon! N,! Lewin! S,! Mathews! C.! Implementing! a! provider<initiated! testing! and! counselling! (PITC)! intervention! in! Cape!town,!South!Africa:!a!process!evaluation!using!the!normalisation!process!model.!Implement!Sci!IS.!2013;!8! (1):!97.!! 19.!! Nzinga!J,!Mbindyo!P,!Mbaabu!L,!Warira!A,!English!M.!Documenting!the!experiences!of!health!workers!expected! to!implement!guidelines!during!an!intervention!study!in!Kenyan!hospitals.!Implement!Sci!IS.!2009;!4:!44.!! 20.!! De!Cock!KM,!Chaisson!RE.!Will!DOTS!do!it?!A!reappraisal!of!tuberculosis!control!in!countries!with!high!rates!of! HIV!infection.!Int!J!Tuberc!Lung!Dis.!1999!Jun;!3:!457–65.!! 21.!! Corbett!EL.!HIV!and!tuberculosis:!surveillance!revisited.!Int!J!Tuberc!Lung!Dis.!2003!Aug;!7:!709.!!
22.!! Wiktor! SZ,! Sassan<Morokro! M,! Grant! AD,! Abouya! L,! Karon! JM,! Maurice! C,! et! al.! Efficacy! of! trimethoprim< sulphamethoxazole!prophylaxis!to!decrease!morbidity!and!mortality!in!HIV<1<infected!patients!with!tuberculosis! in!Abidjan,!Côte!d’Ivoire:!a!randomised!controlled!trial.!Lancet.!1999!May!1;!353!(9163):!1469–75.!!
23.!! Chimzizi! RB,! Harries! AD,! Manda! E,! Khonyongwa! A,! Salaniponi! FM.! Counselling,! HIV! testing! and! adjunctive! cotrimoxazole!for!TB!patients!in!Malawi:!from!research!to!routine!implementation.!Int!J!Tuberc!Lung!Dis.!2004! Aug;!8:!938–44.!!
24.!! Burgess!AL,!Fitzgerald!DW,!Severe!P,!Joseph!P,!Noel!E,!Rastogi!N,!et!al.!Integration!of!tuberculosis!screening!at!an! HIV!voluntary!counselling!and!testing!centre!in!Haiti.!Aids.!2001!Sep!28;!15:!1875–9.!!
25.!! Quigley!MA,!Mwinga!A,!Hosp!M,!Lisse!I,!Fuchs!D,!Porter!JDH,!et!al.!Long<term!effect!of!preventive!therapy!for! tuberculosis!in!a!cohort!of!HIV<infected!Zambian!adults.!Aids.!2001!Jan!26;!15:!215–22.!!
26.!! Hannan! MM,! Azadian! BS,! Gazzard! BG,! Hawkins! DA,! Hoffman! PN.! Hospital! infection! control! in! an! era! of! HIV! infection!and!multi<drug!resistant!tuberculosis.!J!Hosp!Infect.!2000!Jan;!44(1):!5–11.!! 27.!! Sonnenberg!P,!Glynn!JR,!Fielding!K,!Murray!J,!Godfrey<Faussett!P,!Shearer!S.!How!soon!after!infection!with!HIV! does!the!risk!of!tuberculosis!start!to!increase?!A!retrospective!cohort!study!in!South!African!gold!miners.!J!Infect! Dis.!2005!Jan!15;!191:!150–8.!! 28.!! Gandhi!NR,!Moll!A,!Sturm!AW,!Pawinski!R,!Govender!T,!Lalloo!U,!et!al.!Extensively!drug<resistant!tuberculosis!as!a! cause!of!death!in!patients!co<infected!with!tuberculosis!and!HIV!in!a!rural!area!of!South!Africa.!Lancet.!2006!Nov! 4;!368!(9547):!1575–80.!! 29.!! Ministério!da!Saúde.!Inquérito!nacional!de!prevalência,!riscos!comportamentais!e!informação!sobre!o!HIV!e!SIDA! em!Moçambique!(INSIDA!2009)!relatório!final.!2009.!! 30.!! Samo!Gudo!P,!Cuna!Z,!Coelho!E,!Maungate!S,!Borroni!E,!Miotto!P,!et!al.!Is!multidrug<resistant!tuberculosis!on!the! rise!in!Mozambique?!Results!of!a!national!drug!resistance!survey.!Eur!Respir!J!Off!J!Eur!Soc!Clin!Respir!Physiol.! 2011!Jul;!38(1):!222–4.!! 31.!! Nunes!EA,!De!Capitani!EM,!Coelho!E,!Joaquim!OA,!Figueiredo!IR,!Cossa!AM,!et!al.!Patterns!of!anti<tuberculosis! drug!resistance!among!HIV<infected!patients!in!Maputo,!Mozambique,!2002<2003.!Int!J!Tuberc!Lung!Dis.!2005! May;9:!494–500.!! 32.!! World!Health!Organization.!Interim!policy!on!collaborative!TB/HIV!activities.!2004.!!
33.!! World! Health! Organization.! Improving! the! diagnosis! and! treatment! of! smear<negative! pulmonary! and! extrapulmonary!tuberculosis!among!adults!and!adolescents.!2007.!!
34.!! World! Health! Organization.! Policy! on! TB! infection! control! in! health<care! facilities,! congregate! settings! and! households.!2009.!!
35.!! Colebunders!R,!Bastian!I.!A!review!of!the!diagnosis!and!treatment!of!smear<negative!pulmonary!tuberculosis.!Int! J!Tuberc!Lung!Dis.!2000!Feb;!4:!97–107.!!
36.!! Corbett! EL,! Muzangwa! J,! Chaka! K,! Dauya! E,! Cheung! YB,! Munyati! SS,! et! al.! Nursing! and! community! rates! of! Mycobacterium!tuberculosis!infection!among!students!in!Harare,!Zimbabwe.!Clin!Infect!Dis!Off!Publ!Infect!Dis! Soc!Am.!2007!Feb!1;!44(3):!317–23.!! 37.!! Galgalo!T,!Dalal!S,!Cain!KP,!Oeltmann!J,!Tetteh!C,!Kamau!JG,!et!al.!Tuberculosis!risk!among!staff!of!a!large!public! hospital!in!Kenya.!Int!J!Tuberc!Lung!Dis.!2008!Aug;!12:!949–54.!! 38.!! World!Health!Organization.!Tuberculosis!data.!Accessed!15th!December!2014.! 39.!! Peace!Agreement!for!Mozambique.!1992.!! 40.!! Gayer!M,!Legros!D,!Formenty!P,!Connolly!MA.!Conflict!and!emerging!infectious!diseases.!Emerg!Infect!Dis.!2007! Nov;13!(11):!1625–31.!!
41.!! Williams! B.! Health! Care! in! Mozambique:! Wartime! clinics! confront! shortages,! parasites,! and! terror.! Can! Fam! Physician!Médecin!Fam!Can.!1992!May;!38:!1130–4.!! 42.!! Salomao!MA.!The!National!Tuberculosis!Control!Programme!in!Mozambique,!1985<1990.!Bull!Int!Union!Tuberc! Lung!Dis.!1991!Dec;!66(4):!175–8.!! !
!
!
'
2. The'effect'of'tuberculosis'and'antiretroviral'
treatment' on' CD4+' cell' count' response' in' HIVA
positive'tuberculosis'patients'in'Mozambique'
! !
Miranda!Brouwer1,!Paula!Samu!Gudo2,!Chalice!Mage!Simbe3,!Paula!Perdigão4,!Frank!van!Leth5,6! !
1!Health!Alliance!International,!Technical!Assistance!Unit,!Maputo,!Mozambique! 2!Ministry!of!Health,!Maputo,!Mozambique!!
3!Ministry!of!Health,!Provincial!Directorate,!Manica,!Mozambique! 4!Independent!chest!physician,!Maputo,!Mozambique!
5!Department! of! Global! Health,! Academic! Medical! Center,! University! of! Amsterdam,! Amsterdam,! The!
Netherlands! 6!KNCV!Tuberculosis!Foundation,!Den!Haag,!The!Netherlands!
!
BMC!Public!Health!2012;!12:!670.!!
!
'
Abstract' '
Background:! Tuberculosis! (TB)! presents! a! serious! problem! in! Mozambique.! HIV! prevalence! among! TB! patients!is!estimated!at!47%.!A!delay!in!having!their!first!CD4+!cell!count!could!lead!to!a!missed!opportunity! for!ART!initiation!due!to!a!CD4+!cell!increase!above!the!cut<off!caused!by!TB!treatment.!The!objective!is!to! describe!CD4+!cell!response!during!TB!treatment!and!quantify!the!effect!of!TB!treatment!and!ART!on!this! response.! Methods:!All!new!HIV + adult!TB!cases!in!2007!from!three!TB!clinics!in!Mozambique!were!included.!Data!on! TB!diagnosis!and!treatment!and!HIV!parameters!were!collected.!A!general!mixed!model!was!used!for!CD4+! cell!count!response.! Results:!338!HIV + patients!were!notified!and!252!(75%)!were!included!in!the!analysis.!Using!TB!medication! was! not! independently! associated! with! the! CD4+! count! response! (19! cells/mm3;! 95%! CI:! <40! to! 79;! p = 0.529).!ART<use!was!associated!with!statistically!significantly!higher!CD4+!cells!compared!to!no!ART<use! (81!cells/mm3;!95%!confidence!interval!(CI):!12!to!151;!p = 0.022).!
Conclusion:! In! this! study,! no! independent! effect! of! TB! treatment! on! CD4+! cell! count! was! found.! HIV< infected!TB!patients!on!ART!had!a!significantly!higher!CD4+!cell!count!than!those!not!receiving!ART.!CD4+! cell! counts! for! patients! not! on! ART! at! TB! treatment! start,! remained! below! the! cut! off! for! initiating! ART! during! the! first! three! months! of! TB! treatment;! therefore! some! delay! in! getting! the! first! CD4+! cell! count! would!not!lead!to!missing!the!opportunity!to!start!ART.!
!
Background'
Tuberculosis! (TB)! presents! a! serious! problem! in! Mozambique! with! case! notifications! rising! dramatically! since!the!start!of!this!century.!The!World!Health!Organization!(WHO)!estimated!the!incidence!of!all!forms! of!TB!in!Mozambique!in!Mozambique!at!the!time!of!the!study!(2007)!at!431!per!100.000!population.1!The!
increase! in! TB! notifications! is! partly! driven! by! the! Human! Immunodeficiency! Virus! (HIV)! epidemic.2! The!
national! HIV! prevalence! is! estimated! at! 15%,! based! on! antenatal! sentinel! surveillance! among! pregnant! women!15!to!49!years!of!age.3!WHO!estimated!the!HIV!prevalence!in!adult!TB!cases!at!47%!in!2007.1! In!Sub!Saharan!Africa,!people!unaware!of!their!HIV<infection!present!often!to!the!health!care!services!with! TB!as!the!first!AIDS!defining!illness.!Several!studies!found!that!TB!clinics!are!well!positioned!to!identify!new! HIV<infected!individuals!and!to!provide!access!to!HIV!service.4,5!
Following! international! recommendations,! Mozambique! started! implementing! TB<HIV! collaborative! activities! in! 2006.6! TB! treatment! staff! provide! HIV! counselling! and! testing,! and! offer! co<trimoxazole!
preventive!therapy!(CPT)!at!the!TB!clinic!to!HIV<infected!TB!patients.!They!refer!co<infected!patients!to!HIV! services! for! further! care! and! treatment,! including! antiretroviral! therapy! (ART).! According! to! the! 2006! national! guidelines,! the! timing! of! ART! initiation! in! relation! to! TB! treatment! depends! on! the! level! of! immunosuppression.7!Patients!with!a!CD4+!cell!count!less!than!200!cells/mm3,!should!start!ART!as!soon!as! possible,!and!in!those!with!a!CD4 + cell!count!between!200!and!350!cells/mm3!ART!is!delayed!until!the!first! two!months!of!TB!treatment!are!completed.!At!the!end!of!2009,!WHO!published!new!recommendations!to! start!ART!as!soon!as!possible!in!TB<HIV!co<infected!patients!regardless!of!their!immunosuppression.8!At!the! same!time,!the!Ministry!of!Health!in!Mozambique!published!new!HIV!treatment!guidelines!that!had!not!yet! incorporated!the!new!WHO!recommendations.9!These!new!Mozambican!guidelines!are!still!valid!presently! and!the!start!of!ART!in!co<infected!patients!still!depends!on!the!level!of!immunosuppression,!though!the! lower!level!is!of!the!CD4+!cell!count!is!250!cells/mm3!compared!to!200!cells/mm3!in!the!2006!guidelines.! Several! studies! described! an! increase! in! CD4+! cell! count! during! TB! treatment! for! non<immune! compromised!TB!patients.10,11!CD4+!cell!response!during!TB!treatment!in!HIV<infected!TB!patients!is!less! clear!and!only!a!few!studies!addressed!this!question.!One!South!African!study!showed!a!significant!increase! of!CD4+!cell!count!after!3!month!of!TB!treatment.!Another!South!African!study!of!HIV<infected!TB!patients! did!find!an!increase!in!CD4+!cell!count!during!TB!treatment,!though!this!was!not!statistically!significant.12!In! both!these!studies,!ART!was!not!available!to!the!participants.! In!Mozambique,!not!all!health!facilities!delivering!HIV!services!have!equipment!for!the!assessment!of!CD4+! cells.!Therefore,!newly!diagnosed!HIV<infected!TB!patients!may!experience!a!delay!in!having!their!first!CD4+! cell!count!result!available.!Should!the!CD4+!cell!count!during!TB!treatment!increase!in!the!HIV<infected!TB! patients!as!in!non<immune!compromised!TB!patients,!the!CD4+!cell!count!might!become!higher!than!the! cut<off!value!for!initiating!ART.!An!opportunity!for!start!of!ART!would!be!missed.!
The! objective! of! this! study! was! to! describe! the! CD4+! cell! count! response! during! TB! treatment! and! to! quantify!the!effect!of!TB!treatment!and!ART!on!the!CD4+!cell!count!response.!Through!the!CD4+!cell!count! response!we!assessed!whether!a!risk!exists!for!missing!an!opportunity!to!start!ART!in!the!routine!setting!of! Mozambique!due!to!late!CD4+!cell!count!availability!in!HIV<infected!TB!patients,!and!the!prioritization!of! ART!for!TB<HIV!co<infected!patients!with!the!lowest!CD4+!cell!counts.! !
!
'Methods' '
Ethics!statement!
The!National!Bio<ethic!Committee!of!the!Ministry!of!Health!of!Mozambique!and!the!Institutional!Review! Board! of! the! University! of! Washington! in! Seattle,! USA,! approved! the! study! protocol.! Both! ethics! committees! approved! that! informed! consent! was! not! obtained! as! the! study! was! based! on! routinely! collected!data.! Study!design!and!setting! We!performed!a!retrospective!observational!study!in!three!purposely<selected!health!facilities!in!Manica! province,!Mozambique.!Selection!criteria!were!the!presence!of!both!TB!and!HIV!treatment!services!in!the! same!facility!and!at!least!150!TB!patients!notified!in!2007.!One!facility!was!an!urban!health!centre!in!the! provincial!capital;!the!other!two!were!rural!health!facilities!about!20!and!90!kilometres!from!the!provincial! capital.!Within!these!clinics,!we!collected!the!information!on!HIV!disease!parameters!of!all!new!notified!TB! patients! of! 16! years! and! older! with! a! positive! HIV! test! recorded! in! the! TB! register! from! January! to! December!2007.!
In! Mozambique,! smear! microscopy! is! the! main! TB! diagnostic.! In! the! participating! facilities,! diagnosis! of! sputum! smear<negative! and! extrapulmonary! TB! occurs! mainly! on! clinical! assessment! and! hardly! ever! on! radiology.!All!new!adult!TB!patients!receive!a!standard!course!of!TB!treatment!consisting!of!two!months! isoniazid,! rifampicin,! ethambutol! and! pyrazinamide! followed! by! 4! months! isoniazid! and! rifampicin.! The! standard!first!line!ART!regimen!consists!of!two!nucleoside!reverse<transcriptase!inhibitors,!lamivudine!and! stavudine,!with!either!the!non<nucleoside!reverse!transcriptase!inhibitor!(NNRTI)!nevirapine!or!efavirenz.! The! national! guidelines! recommend! switching! from! neviripine! to! efavirenz! in! patients! that! receive! a! rifampicin!containing!treatment!regimen.7!
Data!collection!
The!facility’s!TB!supervisor!collected!the!data!of!the!2007!cohort!using!standard!data!collection!forms!in! July! and! August! 2009.! Data! collected! from! the! TB! register! included:! age,! sex,! type! and! category! of! TB,! treatment! regimen,! start! date! of! TB! treatment,! initial! smear! examination! result,! HIV! test! result! and! TB! treatment!outcome.!If!the!treatment!outcome!was!death,!its!date!was!recorded.!
We! identified! the! HIV! record! of! the! HIV<positive! TB! cases! through! the! unique! HIV! patient! number! if! recorded!in!the!TB!register.!In!addition,!local!staff!familiar!with!the!patients!identified!some!HIV!patient! records.!If!these!methods!did!not!lead!to!identification!of!the!patient!record,!we!searched!the!electronic! HIV<database!using!the!patient’s!name!and!age!taken!from!the!TB!register.!If!the!data!matched,!we!took! the!unique!HIV!patient!number!from!the!electronic!database!and!used!it!to!locate!the!HIV!patient!record.! We!limited!the!identification!of!the!HIV!patient!record!to!those!HIV<positive!TB!patients!registered!with!the! HIV!services!in!the!same!health!facility.!
We! collected! available! CD4+! cell! count! results! in! the! 6! months! TB! treatment! period,! the! date! of! these! results,!the!start!date!for!ART!and!the!ART!regimen!from!the!HIV!patient!record.!
Statistical!analysis!
We! entered! the! data! in! EpiData! version! 3.1! and! performed! descriptive! analysis! with! EpiData! Analysis! V2.2.1.171.!We!used!STATA!version!11!(StataCorp,!College!Station,!Texas,!USA)!for!analysis!of!the!CD4+!cell! counts.!
We!modelled!the!evolution!of!the!CD4+!cell!count!during!TB!treatment!using!a!mixed!effect!model.!This! model!deals!adequately!with!repeated!measurements!of!the!outcome!variable.13!The!model!incorporates!
estimated!values!for!missing!data!based!on!all!other!available!data.!With!this!model!we!used!optimally!all! available!CD4+!cell!counts!including!all!patients!with!at!least!one!CD4+!cell!count!in!the!model,!regardless! of! the! number! of! missing! values! these! patients! have.! We! used! a! random! intercept! model! with! an! independent!covariance!structure!for!estimation!of!the!CD4+!cell!count!over!time.!We!compared!the!mean! CD4+!cell!count!for!the!time!updated!variables!of!TB!treatment!use!and!ART!use.!In!addition!we!included! age!and!sex!in!the!model!as!potential!confounding!variables.!The!model!used!the!absolute!CD4+!cell!count! values! to! estimate! the! effect! of! TB! treatment! and! ART! on! CD4+! cell! response.! We! assumed! that! once! a! patient!starts!ART,!the!patient!continues!ART!until!the!end!of!the!observation!period.!We!did!not!adjust!for! the! type! of! NNRTI! because! there! is! no! evidence! that! there! is! a! differential! CD4+! count! increase! when! comparing!a!nevirapineJbased!or!efavirenzJbased!regimen.14!
Definitions!
We!defined!the!baseline!CD4+!cell!count!at!the!start!of!TB!treatment!as!the!CD4+!count!closest!to!the!start! of! TB! treatment! within! a! window! of! 12! weeks! before! until! 2! weeks! after! the! start! of! TB! treatment.! We! allocated!all!other!CD4+!cell!counts!to!a!single!fixed!timeJpoint!with!a!window!ranging!from!2!to!6!weeks.!If! multiple! CD4+! cell! counts! were! available! for! a! specific! timeJpoint,! we! included! the! one! closest! to! the! midpoint!of!the!time!window!in!the!analysis.!
To!determine!whether!the!CD4+!cell!count!was!obtained!while!using!TB!treatment,!we!used!WHO!standard! treatment!outcomes!to!define!the!end!of!TB!treatment.15!The!end!of!TB!treatment!for!treatment!‘success’!
(cured!or!treatment!completed)!was!180!days!after!start!of!TB!treatment.!For!‘failure’!(smear!positive!after! five!months!for!sputum!smear!positive!cases),!the!end!of!treatment!was!150!days!(5!months)!after!start.! For! ‘default’! (interrupted! treatment! for! two! or! more! consecutive! months),! ‘transfer! out’! (transferred! to! another!TB!unit!with!unknown!treatment!outcome),!or!‘unknown’!the!end!of!TB!treatment!was!90!days! after!the!start!date.!For!patients!who!died,!TB!treatment!ended!at!the!date!of!death!or!90!days!after!start! of!TB!treatment!if!unknown.! ! Results' ' From!January!1st!until!December!31st!2007,!591!new!TB!patients!were!notified.!Of!these,!478!(81%)!were! tested!for!HIV!and!338!(71%)!had!a!positive!test.!Of!these,!274!(81%)!were!registered!with!the!HIV!services! in!the!same!facility.!HIV!patient!records!were!identified!for!256!(93%)!patients.!Four!patients!were!excluded! from!the!analysis!due!to!an!identification!mismatch,!leaving!252!patients!for!analysis.!All!patients!started! TB!treatment.!Patient!characteristics!and!the!ART!status!are!given!in!Table!1.! Of!the!252!patients!available!for!analysis,!25!(10%)!had!not!a!single!CD4+!count!recorded!and!16!(6%)!had! only! CD4+! counts! before! the! period! defined! as! the! start! of! TB! treatment.! For! the! remaining! 211! (84%)! patients,!a!total!of!271!CD4+!counts!were!available!at!the!start!of!or!during!TB!treatment.!Figure!3!shows! the!number!of!available!CD4+!cell!counts!at!each!timeJpoint.!
A! baseline! CD4+! cell! count! was! available! for! 149! patients! with! 48! (32%)! and! 23! (15%)! taken! while! the! patient! received! TB! treatment! or! ART! respectively.! Of! the! 122! CD4+! count! results! after! the! start! of! TB! treatment,!81(66%)!were!obtained!while!the!patient!was!on!ART.!
Over!the!full!observation!period!of!6!months,!using!TB!treatment!was!not!statistically!significant!associated! with!the!CD4+!cell!count!response.!Patients!using!TB!treatment!had!a!CD4+!cell!increase!of!19!cells/mm3! (95%!CI:!<50!to!79;!p = 0.529)!compared!to!patients!not!receiving!TB!treatment.!ART!use!was!statistically! significantly! associated! with! CD4+! cell! response! during! the! observation! period.! Patients! using! ART! had! a! CD4+!cell!increase!of!81!cells!(95%!CI:!12!to!151;!p = 0.222)!compared!to!patients!not!using!ART.! The!CD4+!cell!count!response!during!TB!treatment!by!ART!status!is!shown!in!Figure!3.! Legend:! *One!patient!did!not!have!the!sex!recorded!in!the!TB!register.! IQR = Inter!Quartile!Range;!N/A = Not!applicable! ! Table&1&Demographical&and&clinical&characteristics&for&HIV9positive&new&TB&patients& ! ! !! Registered!at!HIV! services!and!record! available!(n=252)! Not!registered!at! HIV!services!or! record!not!available! (n=82)! Total!(n=334)! N!(%)! N!(%)! N!(%)! Sex*! ! ! ! !!!Male! 107!(43%)! 45!(55%)! 152!(46%)! !!!Female! 144!(57%)! 37!(45%)! 181!(54%)! Median!(IQR)!age!(years)! 32!(26–39)! 33!(24.8<40.3)! 32!(26–39.3)! Type!of!TB! ! ! ! !!!Smear<positive!Pulmonary!TB! 156!(62%)! 49!(60%)! 205!(61%)! !!!Smear<negative!Pulmonary!TB! 79!(31%)! 28!(34%)! 107!(32%)! !!!Extra!Pulmonary!TB! 17!(7%)! 5!(6%)! 22!(7%)! TB!Treatment!outcome! ! ! ! !!!Cure!and!treatment!completed! 196!(78%)! 63!(77%)! 259!(78%)! !!!Died! 52!(21%)! 17!(21%)! 69!(21%)! !!!Other! 4!(2%)! 2!(2%)! 6!(2%)! ART!use! ! ! ! !!!No!ART!during!the!study!period! 67!(27%)! N/A! ! !!!Started!ART!before!TB!diagnosis! 81!(32%)! N/A! ! !!!Started!ART!during!TB!treatment! 86!(34%)! N/A! ! !!!Started!ART!after!TB!treatment! 18!(7%)! N/A! !
! Legend:!The!numbers!below!the!figure!show!the!CD4+!cell!counts!available!per!time<point.! & Figure&3&Estimated&CD4+&cell&counts&by&ART&use& ! Discussion' In!this!study,!TB!treatment!in!TB<HIV!co<infected!patients!had!no!significant!effect!on!CD4+!cell!count.!The! evolution!of!CD4+!cell!count!is!mainly!driven!by!ART!use.!The!average!CD4+!cell!count!for!patients!not!on! ART! remained! below! the! cut<off! for! initiating! ART! of! 350! cells/mm3! during! the! first! 12! weeks! of! TB!
treatment.!Therefore,!a!delayed!assessment!of!the!first!CD4+!cell!count!in!itself!would!probably!not!lead!to! missing!an!opportunity!to!start!ART!based!on!the!cut!off!of!350!cells/mm3.!This!finding!is!relevant!in!the! Mozambican!setting!where!not!all!ART!treatment!facilities!are!capable!of!performing!CD4+!cell!counts!and! prescription! of! ART! is! prioritized.! Health! facilities! sent! blood! samples! for! CD4+! cell! count! to! another! laboratory!daily!or!weekly,!depending!on!the!distance!between!the!sending!and!receiving!facilities.! This!study!showed!a!small!increase!in!CD4+!cell!count!during!TB!treatment!in!both!patients!on!ART!and! patients!not!on!ART!as!has!been!described!in!non<immune!compromised!TB!patients.10,11!In!other!studies! the!CD4+!cell!count!in!HIV<infected!TB!patients!not!on!ART!did!not!increases.12,16!It!seems!that!the!immune! response!in!HIV<infected!TB!patients!not!on!ART!is!variable.! Limitations! This!was!a!retrospective!study!based!on!routine!data!and!as!such!has!several!limitations.!First,!bias!may! have! occurred! by! not! including! patients! who! received! HIV! treatment! at! another! health! facility.! These! patients! may! have! been! treated! differently! or! adherence! may! have! been! different.! This! would! have! influenced! treatment! outcome! and! CD4+! cell! count.! All! health! care! facilities! in! Mozambique! follow! the! same! national! guidelines! and! as! such! the! chance! of! a! difference! in! treatment! strategy! is! unlikely.! Furthermore,! the! characteristics! for! patients! whose! clinical! record! was! identified! were! very! similar! with! those!from!patients!without!an!HIV!record!(Table!1).!
Second,!not!all!TB!patients!in!this!study!had!an!HIV<test!or!the!result!recorded!in!the!TB!register.!Therefore,! not!all!HIV<infected!TB!patients!were!included.!Given!the!high!testing!rate!of!more!than!80%,!it!is!unlikely! that!the!non<availability!of!the!HIV<test!result!would!markedly!bias!the!results!of!the!study.!
Third,!this!study!took!place!in!three!health!facilities!in!a!single!province!of!Mozambique.!The!results!may!be! different!in!other!areas!in!Mozambique.!However,!we!believe!that!the!situation!in!Manica!does!not!differ! much! from! that! in! other! provinces! in! the! country! at! the! time! of! the! study,! apart! from! the! larger! cities! where!more!ART!facilities!are!available.!There!is!also!more!specialist!care!available!in!the!larger!cities.! Fourth,!despite!a!considerable!amount!of!patients,!the!number!of!available!CD4+!cell!counts!per!patient! was!small,!reflecting!the!indications!in!the!national!guidelines!as!to!when!to!perform!this!test.!The!use!of! the!mixed!model!allowed!us!to!use!all!available!data!and!was!therefore!the!recommended!methodology!for! our!data!set.! Fifth,!about!one!third!of!the!patients!that!used!ART!during!TB!treatment!started!their!ART!before!the!start! of!TB!treatment!and!potentially!had!incident!TB!while!using!ART.!Emerging!evidence!shows!that!CD4+!cell! count!response!is!smaller!in!these!patients.17!However,!earlier!evidence!showed!a!similar!CD4+!cell!count! response!in!both!patients!with!prevalent!and!those!with!incident!TB!compared!to!patients!on!ART!without! TB.18!We!cannot!completely!rule!out!a!potential!underestimation!of!the!effect!of!TB!treatment!in!our!study.! However,!the!majority!of!patients!did!not!have!this!incident!TB!and!we!are!confident!that!our!results!are! valid.! Despite!these!limitations,!we!consider!the!results!relevant!and!important!because!limited!data!are!available! on!CD4+!cell!count!response!in!cohorts!of!TB!patients.!
The! presently! used! HIV! treatment! guidelines! in! Mozambique! are! not! yet! in! line! with! the! WHO! recommendation! to! initiate! ART! in! HIV<infected! TB! patients! as! soon! as! possible! after! the! start! of! TB! treatment! irrespective! of! the! CD4+! cell! count.8! The! present! study! supports! this! recommendation! as!
patients! on! ART! had! a! much! better! immune! restoration! than! those! not! on! ART.! However,! like! in! Mozambique,!these!WHO!guidelines!have!not!yet!been!implemented!everywhere.!
Also,!many!countries!with!a!high!burden!of!HIV!struggle!to!maintain!all!HIV<infected!patients!on!ART.!Lack! of!funding!may!lead!to!stock!outs!of!antiretroviral!drugs!at!facility!level.19!Therefore!countries!may!wish!to!
prioritize!new!initiations!of!ART!to!those!most!in!need.!For!HIV<infected!TB!patients,!the!CD4+!cell!count! provides!a!tool!to!prioritize.!This!study!shows!that!obtaining!a!sample!for!CD4+!cell!count!assessment!in!the! first! 12! weeks! of! TB! treatment! will! be! a! reliable! indicator! for! the! need! to! initiate! ART,! since! this! measurement! is! not! influenced! by! concurrent! TB! treatment.! The! opportunity! for! identifying! the! HIV< infected!TB!patients!most!in!need!of!ART!is!unlikely!to!be!missed.! Conclusion' In!this!study!the!higher!CD4+!cell!count!level!during!TB!treatment!in!HIV<infected!TB!patients!is!due!to!ART! use,!and!not!influenced!by!TB<treatment.!Therefore,!these!findings!are!a!strong!argument!to!implement!the! recent!WHO!recommendation!to!start!ART!as!soon!as!possible!in!HIV<infected!TB!patients!irrespective!of! their!CD4+!cell!count.!Should!countries!wish!or!need!to!prioritize!new!ART!initiations!to!those!most!in!need,! a!CD4+!cell!count!result!obtained!in!the!first!12!weeks!of!TB!treatment!provides!a!good!reflection!of!the! immune! status! at! the! start! of! TB! treatment.! This! holds! for! Mozambique! and! probably! for! other! similar! settings!as!well.!
A!prospective!study!will!provide!better!insight!to!the!question!of!the!CD4+!cell!count!response!during!TB! treatment!and!the!effect!of!TB!treatment!and!ART!on!this!response.!
References'
1.!! World! Health! Organization.! Global! Tuberculosis! Control.! Surveillance,! Planning,! Financing.! ! WHO/HTM/TB;! 2009:411![Internet].!2009.!Available!from:!http://www.who.int/tb/publications/global_report/en/!
2.!! Mac<Arthur!A,!Gloyd!S,!Perdigao!P,!Noya!A,!Sacarlal!J,!Kreiss!J.!Characteristics!of!drug!resistance!and!HIV!among! tuberculosis!patients!in!Mozambique.!Int!J!Tuberc!Lung!Dis.!2001!Oct;5:894–902.!!
3.!! Ministério! de! Saúde.! Departemento! Nacional! da! Assistência! Médica.! Programa! Nacional! de! Controle! das! ITS/HIV/SIDA.!Ronda!de!Vigilância.!Epidemiológica!do!HIV!de!2007.!2007.!!
4.!! Chimzizi! R,! Gausi! F,! Bwanali! A,! Mbalume! D,! Teck! R,! Gomani! P,! et! al.! Voluntary! counselling,! HIV! testing! and! adjunctive! cotrimoxazole! are! associated! with! improved! TB! treatment! outcomes! under! routine! conditions! in! Thyolo!District,!Malawi.!Int!J!Tuberc!Lung!Dis.!2004!May;8:579–85.!!
5.!! Centers!for!Disease!Control!and!Prevention!(CDC).!Provider<initiated!HIV!testing!and!counseling!of!TB!patients<< Livingstone! District,! Zambia,! September! 2004<December! 2006.! MMWR! Morb! Mortal! Wkly! Rep.! 2008! Mar! 21;57(11):285–9.!!
6.!! World!Health!Organization.!Interim!policy!on!collaborative!TB/HIV!activities.!WHO.!2004.!!
7.!! Ministério! da! Saúde,! Direcção! Nacional! de! Assistência! Médica.! Tratamento! antiretroviral! e! infecções! oportunistas!adulto!e!adolescente.!2006.!!
8.!! World! Health! Organization.! Rapid! Advice.! Antiretroviral! therapy! for! HIV! infection! in! adults! and! adolescents.! 2009.!!
9.!! Ministério! da# Saúde,# Direcção# Nacional# de# Assistência# Médica.# Guia# de# tratamento# antiretroviral# e# infecções# oportunistas*no*adulto,*adolescente*e*grávida.*2009.*! 10.!! Jones!BE,!Oo!MM,!Taikwel!EK,!Qian!D,!Kumar!A,!Maslow!ER,!et!al.!CD4!cell!counts!in!human!immunodeficiency! virus<negative!patients!with!tuberculosis.!Clin!Infect!Dis.!1997!May;24:988–91.!! 11.!! Martin!DJ,!Sim!JG,!Sole!GJ,!Rymer!L,!Shalekoff!S,!van!Niekerk!AB,!et!al.!CD4+!lymphocyte!count!in!African!patients! co<infected!with!HIV!and!tuberculosis.!J!Acquir!Immune!Defic!Syndr!Hum!Retrovirol.!1995!Apr!1;8:386–91.!! 12.!! Morris!L,!Martin!DJ,!Bredell!H,!Nyoka!SN,!Sacks!L,!Pendle!S,!et!al.!Human!immunodeficiency!virus<1!RNA!levels! and!CD4!lymphocyte!counts,!during!treatment!for!active!tuberculosis,!in!South!African!patients.!J!Infect!Dis.!2003! Jun!15;187:1967–71.!!
13.!! Twisk! JWR.! Longitudinal! data! analysis.! A! comparison! between! generalized! estimating! equations! and! random! coefficient!analysis.!Eur!J!Epidemiol.!2004;19(8):769–76.!!
14.!! Van! Leth! F,! Phanuphak! P,! Ruxrungtham! K,! Baraldi! E,! Miller! S,! Gazzard! B,! et! al.! Comparison! of! first<line! antiretroviral! therapy! with! regimens! including! nevirapine,! efavirenz,! or! both! drugs,! plus! stavudine! and! lamivudine:!a!randomised!open<label!trial,!the!2NN!Study.!Lancet.!2004!Apr!17;363(9417):1253–63.!!
15.!! World! Health! Organization.! Treatment! of! Tuberculosis:! Guidelines! for! national! programmes.! Third! edition.! WHO/CDS/TB;!2003:313.!2003.!!
16.!! Swaminathan! S,! Deivanayagam! CN,! Rajasekaran! S,! Venkatesan! P,! Padmapriyadarsini! C,! Menon! PA,! et! al.! Long! term! follow! up! of! HIV<infected! patients! with! tuberculosis! treated! with! 6<month! intermittent! short! course! chemotherapy.!Natl!Med!J!India.!2008!Jan;21:3–8.!!
17.!! Hermans! SM,! Kiragga! AN,! Schaefer! P,! Kambugu! A,! Hoepelman! AIM,! Manabe! YC.! Incident! tuberculosis! during! antiretroviral!therapy!contributes!to!suboptimal!immune!reconstitution!in!a!large!urban!HIV!clinic!in!sub<Saharan! Africa.!PloS!One.!2010;5(5):e10527.!!
18.!! Lawn!SD,!Myer!L,!Bekker!LG,!Wood!R.!Burden!of!tuberculosis!in!an!antiretroviral!treatment!programme!in!sub< Saharan! Africa:! impact! on! treatment! outcomes! and! implications! for! tuberculosis! control.! Aids.! 2006! Aug! 1;20:1605–12.!!
19.!! Médecins!Sans!Frontières.!No!Time!to!Quit:!HIV/AIDS!Treatment!Gap!Widening!in!Africa.!Analysis!of!the!widening! funding! gap! for! HIV/AIDS! treatment! in! sub<Saharan! Africa.! [Internet].! MSF! USA.! 2010! [cited! 2015! Feb! 2].! Available! from:! http://www.doctorswithoutborders.org/news<stories/special<report/no<time<quit<hivaids< treatment<gap<widening<africa.!
3. Are' routine' tuberculosis' programme' data'
suitable'to'report'on'antiretroviral'therapy'use'
of'HIVAinfected'tuberculosis'patients?'
!
Miranda!Brouwer1,!Paula!Samu!Gudo2,!Chalice!Mage!Simbe3,!Paula!Perdigão4,!Frank!van!Leth5,6!
!
1!Health!Alliance!International,!Technical!Assistance!Unit,!Maputo,!Mozambique! 2!Ministry!of!Health,!Maputo,!Mozambique!!
3!Ministry!of!Health,!Provincial!Directorate,!Manica,!Mozambique! 4!Independent!chest!physician,!Maputo,!Mozambique!
5!Department! of! Global! Health,! Academic! Medical! Center,! University! of! Amsterdam,! Amsterdam,! The!
Netherlands!
6!KNCV!Tuberculosis!Foundation,!Den!Haag,!The!Netherlands!
!
BMC!Research!Notes!2013;!6:!23.!
!
Abstract''
!
Background:!Antiretroviral!therapy!(ART)!is!lifesaving!for!HIV<infected!tuberculosis!(TB)!patients.!ART<use!
by! these! patients! lag! behind! compared! to! HIV<testing! and! co<trimoxazole! preventive! therapy.! TB! programmes! provide! the! data! on! ART<use! by! HIV<infected! TB! patients,! however! often! the! HIV! services! provide!the!ART.!We!evaluated!whether!the!data!on!ART<use!in!the!TB!register!were!complete!and!correct.! The!timing!of!ART!initiation!was!evaluated!to!assess!whether!reporting!on!ART<use!could!have!happened! with!the!TB!case!finding!reporting.!We!collected!data!on!TB!treatment,!HIV!testing!and!ART!for!adult!TB! cases!in!2007!from!three!TB!clinics!in!Manica!Province,!Mozambique.!These!data!on!use!of!ART!from!TB! registers!were!compared!with!those!from!the!HIV!services.! Findings:!Of!624!patients!included,!504!(81%)!were!tested!and!of!these!356!(71%)!were!HIV<infected.!Of!the! co<infected!patients,!81%!registered!with!the!HIV!services!in!the!same!facility.!The!TB!register!was!correct! on!ART<use!in!73%!of!co<infected!cases!and!complete!in!74%.! Information!on!ART<use!could!have!been!reported!with!the!TB!case!finding!reports!in!56%!of!co<infected! patients.!!
Conclusion:! The! TB! register! is! reasonably! correct! and! complete! on! ART<use.! However,! the! HIV! patient!
record!seems!a!much!better!source!to!provide!this!information.!Reporting!on!ART<use!at!the!end!of!the! quarter!in!which!TB!treatment!starts!provides!the!programme!with!timely!but!incomplete!information.!A! more!complete!but!less!timely!picture!is!available!after!a!year.!
Background'
The!use!of!the!potentially!life!saving!antiretroviral!therapy!(ART)!for!tuberculosis!(TB)!patients!co<infected! with! the! Human! Immunodeficiency! Virus! (HIV)! did! not! progress! as! much! as! would! be! necessary! in! addressing!the!dual!TB!and!HIV!epidemic.!Globally,!the!HIV!prevalence!among!new!TB!patients!is!13%.!In! Mozambique! this! figure! is! 61%.1! Worldwide,! 29%! of! co<infected! patients! used! ART! in! 2005,! which! had!
increased! to! 46%! in! 2010.! In! the! same! period,! the! percentage! of! TB! patients! knowing! their! HIV<status! increased!fourfold!and!provision!of!co<trimoxazole!preventive!therapy!(CPT)!reached!75%!of!HIV<infected! TB!patients.!!
The!World!Health!Organization!(WHO)!reports!these!figures!yearly!in!its!global!TB<control!report.!Although! in! many! countries! the! HIV! services! provide! ART,! also! to! TB! patients,! national! tuberculosis! programmes! (NTPs)!provide!the!data!for!this!report.!However,!it!is!not!known!how!complete!and!correct!the!data!on! ART<use! are! within! NTPs.! This! is! relevant! as! access! to! ART! is! one! of! the! main! indicators! of! TB<HIV! collaborative!activities.2!!
To! use! routine! programme! data! to! monitor! progress! on! implementation,! ideally! the! data! are! correct,! complete!and!timely!available.3!WHO!recommends!reporting!of!HIV<testing!for!TB!patients!with!the!TB!case!
finding! data! at! the! end! of! the! quarter.4! Data! are! thus! available! shortly! after! the! end! of! the! quarter.!
However,! for! CPT! and! ART<use! the! recommendation! is! to! report! with! the! treatment! outcome! data! 12! months!after!the!start!of!TB!treatment.!This!is!not!timely!reporting!and!precludes!a!timely!response!from! the!programme!in!case!of!under<utilization.!!
In! Mozambique! TB! treatment! staff! offer! HIV<testing! to! all! TB! patients! and! CPT! to! the! co<infected! since! 2006.!For!further!care!and!treatment!including!ART,!they!refer!the!co<infected!patients!to!the!HIV!services.! TB!staff!report!both!HIV!testing!of!TB!patients,!and!CPT!and!ART<use!by!the!co<infected!together!with!the! TB!case!finding!data!at!the!end!of!the!quarter.!Therefore!the!data!on!CPT!and!ART<use!are!earlier!available! to!the!programme!in!comparison!to!the!WHO!recommended!reporting!timeline.!This!early!availability!can! be!useful!for!programme!management!purposes!if!the!data!are!correct!and!complete.! This!study!therefore!evaluated!the!correctness!and!completeness!of!the!routine!TB!registers!on!ART<use! among!HIV<infected!TB!patients.!We!addressed!the!following!questions:!1)!How!correct!and!complete!are! the!data!in!the!TB!register!on!ART<use?!2)!How!complete!could!the!data!on!ART<use!be!for!reporting!at!the! end!of!the!case!finding!quarter?! ! Methods' ' Study!design!and!setting!
We! selected! purposefully! three! health! facilities! in! Manica! province,! Mozambique.! Criteria! for! selection! included!at!least!150!TB!patients!notified!in!2007!and!the!presence!of!both!TB!and!HIV!treatment!services! in!the!same!facility.!The!participating!health!facilities!were!an!urban!facility!in!the!provincial!capital!and!two! rural!facilities!about!20!and!80!kilometres!from!the!provincial!capital.!
In! the! TB! recording! and! reporting! system! of! Mozambique! all! TB! cases! receive! a! unique! number! in! the! notifying!facility’s!TB!register.!Patients!have!their!HIV!test!result!and!the!start!date!of!ART!recorded!in!this! register.!All!patients!registered!at!the!HIV!clinic!have!a!patient!record,!which!contains!clinical!information,! and! a! unique! number! for! identification! purposes.! A! link! between! the! TB! register! and! HIV! patient! record! does!not!exist.!The!unique!HIV!patient!number!is!not!systematically!recorded!in!the!TB!register,!though!TB!
staff! is! encouraged! to! do! so.! The! three! selected! health! facilities! have,! in! addition! to! the! government’s! paper!recording!system,!an!electronic!HIV!patient!database!installed!by!an!international!non<governmental! organisation.!
Data!collection!
We!included!all!notified!TB!cases!aged!15!years!and!older!from!January!1st!until!December!31st,!2007!from!
the!participating!facilities.!The!facility’s!TB!supervisor!collected!the!data!using!standardized!forms.!Firstly,! data!from!the!TB!register!were!collected.!These!included:!the!start!date!of!TB!treatment,!the!HIV!test!result! and!initiation!date!of!ART!if!the!patient!used!ART.!
Next,!we!used!the!unique!HIV!patient!number,!if!available!in!the!TB!register,!to!identify!the!HIV!records!of! the! HIV<positive! TB! patients.! In! addition,! local! staff! familiar! with! the! patients! identified! some! records.! If! these! methods! did! not! lead! to! identification! of! the! HIV! patient! record,! we! performed! a! search! in! the! electronic!HIV<database!using!the!patient’s!name!and!age!taken!from!the!TB!register.!We!took!the!unique! HIV!patient!number!from!the!electronic!database!and!used!it!to!locate!the!HIV!patient!record!for!positive! matches.!We!limited!the!identification!of!the!HIV!patient!record!to!those!HIV<positive!TB!patients!referred! to!the!HIV!services!in!the!same!health!facility.!! We!collected!CD4+!cell!count!results!and!dates!from!12!weeks!before!and!during!TB!treatment,!ART<use,! and!the!start!date!for!ART!from!the!HIV!patient!record.! To!evaluate!whether!the!TB!register!was!correct!and!complete!on!ART<use,!we!compared!the!data!on!ART< use!from!the!TB!register!with!those!of!the!HIV!patient!record.!In!case!of!discrepancy!on!ART<use,!we!took! the! data! from! the! HIV! patient! record! as! correct! for! assessing! ART<use! because! the! HIV! services! provide! ART.!We!also!verified!if!the!patient!should!have!started!ART!according!to!the!national!guidelines!for!those! co<infected!patient!not!on!ART.!At!the!time!of!the!study,!co<infected!patients!were!eligible!for!ART!when! their!CD4+!count!equalled!or!was!below!350!cells/mm3.5!We!limited!our!analysis!to!the!patients!for!whom! both!the!TB!register!information!and!the!HIV!patient!record!were!available.! We!evaluated!whether!the!patient!started!ART!before!or!in!the!same!quarter!as!TB!was!diagnosed!to!assess! how!complete!the!data!could!be!at!the!end!of!the!TB!case!finding!quarter.!
We!used!standard!WHO!treatment! outcomes!to! define! the!end! of!TB! treatment.6!This! was! necessary! to!
determine!whether!the!patient!initiated!ART!during!the!course!of!TB!treatment.!! Statistical!analysis!
We! used! EpiData! version! 3.1! for! data! entry! and! performed! descriptive! analysis! with! EpiData! Analysis! V2.2.1.171.!
Ethics!
The! study! protocol! was! approved! by! the! National! Bio<ethic! Committee! of! the! Ministry! of! Health! of! Mozambique! and! by! the! Institutional! Review! Board! of! the! University! of! Washington! in! Seattle,! USA.! Because!we!used!routinely!available!data,!we!did!not!obtain!informed!consent.!
!
Findings'
Between! January! 1st! and! December! 31st,! 2007,! the! three! health! facilities! notified! 628! TB! patients! of! 15!
years!and!older.!Figure!4!shows!a!breakdown!of!the!TB!notifications!for!which!we!identified!the!HIV!patient! records!(n=267).!Table!2!shows!the!TB<HIV!data!for!the!individual!health!facilities.!
! Figure&4&Breakdown&of¬ified&TB&patients&and&their&linkage&to&the&HIV&patient&record&
